Imperial College London

ProfessorAndreaFrilling

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Endocrine Surgery
 
 
 
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Contact

 

+44 (0)20 3313 3210a.frilling

 
 
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Location

 

BN2/13 B BlockHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

448 results found

Dubash S, Barwick TD, Kozlowski K, Rockall AG, Khan S, Khan S, Yusuf S, Lamarca A, Valle JW, Hubner RA, McNamara MG, Frilling A, Tan T, Wernig F, Todd J, Meeran K, Pratap B, Azeem S, Huiban M, Keat N, Lozano-Kuehne JP, Aboagye EO, Sharma Ret al., 2024, Somatostatin receptor imaging with [18F]FET-bAG-TOCAPET/CT and [68Ga]Ga-DOTA-peptide PET/CT in patientswith neuroendocrine tumors: a prospective, phase 2comparative study, The Journal of Nuclear Medicine, Vol: 65, Pages: 416-422, ISSN: 0161-5505

There is a clinical need for 18F-labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]-octreotate ([18F]FET-βAG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-βAG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-βAG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6–180 d). Whole-body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-βAG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-βAG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor-to-background ratio of [18F]FET-βAG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 ± 1.9 vs. 3.5 ± 2.3; P < 0.001). Conclusion: [18F]FET-βAG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in rout

Journal article

Mato Prado M, Puik JR, Castellano L, López-Jiménez E, Liu DSK, Meijer LL, Le Large TYS, Rees E, Funel N, Sivakumar S, Pereira SP, Kazemier G, Zonderhuis BM, Erdmann JI, Swijnenburg R-J, Frilling A, Jiao LR, Stebbing J, Giovannetti E, Krell J, Frampton AEet al., 2023, A bile-based microRNA signature for differentiating malignant from benign pancreaticobiliary disease, Experimental Hematology & Oncology, Vol: 12, ISSN: 2162-3619

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68-0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66-0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67-0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67-0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70-0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement c

Journal article

Palaniappan V, Li CH, Frilling A, Clift AKet al., 2023, Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review., J Pers Med, Vol: 13, ISSN: 2075-4426

Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting.

Journal article

Kaltsas G, Walter T, Knigge U, Toumpanakis C, Santos AP, Begum N, Pape UF, Volante M, Frilling A, Couvelard Aet al., 2023, European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for appendiceal neuroendocrine tumours (aNET), JOURNAL OF NEUROENDOCRINOLOGY, ISSN: 0953-8194

Journal article

Clift AK, Thomas R, Frilling A, 2023, Developments in interventional management of hepatic metastases from neuroendocrine tumours., Best Pract Res Clin Endocrinol Metab, Vol: 37

Neuroendocrine tumours commonly metastasise to the liver, particularly those arising from the intestinal tract and pancreas. Whilst surgery offers the only approach with intent to cure, the vast majority of patients with neuroendocrine liver metastases are ineligible. Liver-directed interventional therapies seek to exploit the patho-anatomy of the blood supply of hepatic metastases to deliver therapy to liver deposits. This may involve percutaneous ablation, bland embolization, or the selective infusion of chemotherapeutics, targeted agents or radiolabelled embolic material. Retrospective case series evidence has characterised objective response rates, disease control rates, and longer-term outcomes associated with each approach. Recent advances in this field include ongoing comparative trials of different techniques, but more importantly, combinations of interventional liver-directed therapies and other systemic therapy in multimodal treatment concepts.

Journal article

Clift AK, Drymousis P, von Roon A, Humphries A, Goldin R, Bomanji J, Leaman S, Wasan H, Habib N, Frilling Aet al., 2023, Management of small bowel neuroendocrine tumours: 10 years' experience at a tertiary referral centre, Cancers, Vol: 15, ISSN: 2072-6694

Background: Neuroendocrine tumours (NET) arising from the small bowel are clinically challenging and are often diagnosed at advanced stages. Disease control with surgery alone can be demanding. Multimodal treatment concepts integrating surgery and non-surgical modalities could be of benefit. Method: Retrospective review of consecutive adult patients with SB NET treated at Imperial College Healthcare NHS Trust between 1 January 2010 and 31 December 2019. Data regarding clinicopathological characteristics, treatments, and disease trajectory were extracted and summarised. Overall and progression/recurrence-free survival were estimated at 5 and 10 years. Results: 154 patients were identified, with a median age of 64 years (range 33–87); 135/154 (87.7%) had stage III/IV disease at diagnosis. Surgery was used in 125 individuals (81.2%), typically with either segmental small bowel resection (60.8%) or right hemicolectomy (33.6%) and mesenteric lymphadenectomy for the primary tumour. Systemic and/or liver-directed therapies were used in 126 (81.8%); 60 (47.6%) had more than one line of non-surgical treatment. Median follow-up was 67.2 months (range 3.1–310.4); overall survival at 5 and 10 years was 91.0% (95% CI: 84.9–94.7%) and 82.5% (95% CI: 72.9–88.9%), respectively. Imaging-based median progression-free survival was 42.7 months (95% CI: 24.7 to 72.4); 5-year progression-free survival was 63.4% (95% CI: 55.0–70.6%); 10-year progression-free survival was 18.7% (95% CI: 12.4–26.1). Nineteen patients (12.3%) reached 10 years follow-up without disease recurrence and therefore were considered cured. Conclusions: Most patients with SB NET present in a metastasised stage. Multimodal treatment concepts may be associated with excellent clinical outcomes. Future work should explore optimal approaches to treatment sequencing and patient selection.

Journal article

Clift AK, Hagness M, Lehmann K, Rosen CB, Adam R, Mazzaferro V, Frilling Aet al., 2023, Transplantation for metastatic liver disease, JOURNAL OF HEPATOLOGY, Vol: 78, Pages: 1137-1146, ISSN: 0168-8278

Journal article

Reccia I, Pai M, Kumar J, Spalding D, Frilling Aet al., 2023, Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms, CANCERS, Vol: 15

Journal article

Heidsma C, Engelsman A, Klumpen HJ, Falconi M, Frilling A, Fazio N, Garcia-Carbonero R, de Herder W, Horsch D, Pavel M, Nieveen VDEet al., 2023, Adjuvant therapy for pancreatic neuroendocrine tumors - Expert consensus and recommendations for future research, 20th Annual ENETs Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, Publisher: WILEY, Pages: 224-224, ISSN: 0953-8194

Conference paper

Nesti C, Bräutigam K, Benavent M, Bernal L, Boharoon H, Botling J, Bouroumeau A, Brcic I, Brunner M, Cadiot G, Camara M, Christ E, Clerici T, Clift AK, Clouston H, Cobianchi L, Ćwikła JB, Daskalakis K, Frilling A, Garcia-Carbonero R, Grozinsky-Glasberg S, Hernando J, Hervieu V, Hofland J, Holmager P, Inzani F, Jann H, Jimenez-Fonseca P, Kaçmaz E, Kaemmerer D, Kaltsas G, Klimacek B, Knigge U, Kolasińska-Ćwikła A, Kolb W, Kos-Kudła B, Kunze CA, Landolfi S, La Rosa S, López CL, Lorenz K, Matter M, Mazal P, Mestre-Alagarda C, Del Burgo PM, van Dijkum EJMN, Oleinikov K, Orci LA, Panzuto F, Pavel M, Perrier M, Reims HM, Rindi G, Rinke A, Rinzivillo M, Sagaert X, Satiroglu I, Selberherr A, Siebenhüner AR, Tesselaar MET, Thalhammer MJ, Thiis-Evensen E, Toumpanakis C, Vandamme T, van den Berg JG, Vanoli A, van Velthuysen M-LF, Verslype C, Vorburger SA, Lugli A, Ramage J, Zwahlen M, Perren A, Kaderli RMet al., 2023, Hemicolectomy versus appendectomy for patients with appendiceal neuroendocrine tumours 1-2 cm in size: a retrospective, Europe-wide, pooled cohort study, The Lancet Oncology, Vol: 24, Pages: 187-194, ISSN: 1213-9432

BACKGROUND: Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1-2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1-2 cm in size in patients with or without right-sided hemicolectomy. METHODS: In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1-2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. FINDINGS: 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1-2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0-15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distan

Journal article

Partelli S, Massironi S, Zerbi A, Niccoli P, Kwon W, Landoni L, Panzuto F, Tomazic A, Bongiovanni A, Kaltsas G, Sauvanet A, Bertani E, Mazzaferro V, Caplin M, Armstrong T, Weickert MO, Ramage J, Segelov E, Butturini G, Staettner S, Cives M, Frilling A, Moulton CA, He J, Boesch F, Selberheer A, Twito O, Castaldi A, De Angelis CG, Gaujoux S, Holzer K, Wilson CH, Almeamar H, Vigia E, Muffatti F, Luca M, Lania A, Ewald J, Kim H, Salvia R, Rinzivillo M, Smid A, Gardini A, Tsoli M, Hentic O, Colombo S, Citterio D, Toumpanakis C, Ramsey E, Randeva HS, Srirajaskanthan R, Croagh D, Regi P, Gasteiger S, Invernizzi P, Ridolfi C, Giovannini M, Jang JY, Bassi C, Falconi Met al., 2022, Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of prospective ASPEN trial, British Journal of Surgery, Vol: 109, Pages: 1186-1190, ISSN: 0007-1323

Journal article

Hicks RJ, Dromain C, de Herder WW, Costa FP, Deroose CM, Frilling A, Koumarianou A, Krenning EP, Raymond E, Bodei L, Sorbye H, Welin S, Wiedenmann B, Wild D, Howe JR, Yao J, O'Toole D, Sundin A, Prasad Vet al., 2022, ENETS standardized (synoptic) reporting for molecular imaging studies in neuroendocrine tumours, JOURNAL OF NEUROENDOCRINOLOGY, Vol: 34, ISSN: 0953-8194

Journal article

Hofland J, Lamarca A, Steeds R, Toumpanakis C, Srirajaskanthan R, Riechelmann R, Panzuto F, Frilling A, Denecke T, Christ E, Grozinsky-Glasberg S, Davar Jet al., 2022, Synoptic reporting of echocardiography in carcinoid heart disease (ENETS Carcinoid Heart Disease Task Force), Journal of Neuroendocrinology, Vol: 34, Pages: 1-11, ISSN: 0953-8194

BackgroundThis European Neuroendocrine Tumor Society (ENETS) Expert Consensus document aims to provide practical guidance and standardization for echocardiography in the screening and follow-up of carcinoid heart disease (CHD) in patients with a neuroendocrine tumour (NET) and carcinoid syndrome.MethodsNET experts within the ENETS Carcinoid Heart Disease Task Force reviewed both general reporting guidelines and specialized scoring systems for transthoracic echocardiography (TTE) in CHD. Based on this review, a dedicated template report was designed by the multidisciplinary working group of cardiologists, oncologists, endocrinologists, gastroenterologists, surgeons and radiologists.ResultsWe propose a Synoptic Reporting of Echocardiography in Carcinoid Heart Disease which represents an agreed peer reviewed proforma to capture information at the time of referral and enable a detailed outcome of CHD assessment. This includes a systematic and detailed list of structures to evaluate data to capture at the time of reporting of TTE.ConclusionsAdherence to these reporting guidelines aims to promote homogeneous and detailed evaluation of CHD to secure accurate assessment and allow comparison of studies performed intra- and inter-individually. These guidelines could also facilitate CHD assessment as part of prospective clinical trials to enable standardization of the findings seen in response to therapy.

Journal article

Modlin IM, Kidd M, Falconi M, Filosso PL, Frilling A, Malczewska A, Toumpanakis C, Valk G, Pacak K, Bodei L, Öberg KEet al., 2021, A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility., Annals of Oncology, Vol: 32, Pages: 1425-1433, ISSN: 0923-7534

BACKGROUND: Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. PATIENTS AND METHODS: An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n = 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n = 922) versus other diseases and controls (n = 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). STATISTICS: Mann-Whitney U-test, AUROC, chi-square and McNemar' test. RESULTS: Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n = 153) were positive (100%). After palliative R1/R2 surgery (n = 51) all (100%) remained elevated. After curative R0-surgery (n = 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square = 7.7, OR = 18.5) and metastatic identification

Journal article

Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hoersch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti Aet al., 2021, Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up (vol 32, pg 439, 2021), ANNALS OF ONCOLOGY, Vol: 32, Pages: 1453-1455, ISSN: 0923-7534

Journal article

Modlin IM, Kidd M, Frilling A, Falconi M, Filosso PL, Malczewska A, Kitz Aet al., 2021, Molecular genomic assessment using a blood-based mRNA signature (NETest) is cost effective and predicts neuroendocrine tumor recurrence with 94% accuracy., Annals of Surgery, Vol: 274, Pages: 481-490, ISSN: 0003-4932

INTRODUCTION: Identification of residual disease after neuroendocrine tumor (NET) resection is critical for management. Post-surgery imaging is insensitive, expensive and current biomarkers ineffective. We evaluated whether the NETest, a multigene liquid biopsy blood biomarker, correlated with surgical resection and could predict recurrence. METHODS: Multicenter evaluation of NET resections over 24 months (n=103): 47 pancreas, 26 small bowel, 26 lung, 2 appendix, 1 duodenum, 1 stomach. Surgery: R0 (83), R1/R2 (20). 1 ml blood collected at D0 and POD30. Transcript quantification by PCR (normal: ≤20), CgA by NeoLISA (normal≤108ng/mL). Standard-of-care (SoC) follow-up costs were calculated and compared to POD30 NETest-stratification approach. Analyses: Wilcoxon-paired test, Chi2-test. RESULTS: D0 biomarkers: NETest: 103/103 (100%)-positive while 23/103 (22%) were CgA-positive (Chi2=78, p<0.0001).In the R0 group, the NETest decreased 59±28 to 26±23 (p<0.0001); 36% (30/83) remained elevated. No significant decrease was evident for CgA. In the R1/R2 group the NETest decreased but 100% remained elevated. CgA levels did not decrease.An elevated POD30 NETest were present in R0 and 25 (83%) developed radiological recurrences. Normal score R0 s (n=53) did not develop recurrence (Chi2=56, p<0.0001). Recurrence prediction was 94% accurate with the NETest.Cost evaluation: Using the NETest to stratify postoperative imaging resulted in a cost-savings of 42%. CONCLUSION: NETest diagnosis is more accurate than CgA (100% vs. 22%). Surgery significantly decreased NETest. An elevated POD30 NETest predicted recurrence with 94% accuracy and post-surgical POD30 NETest follow-up stratification decreased costs by 42%. CgA had no surgical utility. Further studies would define the accuracy and cost-effectiveness of the NETest in the detection of post-operative recurrent disease.

Journal article

Malczewska A, Frampton AE, Mato Prado M, Ameri S, Dabrowska AF, Zagorac S, Clift AK, Kos-Kudła B, Faiz O, Stebbing J, Castellano L, Frilling Aet al., 2021, Circulating microRNAs in small-bowel neuroendocrine tumors: a potential tool for diagnosis and assessment of effectiveness of surgical resection, Annals of Surgery, Vol: 274, Pages: e1-e9, ISSN: 0003-4932

OBJECTIVE: To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND: MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS: This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS: Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS: Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Journal article

Steinkraus K, Andresen JR, Clift AK, Liedke MO, Frilling Aet al., 2021, Multifocal neuroendocrine tumour of the small bowel presenting as an incarcerated incisional hernia: a surgical challenge in a high-risk patient, Journal of Surgical Case Reports, Vol: 2021, ISSN: 2042-8812

Neuroendocrine tumours (NET) of the small bowel present significant clinical challenges, such as their rate of metastasis at initial presentation, common multifocality and understaging even with gold standard imaging. Here, we present a case of a high-risk surgical patient with a complex medical history initially presenting as an acute abdomen due to an incarcerated incisional hernia. He was found at emergency laparotomy to have three small NET deposits in a 30-cm segment of incarcerated ileum which was resected. Postoperative morphological and functional imaging and biochemical markers were unremarkable, but due to clinical suspicion for undetected residual tumour bulk given the non-systematic palpation of the entire small bowel at initial operation, underwent re-operation where a further 70 cm of ileum was found to harbour multiple tumour deposits (n = 25) and was resected. There was no surgical morbidity and the patient remains tumour-free at 9-month follow-up.

Journal article

Modlin IM, Kidd M, Oberg K, Falconi M, Filosso PL, Frilling A, Malczewska A, Salem R, Toumpanakis C, Laskaratos F-M, Partelli S, Roffinella M, von Arx C, Kudla BK, Bodei L, Drozdov IA, Kitz Aet al., 2021, Early identification of residual disease after neuroendocrine tumor resection using a liquid biopsy multigenomic mRNA signature (NETest), Annals of Surgical Oncology, Vol: 28, Pages: 7506-7517, ISSN: 1068-9265

IntroductionSurgery is the only cure for neuroendocrine tumors (NETs), with R0 resection being critical for successful tumor removal. Early detection of residual disease is key for optimal management, but both imaging and current biomarkers are ineffective post-surgery. NETest, a multigene blood biomarker, identifies NETs with >90% accuracy. We hypothesized that surgery would decrease NETest levels and that elevated scores post-surgery would predict recurrence.MethodsThis was a multicenter evaluation of surgically treated primary NETs (n = 153). Blood sampling was performed at day 0 and postoperative day (POD) 30. Follow-up included computed tomography/magnetic resonance imaging (CT/MRI), and messenger RNA (mRNA) quantification was performed by polymerase chain reaction (PCR; NETest score: 0–100; normal ≤20). Statistical analyses were performed using the Mann–Whitney U-test, Chi-square test, Kaplan–Meier survival, and area under the receiver operating characteristic curve (AUROC), as appropriate. Data are presented as mean ± standard deviation.ResultsThe NET cohort (n = 153) included 57 patients with pancreatic cancer, 62 patients with small bowel cancer, 27 patients with lung cancer, 4 patients with duodenal cancer, and 3 patients with gastric cancer, while the surgical cohort comprised patients with R0 (n = 102) and R1 and R2 (n = 51) resection. The mean follow-up time was 14 months (range 3–68). The NETest was positive in 153/153 (100%) samples preoperatively (mean levels of 68 ± 28). In the R0 cohort, POD30 levels decreased from 62 ± 28 to 22 ± 20 (p < 0.0001), but remained elevated in 30% (31/102) of patients: 28% lung, 29% pancreas, 27% small bowel, and 33% gastric. By 18 months, 25/31 (81%) patients with a POD30 NETest >20 had image-identifiable recurrence. An NETest score of >20 predicted recurrence with 100% sensitivity and correlated with residual disease (Chi-square 17.1, p < 0.0001). A

Journal article

Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hoersch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti Aet al., 2021, Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, ANNALS OF ONCOLOGY, Vol: 32, Pages: 439-451, ISSN: 0923-7534

Journal article

Clift AK, Frilling A, 2021, Liver-Directed Therapies for Neuroendocrine Neoplasms, CURRENT ONCOLOGY REPORTS, Vol: 23, ISSN: 1523-3790

Journal article

Frilling A, Clift AK, Frampton AE, Bomanji J, Kaemmerer D, Al-Nahhas A, Alsafi A, Kidd M, Modlin IM, Hoersch D, Baum RPet al., 2021, A combination of surgery, theranostics, and liquid biopsy - a personalised oncologic approach to treatment of patients with advanced metastatic neuroendocrine neoplasms, International Journal of Medical Sciences, Vol: 18, Pages: 2166-2175, ISSN: 1449-1907

Rationale: Neuroendocrine neoplasia (NEN) of small bowel (SBNEN) frequently present with metastatic disease. Theranostics (molecular imaging followed by targeting therapy) allow for personalised medicine. Liquid biopsies enable precise identification of residual disease and real-time monitoring of therapeutic response. Our aim was to determine the clinical utility of a combination of surgery, theranostics, and a multigene blood measurement in metastasised SBNEN. Methods: Inclusion criteria were SBNEN, G1/G2 NEN, initial tumour diagnosis, stage IV NEN, positivity on 68Ga somatostatin analogue PET/CT, eligible for surgery, and 177Lu peptide receptor radionuclide therapy (PRRT). Blood samples for NETest were collected longitudinally. Progression-free survival (PFS) and overall survival (OS) were calculated. NETest results were assessed prior to surgery and during clinical follow-up. Results: A surgical cohort of 39 SBNEN patients met eligibility criteria. Thirty-two patients underwent ileal resection and 7 right hemicolectomy. The mean number of 177Lu PRRT cycles was 4. Mortality was nil. Surgical morbidity was 10.3%. Transient grade 1/2 toxicity occurred in 41% (PRRT). NETest scores (n=9 patients) decreased in 100% following treatment and correlated with diminished tumour volume and disease stabilization following surgery and PRRT. Median follow-up: 78 months. Median PFS and OS: 42.7 and 110 months, respectively. Progression-free survival at 1-, 3-, and 5-years was 79.4%, 57.1% and 40.5%, respectively. Overall survival at 1-, 3-, and 5-years was 97.4%, 97.4%, and 94.1%, respectively. Conclusions: Surgery combined with 177Lu PRRT is safe and provides favourable PFS and OS in selected patients with advanced SBNEN. Liquid biopsy (NETest) has the potential to accurately delineate disease status.

Journal article

Modlin I, Falconi M, Filosso PL, Frilling A, Malczewska A, Kidd M, Oberg Ket al., 2021, A Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Tumor and Accurately Predicts Recurrence After Surgery, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 444-444, ISSN: 0885-3177

Conference paper

Modlin I, Falconi M, Filosso PL, Frilling A, Malczewska A, Kidd M, Oberg Ket al., 2021, A Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Tumor and Accurately Predicts Recurrence After Surgery, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 444-444, ISSN: 0885-3177

Conference paper

Jimenez B, Abellona MRU, Drymousis P, Kyriakides M, Clift AK, Liu DSK, Rees E, Holmes E, Nicholson JK, Kinross JM, Frilling Aet al., 2021, Neuroendocrine neoplasms: identification of novel metabolic circuits of potential diagnostic utility, Cancers, Vol: 13, ISSN: 2072-6694

The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36–85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.

Journal article

Partelli S, Ramage JK, Massironi S, Zerbi A, Kim HB, Niccoli P, Panzuto F, Landoni L, Tomazic A, Ibrahim T, Kaltsas G, Bertani E, Sauvanet A, Segelov E, Caplin M, Coppa J, Armstrong T, Weickert MO, Butturini G, Staettner S, Boesch F, Cives M, Moulton CA, He J, Selberherr A, Twito O, Castaldi A, De Angelis CG, Gaujoux S, Almeamar H, Frilling A, Vigia E, Wilson C, Muffatti F, Srirajaskanthan R, Invernizzi P, Lania A, Kwon W, Ewald J, Rinzivillo M, Nessi C, Smid LM, Gardini A, Tsoli M, Picardi EE, Hentic O, Croagh D, Toumpanakis C, Citterio D, Ramsey E, Mosterman B, Regi P, Gasteiger S, Rossi RE, Smiroldo V, Jang J-Y, Falconi Met al., 2020, Management of Asymptomatic Sporadic Nonfunctioning Pancreatic Neuroendocrine Neoplasms (ASPEN) ≤2 cm: Study Protocol for a Prospective Observational Study, FRONTIERS IN MEDICINE, Vol: 7

Journal article

Modlin IM, Kidd M, Falconi M, Frilling A, Malczewska A, Drozdov IA, Kitz Aet al., 2020, Blood-Based Neuroendocrine Tumor mRNA Signature Identifies Residual Disease and at Day 30 after Operation Predicts Tumor Recurrence with 98% Specificity, Annual Clinical Congress of the American-College-of-Surgeons, Publisher: ELSEVIER SCIENCE INC, Pages: E53-E53, ISSN: 1072-7515

Conference paper

Clift AK, Frilling A, 2020, Using genetics to inform pharmacological targeting of neuroendocrine neoplasms., Endocrine-Related Cancer, Vol: 27, Pages: R293-R305, ISSN: 1351-0088

Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago - since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour's molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches, and also posit avenues for future developments in this arena.

Journal article

Frilling A, Clift AK, 2020, Combining radiolabelled therapies for neuroendocrine neoplasms, NATURE REVIEWS ENDOCRINOLOGY, Vol: 16, Pages: 347-348, ISSN: 1759-5029

Journal article

Linecker M, Kambakamba P, Raptis DA, Malago M, Ratti F, Aldrighetti L, Robles-Campos R, Lehwald-Tywuschik N, Knoefel WT, Balci D, Ardiles V, De Santibanes E, Truants S, Pruvot F-R, Stavrou GA, Oldhafer KJ, Voskanyan S, Mahadevappa B, Kozyrin I, Low JK, Ferrri V, Vicente E, Prachalias A, Pizanias M, Clift AK, Petrowsky H, Clavien P-A, Frilling Aet al., 2020, ALPPS in neuroendocrine liver metastases not amenable for conventional resection - lessons learned from an interim analysis of the International ALPPS Registry, HPB, Vol: 22, Pages: 537-544, ISSN: 1365-182X

Journal article

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