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Role of chromogranin A-derived fragments after resection of nonfunctioning pancreatic neuroendocrine tumors

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Abstract

Purpose

No single reliable biomarker is available for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). Vasostatin-1 (VS-1), the N-terminal fragment of chromogranin A (CgA), seems to be a more accurate biomarker compared to its precursor. Primary aim was to investigate the ability of VS-1, compared to total-CgA, to assess the effectiveness of surgical resection performed for NF-PanNETs. Secondary aim was to evaluate two additional CgA-derived fragments, pancreastatin (PST) and vasostatin-2 (VS-2), as possible biomarkers for NF-PanNETs.

Methods

Consecutive patients who underwent surgery for NF-PanNETs at San Raffaele Scientific Institute were included (n = 35). Plasma levels of CgA and CgA-derived fragments were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA), preoperatively and postoperatively.

Results

Preoperative VS-1 was significantly higher compared to VS-1 measured on postoperative day 5 (POD5) (pre: 0.338 nM versus POD5: 0.147 nM, P < 0.001), whereas total-CgA significantly increased after surgery (pre: 1.123 nM versus POD5: 1.949 nM, P = 0.006). Overall, 24 patients showed ≥ 1 feature of tumor aggressiveness (T3-T4, nodal/distant metastases, Ki67 > 5%, microvascular/perineural invasion, necrosis). The median percentage decrease in VS-1 plasma levels was 63% (IQR 28–88%) among patients with aggressive tumors, compared to 13% (IQR 0–57%) in the remaining population (P = 0.033). No significant differences in terms of PST (P = 0.870) and VS-2 (P = 0.909) were observed between preoperative and postoperative time.

Conclusion

VS-1 provides an early assessment of surgical efficacy in patients who undergo resection for NF-PanNETs, especially in those with aggressive neoplasms. Total-CgA, PST and VS-2 have no clinical utility in this setting.

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All the data generated or analyzed during this study are included in the manuscript or in the supplementary material.

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References

  1. Dasari A, Shen C, Halperin D et al (2017) Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol 3:1335–1342. https://doi.org/10.1001/jamaoncol.2017.0589

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vagefi PA, Razo O, Deshpande V et al (2007) Evolving patterns in the detection and outcomes of pancreatic neuroendocrine neoplasms: the Massachusetts General Hospital experience from 1977 to 2005. Arch Surg 142:347–354. https://doi.org/10.1001/archsurg.142.4.347

    Article  PubMed  PubMed Central  Google Scholar 

  3. Falconi M, Eriksson B, Kaltsas G et al (2016) ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology 103:153–371. https://doi.org/10.1159/000443171

    Article  CAS  PubMed  Google Scholar 

  4. Genç CG, Falconi M, Partelli S et al (2018) Recurrence of pancreatic neuroendocrine tumors and survival predicted by Ki67. Ann Surg Oncol 25:2467–2474. https://doi.org/10.1245/s10434-018-6518-2

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hashim YM, Trinkaus KM, Linehan DC et al (2014) Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg 259:197–203. https://doi.org/10.1097/SLA.0000000000000348

    Article  PubMed  Google Scholar 

  6. Partelli S, Javed AA, Andreasi V et al (2018) The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms. Eur J Surg Oncol 44:778–783. https://doi.org/10.1016/j.ejso.2018.03.005

    Article  PubMed  Google Scholar 

  7. Zaidi MY, Lopez-Aguiar AG, Switchenko JM et al (2019) A novel validated recurrence risk score to guide a pragmatic surveillance strategy after resection of pancreatic neuroendocrine tumors: an international study of 1006 patients. Ann Surg 270:422–433. https://doi.org/10.1097/SLA.0000000000003461

    Article  PubMed  Google Scholar 

  8. Howe JR, Merchant NB, Conrad C et al (2020) The North American neuroendocrine tumor society consensus paper on the surgical management of pancreatic neuroendocrine tumors. Pancreas 49:1–33. https://doi.org/10.1097/MPA.0000000000001454

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jilesen APJ, Busch ORC, van Gulik TM et al (2014) Standard pre- and postoperative determination of chromogranin a in resectable non-functioning pancreatic neuroendocrine tumors–diagnostic accuracy: NF-pNET and low tumor burden. Dig Surg 31:407–414. https://doi.org/10.1159/000370007

    Article  CAS  PubMed  Google Scholar 

  10. Partelli S, Andreasi V, Muffatti F et al (2020) Circulating neuroendocrine gene transcripts (NETest): a postoperative strategy for early identification of the efficacy of radical surgery for pancreatic neuroendocrine tumors. Ann Surg Oncol 27:3928–3936. https://doi.org/10.1245/s10434-020-08425-6

    Article  PubMed  Google Scholar 

  11. Marotta V, Zatelli MC, Sciammarella C et al (2018) Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer 25:R11–R29. https://doi.org/10.1530/ERC-17-0269

    Article  CAS  PubMed  Google Scholar 

  12. Oberg K (2011) Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 18(Suppl 1):S17-25. https://doi.org/10.1530/ERC-10-0280

    Article  CAS  PubMed  Google Scholar 

  13. Andreasi V, Partelli S, Muffatti F et al (2021) Update on gastroenteropancreatic neuroendocrine tumors. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver 53:171–182. https://doi.org/10.1016/j.dld.2020.08.031

    Article  CAS  Google Scholar 

  14. Giusti M, Sidoti M, Augeri C et al (2004) Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man. Eur J Endocrinol 150:299–303. https://doi.org/10.1530/eje.0.1500299

    Article  CAS  PubMed  Google Scholar 

  15. Pregun I, Herszenyi L, Juhasz M et al (2011) Effect of proton-pump inhibitor therapy on serum chromogranin a level. Digestion 84:22–28. https://doi.org/10.1159/000321535

    Article  CAS  PubMed  Google Scholar 

  16. Dam G, Grønbæk H, Sorbye H et al (2020) Prospective study of chromogranin a as a predictor of progression in patients with pancreatic, small-intestinal, and unknown primary neuroendocrine tumors. Neuroendocrinology 110:217–224. https://doi.org/10.1159/000503833

    Article  CAS  PubMed  Google Scholar 

  17. Brehm Hoej L, Parkner T, Soendersoe Knudsen C, Grønbaek H (2014) A comparison of three chromogranin A assays in patients with neuroendocrine tumours. J Gastrointestin Liver Dis 23:419–424. https://doi.org/10.15403/jgld.2014.1121.234.3ca

  18. Baekdal J, Krogh J, Klose M et al (2020) Limited diagnostic utility of chromogranin a measurements in workup of neuroendocrine tumors. Diagnostics (Basel, Switzerland) 10:881. https://doi.org/10.3390/diagnostics10110881

    Article  CAS  Google Scholar 

  19. Giovinazzo F, Schimmack S, Svejda B et al (2013) Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation. PLoS One 8:e81111. https://doi.org/10.1371/journal.pone.0081111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Corsello A, Di Filippo L, Massironi S et al (2018) Vasostatin-1: A novel circulating biomarker for ileal and pancreatic neuroendocrine neoplasms. PLoS ONE 13:e0196858. https://doi.org/10.1371/journal.pone.0196858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sherman SK, Maxwell JE, O’Dorisio MS et al (2014) Pancreastatin predicts survival in neuroendocrine tumors. Ann Surg Oncol 21:2971–2980. https://doi.org/10.1245/s10434-014-3728-0

    Article  PubMed  PubMed Central  Google Scholar 

  22. Andreasi V, Partelli S, Manzoni M et al (2019) Association between preoperative Vasostatin-1 and pathological features of aggressiveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET). Pancreatology 19:57–63. https://doi.org/10.1016/j.pan.2018.11.005

    Article  CAS  PubMed  Google Scholar 

  23. Bossuyt PM, Reitsma JB, Bruns DE et al (2015) STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. BMJ 351:h5527. https://doi.org/10.1136/bmj.h5527

    Article  PubMed  PubMed Central  Google Scholar 

  24. Crippa L, Bianco M, Colombo B et al (2013) A new chromogranin A-dependent angiogenic switch activated by thrombin. Blood 121:392–402. https://doi.org/10.1182/blood-2012-05-430314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dindo D, Demartines N, Clavien P-A (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213. https://doi.org/10.1097/01.sla.0000133083.54934.ae

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rindi G, Kloppel G, Alhman H et al (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395–401. https://doi.org/10.1007/s00428-006-0250-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lloyd RV, Osamura RY, Kloppel G, Rosai J (2017) WHO Classification of Tumours of Endocrine Organs, 4th edn. IARC Press, Lyon

    Google Scholar 

  28. Oberg K, Modlin IM, De Herder W et al (2015) Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol 16:e435–e446. https://doi.org/10.1016/S1470-2045(15)00186-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tran CG, Sherman SK, Scott AT et al (2021) It is time to rethink biomarkers for surveillance of small bowel neuroendocrine tumors. Ann Surg Oncol 28:732–741. https://doi.org/10.1245/s10434-020-08784-0

    Article  PubMed  Google Scholar 

  30. Woltering EA, Voros BA, Beyer DT et al (2019) Plasma pancreastatin predicts the outcome of surgical cytoreduction in neuroendocrine tumors of the small bowel. Pancreas 48:356–362. https://doi.org/10.1097/MPA.0000000000001263

    Article  PubMed  Google Scholar 

  31. Pulvirenti A, Rao D, Mcintyre CA et al (2019) Limited role of Chromogranin A as clinical biomarker for pancreatic neuroendocrine tumors. HPB (Oxford) 21:612–618. https://doi.org/10.1016/j.hpb.2018.09.016

    Article  Google Scholar 

  32. Tseng C-M, Cheng T-Y, Chen T-B et al (2018) Low accuracy of chromogranin A for diagnosing early-stage pancreatic neuroendocrine tumors. Oncol Lett 15:8951–8958. https://doi.org/10.3892/ol.2018.8472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Qiu W, Christakis I, Silva A et al (2016) Utility of chromogranin A, pancreatic polypeptide, glucagon and gastrin in the diagnosis and follow-up of pancreatic neuroendocrine tumours in multiple endocrine neoplasia type 1 patients. Clin Endocrinol (Oxf) 85:400–407. https://doi.org/10.1111/cen.13119

    Article  CAS  Google Scholar 

  34. Strosberg D, Schneider EB, Onesti J et al (2018) Prognostic impact of serum pancreastatin following chemoembolization for neuroendocrine tumors. Ann Surg Oncol 25:3613–3620. https://doi.org/10.1245/s10434-018-6741-x

    Article  PubMed  Google Scholar 

  35. Woltering EA, Beyer DT, Thiagarajan R et al (2016) Elevated plasma pancreastatin, but not chromogranin a, predicts survival in neuroendocrine tumors of the duodenum. J Am Coll Surg 222:534–542. https://doi.org/10.1016/j.jamcollsurg.2015.12.014

    Article  PubMed  Google Scholar 

  36. Pavel M, Jann H, Prasad V et al (2017) NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive. Neuroendocrinology 104:170–182. https://doi.org/10.1159/000446025

    Article  CAS  PubMed  Google Scholar 

  37. Laskaratos F-M, Liu M, Malczewska A et al (2020) Evaluation of circulating transcript analysis (NETest) in small intestinal neuroendocrine neoplasms after surgical resection. Endocrine 69:430–440. https://doi.org/10.1007/s12020-020-02289-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Modlin IM, Kidd M, Frilling A et al (2021) Molecular genomic assessment using a blood-based mRNA signature (NETest) is cost effective and predicts neuroendocrine tumor recurrence with 94% accuracy. Ann Surg 274:481–490. https://doi.org/10.1097/SLA.0000000000005026

    Article  PubMed  Google Scholar 

  39. Modlin IM, Kidd M, Oberg K et al (2021) Early identification of residual disease after neuroendocrine tumor resection using a liquid biopsy multigenomic mRNA signature (NETest). Ann Surg Oncol 28:7506–7517. https://doi.org/10.1245/s10434-021-10021-1

    Article  PubMed  Google Scholar 

  40. Oberg K, Krenning E, Sundin A et al (2016) A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management. Endocr Connect 5:174–187. https://doi.org/10.1530/EC-16-0043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are grateful to Gioja Bianca Costanza Fund for supporting the PhD Scholarship of Dr Valentina Andreasi and the Research Fellowship of Dr Francesca Muffatti. The present study was supported by ENETS Translational Medicine Fellowship Grant 2019. The authors thank the ERN EURACAN initiative.

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Author notes

  1. V. Andreasi and S. Partelli authors share the first authorship.

Authors and Affiliations

  1. Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132, Milan, Italy

    V. Andreasi, S. Partelli, F. Muffatti, S. Crippa & M. Falconi

  2. Vita-Salute San Raffaele University, Milan, Italy

    V. Andreasi, S. Partelli, S. Crippa, A. Corti & M. Falconi

  3. San Raffaele Hospital Neuroendocrine Tumor Group (ENETS Center of Excellence), Milan, Italy

    V. Andreasi, S. Partelli, M. F. Manzoni, F. Muffatti, L. Di Filippo, S. Crippa, A. Corti & M. Falconi

  4. Endocrinology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy

    M. F. Manzoni & L. Di Filippo

  5. Tumor Biology and Vascular Targeting Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, Milan, Italy

    V. Andreasi & A. Corti

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Contributions

Study concept and design: VA, SP, AC, and MF. Data collection: VA, FM, and LDF. Analysis of the data: VA and SP. Interpretation of the data: VA, SP, MFM, SC, AC, and MF. Drafting the manuscript: VA and SP. Critical revision of the manuscript: all the authors.

Corresponding author

Correspondence to M. Falconi.

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The authors declare that they have no conflicts of interest.

Ethical approval

The present study was approved by the San Raffaele Scientific Institute Ethics Committee (protocol NETBANK001).

Research involving human participants

All procedures performed in human participants were in accordance with the ethical standards of the institutional ethics committee and with the Declaration of Helsinki.

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Written informed consent was obtained from all the participants included in the study.

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Andreasi, V., Partelli, S., Manzoni, M.F. et al. Role of chromogranin A-derived fragments after resection of nonfunctioning pancreatic neuroendocrine tumors. J Endocrinol Invest 45, 1209–1217 (2022). https://doi.org/10.1007/s40618-022-01750-5

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  • DOI: https://doi.org/10.1007/s40618-022-01750-5

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