International Journal of Endocrine OncologyVol. 7, No. 2 EditorialOpen AccessBad kits in the diagnosis of endocrine tumorsJens F RehfeldJens F Rehfeld*Author for correspondence: Tel.: +45 3545 3018; Fax: +45 3545 2880; E-mail Address: jens.f.rehfeld@regionh.dkDepartment of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100, Copenhagen, DenmarkPublished Online:6 Mar 2020https://doi.org/10.2217/ije-2020-0003AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: diagnosticsendocrine tumorshormone chaperones (granins)immunoassayspeptide-hormone biosynthesispeptide-producing tumorsplasma measurementspost-translational processingBad kits are like bad kids. Both behave badly. But bad kits can be pretty harmful to innocent people, including patients with serious malignant diseases. Several factors are necessary to explain the occurrence of bad behaving kids and kits. The following, however, will focus on some commercial, immunochemical kits used diagnostically in endocrine oncology.The correct diagnosis of hormone-producing tumors requires measurements of the true biomarker concentrations in circulation. Often the biomarker is a peptide hormone or neuroendocrine chaperone protein, whose concentration is to be measured immunochemically, using assay technologies such as a radioimmunoassay (RIA) or enzyme-linked immunosorbent assay. It seems simple and straightforward, which it is when you are dealing with simple systems. For instance, the measurement of insulin in patients suspected for harboring an insulin-producing tumor, an insulinoma. The simplicity of insulin measurement is, however, atypical and primarily due to the fact that there is only one insulin molecule (except in rats). Moreover, the concentration levels of insulin in plasma are in a relatively high picomolar range. In addition, it is easy to raise specific high-titer and high-affinity antibodies to insulin for immunoassay purposes.In contrast to insulin, however, most other peptide hormones and endocrine chaperone proteins – like the granins – are complex, heterogeneous systems, which are extensively processed during the post-translational phase of their biogenesis, both in normal endocrine cells and in tumor cells [1,2]. Consequently, these cells release not a single hormonal molecule to blood, but a mixture of peptides and protein fragments with varying size, bio- and immuno-reactivity. The cellular post-translational processing of prohormones and granins is extensive and includes three sorts of processes: endoproteolytic cleavages, primarily at mono- and di-basic sites (i.e., at C-termini of arginyl- and lysyl-residues); exoproteolytic trimmings of N- and C-termini of terminal amino acid residues (in order to protect against amino- and carboxy-peptidase degradations) and amino acid derivatizations, of which there are many different types. The modifications are well-described for some peptide–hormone systems, but far from fully elucidated for all [3,4]. For instance, the types and extension of glycosylations of peptide hormones have only just come into recognition in recent years [5]. The degree and chemical nature of the molecular heterogeneity has to be considered when the hormones and their chaperones are going to be measured for diagnostic purposes. Not least because the molecular pattern of heterogeneity in plasma may vary between tumor patients and healthy persons [6,7]. Thus, the molecular heterogeneity of the tumor marker is one side of the coin.The other side is the immunochemistry of the assay used for the tumor marker. For the immunoassay, it is important to realize that the binding site of an antibody has a size corresponding to a peptide sequence of four to seven amino acid residues [8]. Exactly how many residues depends on the size of each residue. Consequently, the antibody will recognize only a small part of a protein or peptide tumor marker. If the epitope is present in other proteins or peptides, the immunoassay will be unspecific and often useless for diagnostic purposes. But even if the epitope is specific, the hormone heterogeneity may cause decisive problems for the antibody binding, if the epitope is cleaved, trimmed and/or derivatized.One way out of these problems is to use an analysis that is independent of post-translational modifications, in other words, the molecular heterogeneity. Such 'processing-independent analysis' (PIA) can be established by careful examination of the prohormone structure and finding an epitope sequence, which is known neither to be cleaved nor derivatized; but it has at its N-terminus to neighbor a trypsin-sensitive cleavage site. If you then pre-analytically trypsinize the plasma sample, the selected epitope will be exposed and can be quantitated with the immunoassay specific for the N-terminal sequence of the epitope. We have developed such PIA-assays for a number of peptide hormones and for a general neuroendocrine tumor marker (chromogranin A) [9–12]. The PIA-assays seem to fulfill their promises, not only in terms of diagnosis, but also in prognosis, because they provide a measure of the tumor burden.During the last 3 to 4 decades of the previous century, the assays for endocrine tumor markers were developed in research laboratories at universities and university hospitals, often in association with clinical projects to improve the diagnosis and therapy for patients with these relatively rare, but often serious neuroendocrine tumors. The academic, scientific background of the laboratories that developed the original immunoassays ensured that the available basic biochemical, pathobiochemical and oncologic knowledge about the endocrine tumor markers and the tumors was taken into account in the design of the assays. Consequently, the reliability of these assays was quite high regarding accuracy, quality of the plasma measurements and the diagnostic sensitivity and specificity. But this picture has now changed. Hence, commercial diagnostic companies have, during the last 2 or 3 decades, now taken a dominant position in the production of diagnostic kits for endocrine tumors (often in association with new automatized analytical platforms), for which the proper diagnosis in the majority of patients suspected to have endocrine tumors today is now dependent on the quality of commercial immunoassay kits. Among these, there are indeed some bad kits as described in studies from the last decade.One study was regarding gastrin kits [7]: 12 years ago, some gastroenterologists began to note that occasionally patients with symptoms of fulminant Zollinger–Ellison syndrome (which is caused by hypersecretion from gastrin-producing tumors [gastrinomas]) were denied the expected gastrinoma diagnosis. The reason was that their gastrin concentrations in plasma were measured to be normal. These Zollinger–Ellison patients, however, were in hospitals whose diagnostic laboratory used commercial kits for gastrin measurements. Therefore, in order to examine the situation, we bought available commercial kits on the market (n = 12) and compared their results with those of a thoroughly validated in-house gastrin radioimmunoassay, on plasma samples from 40 patients with well-characterized Zollinger–Ellison syndromes. The results indicated that more than half (seven) of the kits were misleading. In other words, they were bad. The false low results caused months of delays in the diagnosis, which resulted in severe complications of nearly fatal character. According to the guiding kit instructions from the commercial manufacturers, the mismeasuring kits had been insufficiently validated.CgA is a widely used general marker for neuroendocrine tumors. Like most prohormones, however, the CgA protein undergoes extensive cellular processing and therefore also circulates as a mixture of modified peptide fragments [13]. Consequently, the results of different CgA-assays vary and so does the diagnostic sensitivity of the measurements in patient plasma. Two recent studies have examined commercial CgA kits and again compared the kit results with those of carefully validated in-house CgA RIAs (including a CgA-PIA assay) [14]. In the largest study, the material comprised plasma samples from 130 well-characterized patients with small intestinal neuroendocrine tumors [unpublished data]. The results demonstrated that three commercial CgA kits displayed an unacceptably low diagnostic sensitivity. They were bad. But even the most sensitive commercial kits missed the diagnosis in some patients with metastatic disease. The best results were obtained with the in-house CgA-PIA assay [12].Although glucagonomas and cholecystokininomas are rare tumors [15,16], patients with the specific syndromes caused by glucagonomas and cholecystokininomas also deserve the correct diagnosis. But again – as detailed above for CgA in neuroendocrine tumors and progastrin in gastrinomas, proglucagon and procholecystokinin are also heavily processed during the post-translational maturation to several different peptides. Consequently, the concentrations measured by the vast number of commercial kits on the market vary so widely that their use in tumor diagnosis is questionable [17–19]. Again, a majority of these kits need careful reliability assessments for measurements.A last, but different problem with commercial kits, even with those of acceptable diagnostic quality, is a business-attitude among kit-producers, which copes poorly with the ethics of medical diagnostics. Hence, some diagnostic companies suddenly and without warning discontinue their production of selected kits. Such discontinuation may jeopardize a timely diagnosis in tumor patients and endanger costly oncological projects at hospitals. This behavior is bad, calling for a regulation of the market for diagnostic kits in a manner similar to that of the pharmaceutical drug market.AcknowledgmentsThe skillful secretarial assistance of C Bundgaard (MA) is gratefully acknowledged.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Rehfeld JF, Bardram L, Blanke S et al. Peptide hormone processing in tumours: biogenetic and diagnostic implications. Tumour Biol. 14, 174–183 (1993).Crossref, Medline, CAS, Google Scholar2. Rehfeld JF, Goetze JP. The posttranslational phase of gene expression: new possibilities in molecular diagnosis. Curr. Mol. Med. 3, 25–38 (2003).Crossref, Medline, CAS, Google Scholar3. Walsh CT. Posttranslational Modifications of Proteins. Roberts and Company Publishers, CO, USA, 1–477 (2006).Google Scholar4. Kastin AJMinamino N (Eds). Handbook of Biologically Active Peptides: Peptide Biosynthesis/Processing, Academic Press/Elsevier, CA, USA, 1711–1835 (2013).Google Scholar5. Hansen LH, Madsen TD, Goth CK et al. Discovery of O-glycans on atrial natriuretic peptide (ANP) that affects both its proteolytic degradation and potency at its cognate receptor. J. Biol. Chem. 294, 12567–12578 (2019).Crossref, Medline, CAS, Google Scholar6. Rehfeld JF. The art of measuring gastrin in plasma: a dwindling diagnostic discipline? Scand. J. Clin. Lab. Invest. 68, 353–361 (2008).Crossref, Medline, CAS, Google Scholar7. Rehfeld JF, Gingras MH, Bardram L, Hilsted L, Goetze JP, Poitras P. The Zollinger–Ellison syndrome and mismeasurement of gastrin. Gastroenterology 40, 1444–1453 (2011).Crossref, Google Scholar8. Schechter I. Mapping of the combining sites of antibodies specific for poly-L-alanine determinants. Nature 228, 639–641 (1970).Crossref, Medline, CAS, Google Scholar9. Bardram L, Rehfeld JF. Processing-independent radioimmunoanalysis: a general analytical principle applied to progastrin and its products. Anal. Biochem. 175, 537–543 (1988).Crossref, Medline, CAS, Google Scholar10. Paloheimo LI, Rehfeld JF. A processing-independent assay for human procholecystokinin and its products. Clin. Chim. Acta 229, 49–65 (1994).Crossref, Medline, CAS, Google Scholar11. Goetze JP, Kastrup J, Pedersen F, Rehfeld JF. Quantification of pro-B-type natriuretic peptide and its products in human plasma by use of an analysis independent of precursor processing. Clin. Chem. 48, 1035–1042 (2002).Crossref, Medline, CAS, Google Scholar12. Børglum T, Rehfeld JF, Drivsholm LB, Hilsted L. Processing-independent quantitation of chromogranin A in plasma from patients with neuroendocrine tumors and small-cell lung carcinomas. Clin. Chem. 53, 438–446 (2007).Crossref, Medline, Google Scholar13. Helle KB. Chromogranins A and B and secretogranin II as prohormones for regulatory peptides from the diffuse neuroendocrine system. Results Probl. Cell Differ. 50, 21–44 (2010).Medline, CAS, Google Scholar14. Hoej LB, Parkner T, Knudsen CS, Grønbaek H. A comparison of three chromogranin A assays in patients with neuroendocrine tumours. J. Gastrointestin. Liver Dis. 23, 419–424 (2014).Crossref, Medline, Google Scholar15. McGavran MH, Unger RH, Recant L, Polk HC, Kilo C, Levin ME. A glucagon-secreting alpha-cell carcinoma of the pancreas. N. Engl. J. Med. 274, 1408–1413 (1966).Crossref, Medline, CAS, Google Scholar16. Rehfeld JF, Federspiel B, Bardram L. A neuroendocrine tumor syndrome from cholecystokinin secretion. N. Engl. J. Med. 368, 1165–1166 (2013).Crossref, Medline, CAS, Google Scholar17. Albrechtsen NJ, Veedfald S, Plamboeck A et al. Inability of some commercial assays to measure suppression of glucagon secretion. J. Diabetes Res. doi: 0.1155/2016/8352957 (2016).Google Scholar18. Bak MJ, Albrechtsen NJ, Pedersen J et al. Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1): implications for GLP-1 measurements in clinical studies. Diabetes Obes. Metab. 16, 1155–1164 (2014).Crossref, Medline, CAS, Google Scholar19. Rehfeld JF. Measurement of cholecystokinin in plasma with reference to obesity studies. Nutr. Res. doi.org/10.1016/j.nutres.2020.01.003 (2020).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Vol. 7, No. 2 Follow us on social media for the latest updates Metrics Downloaded 391 times History Received 30 January 2020 Accepted 6 February 2020 Published online 6 March 2020 Published in print June 2020 Information© 2020 Jens F. RehfeldKeywordsdiagnosticsendocrine tumorshormone chaperones (granins)immunoassayspeptide-hormone biosynthesispeptide-producing tumorsplasma measurementspost-translational processingAcknowledgmentsThe skillful secretarial assistance of C Bundgaard (MA) is gratefully acknowledged.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download
A 43-year old woman demonstrated an intra-abdominal drop metastasis 6 years after initial presentation of stage-III adrenocortical carcinoma (ACC), previously treated with resection, adjuvant radiation and mitotane therapy. This recurrence was managed aggressively with complete excision, adjuvant radiation and mitotane. Imaging at 3.25-year follow-up showed no evidence of recurrence, a remarkable response given ACC’s poor prognosis and high recurrence rates. Management of oligometastatic ACC remains unclear and intra-abdominal drop metastases are particularly rare in ACC; both require further documentation. Aggressive management with adjuvant radiation and mitotane therapy may represent an effective and well-tolerated approach for improving local control for recurrent ACC, including drop metastases. Further research is required to codify potential benefits.
We report a 65-year old female with advanced papillary thyroid carcinoma involving the critical vessels including common carotid artery (CCA). She initially refused surgery and lenvatinib (LEN) was used in neoadjuvant setting. Primary tumor effectively shrank by LEN without any critical adverse effect. Total thyroidectomy and modified neck dissection were curatively performed. Tumor invading into internal jugular vein exhibited remarkable response to LEN and was almost replaced with necrosis and fibrosis. CCA was surrounded by fibrosis but was smoothly dissected from tumor and preserved. The patient shows no sign of recurrence for 2 years after surgery at present. Neoadjuvant LEN treatment can be new option for locally advanced papillary thyroid carcinoma involving critical vessels, particularly CCA, to reduce risk of surgical morbidity.
Background: There is a lack of knowledge regarding the experience of patients with neuroendocrine tumors (NET) in France. Materials & methods: A patient survey that captured information on diagnosis, disease impact/management and awareness was conducted. Data of respondents from France were analyzed and compared with US data as a reference. Results: Key topics included delays in diagnosis, negative impact on quality of life, patient access to NET medical experts and treatments, and information on NET and treatments. Significant differences were observed between France and the USA regarding NET diagnosis. Conclusion: This survey highlights the considerable burden experienced by patients in France with NET and differences in patient experience between France and the USA that may result from different healthcare and social systems.
Aim: This study investigates if serum calcitonin or carcinoembryonic antigen (CEA) levels can differentiate between locoregional and metastatic medullary thyroid cancer. Methods: A single institution retrospective analysis was performed on 88 patients with medullary thyroid cancer between 2008 and 2014. Results: In M0disease, calcitonin (p < 0.001) and CEA (p = 0.003) significantly decreased postoperatively. Not only was the correlation significant between calcitonin and CEA preoperatively (r = 0.72; p < 0.001) and postoperatively (r = 0.68; p < 0.001), calcitonin could extrapolate CEA levels (p < 0.001). These findings were statistically insignificant in metastatic disease. Conclusion: Independently, calcitonin and CEA fail to differentiate between locoregional and metastatic disease. Both are essential for prognostication: loss of concordance is suspicious for metastatic disease. Hence, discordant CEA and calcitonin levels should be an indication to pursue additional imaging.
Aim: Hyperfunctioning intrathyroidal parathyroid glands are rare and often result in thyroid lobectomy. This study examines the utility of radioguided surgery to guide enucleation of intrathyroidal parathyroids. Methods: Between December 2002 and March 2018, 2291 patients underwent parathyroidectomy by one surgeon for primary hyperparathyroidism. A total of 74 (3%) patients had an ectopic intrathyroidal parathyroid gland and underwent radioguided. Results: All of intrathyroidal parathyroid glands were localized with the gamma probe. In vivo radionuclide counts were above 120% of the background in all but three patients. All intrathyroidal parathyroids were enucleated with the guidance of the gamma probe. Conclusion: Radioguided surgery is useful for intraoperative identification of hyperfunctioning, intrathyroidal parathyroid glands. This technique allows for enucleation of the abnormal parathyroid gland, avoiding thyroid lobectomy and preserving healthy thyroid parenchyma.
International Journal of Endocrine OncologyVol. 7, No. 1 ForewordOpen AccessWelcome to Volume 7 of the International Journal of Endocrine OncologyLauren WoolfeLauren Woolfe*Author for correspondence: E-mail Address: l.woolfe@future-science.comFuture Science Group, Unitec House, 2 Albert Place, London, N3 1QB, UKPublished Online:14 Feb 2020https://doi.org/10.2217/ije-2020-0001AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Happy New year and welcome to Volume 7 of International Journal of Endocrine Oncology. As the new Editor of the journal, I am extremely excited to work on new projects and ideas for 2020, as well as working with our excellent authors, peer reviewers and editorial board members.Content highlights of 2019International Journal of Endocrine Oncology publishes four issues per year, each filled with a variety of articles of high standard and interest. A personal highlight was the two-part interview with leading endocrine oncologist Dr. Gary Hammer (Rogel Cancer Center, MA, USA). In Part 1, Hammer discussed the current research currently underway in his lab at the University of Michigan, as well as the development and current challenges in diagnosis and management of endocrine neoplasia [1]. Hammer also shared a personal story surrounding the development of the company Millendo Therapeutics. In Part 2, Hammer explained how the University of Michigan developed the leading endocrine neoplasia group, alongside the importance of patient advocacy and global engagement for rare diseases [2]. These Interviews are well worth a read and have the highest number of downloads within the first month of publication for 2019.Another fantastic article was an editorial on bronchial carcinoids, written by Dan Granberg (Uppsala University, Sweden) [3]. In the article, he explains how these neuroendocrine tumor symptoms, pathology, diagnosis and treatment vary, as well as providing alternative treatment options, and explaining the need for the development of novel therapeutics.Finally, we have a brilliant case report – one of our top three most-read articles of 2019 – entitled 'Familial paraganglioma due to a novel SDHB mutation: familial phenotypic heterogeneity and a potentially novel manifestation' written by researchers from King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia [4]. This case report provides in-depth clinical diagnosis and management of a patient with Familial paraganglioma with primary hyperparathyroidism – a combination not well described in the literature. The authors highlight the importance of lifelong surveillance with this novel SDHA mutation due to the variability in phenotypic presentations and heterogeneityArticle outreachThe majority of the International Journal of Endocrine Oncology readers are from the Americas (37%), Europe (31%) and Asia (29%) (Figure 1). We are continuing our work on harnessing the power of social media to disseminate our high-quality research and aim to reach all relevant stakeholders in the endocrine oncology space.Figure 1. Reader demographics 2019.If you do not already, we welcome you to follow us on twitter (@fsgije) as well as subscribe to our partnered website Oncology Central [5], to keep up to date with the latest research and news.Editorial BoardInternational Journal of Endocrine Oncology would also like to thank its Editorial Board for its continued support, which has enabled 2019 to be an amazing year. We would also like to say a special thank you to our Senior Editors Electron Kebebew and Karel Pacak (both of the National Cancer Institute, MD, USA) for their hard work in 2019 and continued guidance for the year to come. If you would like to learn more about what our Editorial Board members do or how to get involved, please do not hesitate to get in touch. We are always on the lookout for more experts in such a diverse space as endocrine oncology.ConclusionWorking on the International Journal of Endocrine Oncology this past year has been fantastic, and we have some exciting plans for 2020. If you have any ideas for the journal, be it an outline for an article or a theme for an issue, we would love to hear it so please get in touch.Once again thank you to our readers, authors, peer reviewers and Editorial Board members for all of their hard work and support throughout 2019 – we look forward to working together in 2020.Financial & competing interest disclosureL Woolfe is an employee of Future Science Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Hammer G . An interview with Gary D Hammer, MD, PhD. Int. J. Endo. Oncol. 6(4), IJE23 (2019). Link, CAS, Google Scholar2. Hammer G . Gary D Hammer on the improvement of patient care in endocrine neoplasia. Int. J. Endo. Oncol. 6(4), IJE24 (2019). Link, CAS, Google Scholar3. Granberg D . Bronchial carcinoids. Int. J. Endo. Oncol. 6(1), IJE16 (2019). Link, CAS, Google Scholar4. Alzahrani A , Alswailem M , Albattal S , Qasem E , Murugan A , Al-Hindi A . Familial paraganglioma due to a novel SDHB mutation: familial phenotypic heterogeneity and a potentially novel manifestation. Int. J. Endo. Oncol. 6(1), IJE12 (2019). Link, CAS, Google Scholar5. Oncology Central (2019). www.oncology-central.com/ Google ScholarFiguresReferencesRelatedDetails Vol. 7, No. 1 Follow us on social media for the latest updates Metrics History Received 10 January 2020 Accepted 10 January 2020 Published online 14 February 2020 Published in print March 2020 Information© 2020 Future Medicine LtdFinancial & competing interest disclosureL Woolfe is an employee of Future Science Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download
densely granulated adenomas • histological types of growth hormone secreting
Aim: This study assesses if clinically developed quality of life (QoL) tools are as effective in small bowel neuroendocrine tumors (NETs) as NET-specific research questionnaires. Methods: QoL in patients with small bowel NETs treated with Lu-DOTA-TATE was assessed with The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-GI.NET21 and Edmonton Symptom Assessment System Revised (ESAS-r) at baseline and after four treatments. Repeated measures ANOVA was performed. Results: Both EORTC and ESAS-r demonstrated maintained overall QoL. EORTC demonstrated statistically and clinically significant improvement in insomnia, diarrhea, gastrointestinal, endocrine symptoms and social function. ESAS-r demonstrated statistically and clinically significant improvement in overall total symptom distress score. Conclusion: ESAS-r is quick and easy to interpret. It is not as sensitive to individual symptoms but does track overall function. EORTC assessment is more complex, but better reflects QoL for NET specific symptoms.
An increasingly recognized mechanism of prostate cancer resistance is the transdifferentiation from adenocarcinoma to treatment-emergent neuroendocrine prostate cancer (t-NEPC), an extremely aggressive malignancy. The incidence of t-NEPC has been increasing in recent years, in part due to novel treatments that target the androgen receptor pathway. While clinicians historically had very few options for t-NEPC detection and treatment, recent research has uncovered key diagnostic tools and therapeutic targets that can be translated into improved patient care. In this article, we will outline the clinical features of t-NEPC and its molecular pathogenesis. Importantly, we will also discuss recently uncovered molecularly based strategies aimed at improving the diagnosis and treatment of t-NEPC. Finally, we will propose a unified algorithm that integrates clinical and molecular information for the clinical management of t-NEPC.
Dr Gary D Hammer is the cofounder of Millendo Therapeutics (NASDAQ, MLND, MI, USA) and the founder of Vasaragen (MI, USA), two biotechnology companies focused on rare endocrine diseases. Hammer is also an employee of the University of Michigan.
Dr Hammer is the cofounder of Millendo Therapeutics (NASDAQ, MLND, MI, USA) and the founder of Vasaragen (MI, USA), two biotechnology companies focused on rare endocrine diseases. Hammer is also an employee of the University of Michigan.
Aim: To study primary hyperparathyroidism (pHPT) in an oncology center, including its possible association with malignancy and ionizing radiation. Methods: Retrospective analysis of 188 patients with sporadic pHPT treated with parathyroidectomy between 2000 and 2018. We studied the etiology, clinical and biochemical features of pHPT, history of malignancies and exposure to radiotherapy. Results: pHPT was caused by parathyroid adenoma in 90.4%, hyperplasia in 5.3% and carcinoma in 4.3%. Cure and recurrence rates of pHPT were 99 and 4.3%, respectively. Median follow-up time was 19 months. Prevalence of malignancies was 30%, mostly thyroid and breast cancer. Radiotherapy of the head, neck or thorax (8.5%) was not associated with worse hypercalcaemia or recurrence. Males had larger adenomas, higher calcium and parathyroid hormone (p < 0.01). Conclusion: Prevalence of parathyroid carcinoma and other malignancies was higher than reported in other studies. Ionizing radiation exposure was unrelated with pHPT severity. Men had more severe pHPT. High cure and low recurrence rates were achieved.
International Journal of Endocrine OncologyVol. 6, No. 4 Case SeriesOpen AccessTherapy with tyrosine kinase inhibitor lenvatinib in radioactive iodine-naive advanced differentiated thyroid cancerJasmine Singh Sukumar, William Moore & Saad A KhanJasmine Singh SukumarDivisions of Hematology and Medical Oncology, The Ohio State University Medical Center, Columbus, OH 43210, USA, William MooreDepartment of Radiology, UT Southwestern Medical Center, Dallas, TX 75390, USA & Saad A Khan*Author for correspondence: E-mail Address: Saad.Khan@UTSouthwestern.eduUT Southwestern Department of Internal Medicine and Harold C Simmons Comprehensive Cancer Center, Dallas, TX 75390, USAMD, UT Southwestern Medical Center, Dallas, TX 75390-8852, USAPublished Online:7 Nov 2019https://doi.org/10.2217/ije-2019-0007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: differentiated thyroid cancerlenvatinibpapillary thyroid cancerradioactive iodine-naivetyrosine kinase inhibitorLenvatinib is a tyrosine kinase inhibitor (TKI) approved for the management of radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC) [1]. In the Phase III SELECT trial, lenvatinib extended median progression free survival to 18.3 months compared with 3.6 months for placebo and a response rate of 64.8% [2]. This trial required that enrolled patients have previously received and deemed refractory to RAI. There are no published data on the efficacy of TKIs in patients who have not previously received RAI and it is unclear if the molecular changes that thyroid cancer undergoes after exposure to RAI are critical for response to lenvatinib.RAI is an established adjuvant treatment for high-risk patients who have undergone surgical resection and in those that have recurrent or metastatic disease. However, the 2015 American Thyroid Association (ATA) guidelines [3] do not address the role of RAI prior to thyroidectomy, aisutionat that commonly arises in clinical practice. Patients that present with locoregionally advanced DTC initially are offered drastic surgical options that may be declined due to patient- or tumor-specific factors. Extremely large tumors may require a laryngectomy which can negatively impact quality of life and increase morbidity [4]. Also, these patients may not be ideal candidates for RAI as RAI may be less likely to concentrate in patients with large tumors and may not effectively reduce tumor burden [5]. There are limited data on the impact of preoperative RAI [6], though two recent reports described 'neoadjuvant' lenvatinib without prior RAI [7–9]. Both cases resulted in dramatic tumor reduction and were followed by surgery and post-lenvatinib RAI. Preoperative or palliative radiation therapy (with or without systemic therapy) is widely recognized as leading to increased complication rates after head and neck cancer surgery, especially if reconstruction is required [10–14]. However, it is not universally effective and additional treatment options are needed for patients with large thyroid cancers who are unlikely to benefit from RAI due to their large tumor burden.Patients who present with large thyroid cancers and decline surgery due to concerns about functional outcome present distinct challenges. Any decrease in tumor size with systemic therapy may reduce the extent of surgical interventions such as laryngectomy, tracheal resection and esophageal–pharyngeal resection in favor of less radical surgical approaches. Thus, even though the approved indication for lenvatinib is for patients with radioactive iodine refractory thyroid cancer, early systemic therapy may be particularly beneficial in patients with extensively invasive DTC or more aggressive histologies such as poorly differentiated thyroid cancer. While tumor shrinkage may be expected with preoperative lenvatinib, it is unknown what other impact this may have; whether the anti-angiogenic effects of lenvatinib complicate surgery, whether pathologic evidence of lymph node is impaired or if outcomes are improved. Ongoing clinical trials may help answer some of these questions (NCT03506048).Lenvatinib use should not be routinely expanded out to patients before they receive RAI. However, in practices such as ours where patients present with extremely large bulky thyroid cancers and the only surgical option is a laryngectomy followed by RAI, our experience suggests that treating such patients with lenvatinib prior to any RAI therapy yields durable disease control and opens up additional treatment options. Our novel results suggest lenvatinib therapy is active in patients with bulky thyroid cancer who require major surgery, even those who have never previously been treated with RAI. The goal of this approach is to delay surgery or make it unnecessary, enhance the chance of cure and provide more treatment options for patients. We present a report of two patients who had not received any prior RAI when they were treated with lenvatinib (Table 1).Table 1. Description of patients receiving lenvatinib and their responses.AgeRaceSexPrimary siteTreatment prior to lenvatinibLenvatinib toxicityBest response to lenvatinib69CaucasianMLeft thyroid with extension to trachea and superior mediastinum1. Total thyroidectomy with left paratracheal dissection 2. External beam radiation 70 GyMyalgias, dysgeusia, weight loss Partial response: – Reduction in paratracheal mass 4.3 × 1.4→ 1.0 × 1.0 cm – Followed by radioactive iodine and no resumption of lenvatinib for >12 months (ongoing) 69HispanicFLeft thyroid with invasion to trachea and esophagus, cervical and mediastinal lymph nodes, lungNoneHypertension, neuropathy, myalgias, weight loss Partial response: – Decrease in size of bilateral pulmonary nodules, mediastinal lymph nodes, and thyroid mass, improvement in malignant pleural effusion – Followed by radioactive iodine (suboptimal response), remains on lenvatinib PatientPatient 1A 69-year-old Caucasian male presented with 6 months of dyspnea and, in August 2016, a computed tomography (CT) neck scan showed enlargement of the left thyroid with extension into the superior mediastinum and rightward tracheal deviation. Thyroid ultrasound revealed a multinodular thyroid with a large exophytic left lobe nodular conglomerate (approximately 9.3 × 4.3 × 7.1 cm) and biopsy showed papillary thyroid carcinoma.He underwent a total thyroidectomy with left paratracheal dissection with median sternotomy in September 2016. Residual disease was left on the anterior tracheal wall, left cricotracheal junction and right thyroid bed. The pathology returned as papillary thyroid carcinoma, classic type with predominantly follicular and focal trabecular growth pattern (up to 12 cm), with positive margins, lymphovascular invasion and extrathryoidal extension. There was also microscopic papillary thyroid carcinoma (0.1 mm) in the right thyroid lobe. He was started on levothyroxine suppression. His surgical recovery was complicated by vocal cord paresis, severe dysphagia and aspiration with subsequent gastrostomy tube placement.He received adjuvant external beam radiation therapy to the neck and superior mediastinum with a total of 70 Gy from November to December 2016. After radiation, he developed improved swallow function and voice quality. Positron Emission Tomography in April 2017 showed paraesophageal mass in the thyroidectomy bed of 4.3 × 1.4 cm consistent with recurrence and fine needle aspiration revealed recurrent papillary thyroid cancer. He was offered surgical intervention with total laryngectomy but he did not want to pursue this. He was assessed by endocrinology for RAI administration. Due to the fluorodeoxyglucose (FDG) avidity and bulkiness of the tumor as well as logistical difficulty of administering RAI in a gastrostomy tube-dependent patient, he was not administered RAI because these features suggested the tumor would be RAI resistant. He was thus started on lenvatinib 20 mg daily in May 2017, which would be considered an off-label use as he had not received any prior RAI. Thyroglobulin was 20 ng/ml after radiation was completed and then dropped to 1 ng/ml and 0.6 ng/ml after 2 and 3 months of lenvatinib respectively.A CT neck and chest scan in July 2017 showed reduction in size of paratracheal mass, demonstrating favorable response to TKI. Lenvatinib was held in August 2017, after the patient developed an axillary abscess, which was treated. He also developed myalgias and dysgeusia which he attributed to the medication. Repeat positron emission tomography in September showed decreased side of paraesophageal mass to 2.6 × 1 cm. He was restarted on lenvatinib in October 2017 at 10 mg daily. The patient was again offered surgery but declined both a mass resection and laryngectomy due to his concern about potential damage to his voice. Lenvatinib was continued for a total of 14 months until the size of the mass reduced to 1.1 cm in the longest dimension. At that time, he was administered 127 mCi radioactive iodine (I-131) after thyrogen stimulation, with a subsequent scan showing no uptake in the neck. He then resumed taking his leftover supply of lenvatinib 10 mg for 3 weeks. He had not been taking lenvatinib or any other anticancer treatment for 2 months when he had repeat imaging of this area performed. A CT scan of the area was described as being 'without evidence of residual/recurrent disease', with personal review of images identifying a 1 × 1 cm mass in that area. The patient reported no symptoms of pain or residual toxicity. Thyroglobulin at that time increased to 3.7 from 1.8 prior to RAI.Patient 2A 69-year-old Hispanic female presented with persistent hoarseness and dysphagia for 1 year. Her past medical history included chronic lymphocytic leukemia, for which she received whole body radiation therapy and stem cell transplant in 2009 but was now in remission. Thyroid ultrasound in June 2016 showed a left thyroid lobe mass of 4.1 × 2.3 × 3.7 cm, lymphadenopathy in the bilateral jugular chains and calcification of the right posterior midpole. A CT neck scan showed the left mass to be 3.1 × 2.8 cm and biopsy revealed papillary thyroid carcinoma. A CT chest scan showed multiple pulmonary nodules and mediastinal lymphadenopathy suspicious for metastasis. A repeat CT chest scan in August 2016 showed progression of known left thyroid papillary carcinoma with concern for invasion of the trachea and esophagus with left vocal cord paralysis. Her bulky tumor was considered as likely resistant to RAI based on the 2015 ATA Guidelines and therefore RAI was felt to be of minimal benefit in causing rapid tumor shrinkage.The patient was started on lenvatinib with a goal to shrink tumor size prior to surgical intervention, which would require laryngectomy if pursued early. She started lenvatinib 24 mg daily in August 2016 but subsequently developed hypertension. Lenvatinib was decreased to 14 mg daily, which she received for 2 weeks in August 2016, but given persistent hypertension, it was then held. In September, lenvatinib was restarted at 10 mg daily and was further reduced to 8 mg daily in November due to neuropathy and myalgias. A repeat CT chest scan in October 2016 demonstrated favorable response to treatment, including decrease in size of bilateral pulmonary nodules, mediastinal lymphadenopathy and left thyroid mass. MRI of the neck showed persistent invasion of the left trachea, left vocal cord and esophagus.From March to April 2017, lenvatinib was held and she received intensity-modulated radiotherapy of 60 Gy in 25 fractions to the left thyroid and neck over a duration of 5 weeks. In September 2017, she received RAI with 129 millicuries of I-131 after thyrogen stimulation. She was then started on levothyroxine suppression. Subsequent radioiodine whole body scan revealed evidence of lung metastases with poor response to iodine uptake. Lenvatinib was resumed at 8 mg daily in October 2017 but then stopped in November due to dyspnea and hypertension. A CT chest scan showed multifocal areas of nodular pleural thickening worrisome for pleural metastases with moderate sized left pleural effusion. Her blood pressure was controlled with antihypertensive medications. Thoracentesis improved symptoms and cytology was consistent with malignant pleural effusion. Lenvatinib was restarted at 8 mg daily in December 2017. Given reaccumulating nature of pleural effusion indwelling intrapleural catheter was placed and she received pleurodesis in December 2017. Catheter was removed in February 2018 given improvement in pleural effusion. She had progressive weight loss and, in March 2018, lenvatinib was decreased to 4 mg daily. Imaging in June 2019 shows sustained stability of disease.DiscussionThe two presented cases demonstrate that lenvatinib can play a major role in disease control in patients who have never previously received RAI. Our findings are consistent with that of Danilovic et al., who described a patient with unresectable papillary thyroid carcinoma, in whom preoperative treatment with TKI sorafenib allowed for reduction in tumor volume, leading to new treatment options, including surgical intervention via thyroidectomy and RAI [15]. Two other published reports have described lenvatinib responses in differentiated thyroid cancer patients who have not received prior RAI [7–9]. Similar outcomes have also been observed with neoadjuvant targeted systemic therapy for anaplastic thyroid cancer [16].To be clear, such usage of lenvatinib is not considered standard practice nor is it one of the indications for use in its regulatory approval. Practices such as ours regularly see patients with large thyroid cancers who may not be candidates for, or decline, surgery, radiation or RAI. These patients still require treatment and the tolerability and anticancer efficacy of lenvatinib make it an attractive option. In cases where the likelihood of RAI without drastic surgery being effective is low to zero, administering it before lenvatinib may be the incorrect option even if it is considered the standard option. While laryngectomy followed by RAI for residual disease may indeed be the correct option for many patients, some patients with a curative option that mandated laryngectomy were more receptive to disease control with medication. The decision against surgery in favor of lenvatinib is based on the perceived improved life with retaining a functioning larynx, even if it comes at the expense of a theoretically shorter lifespan with noncurative lenvatinib.In these two patients, lenvatinib showed excellent activity in RAI-naive patients, but did not result in converting a radical surgery into a simpler procedure. In one patient, there also did not appear to be significant activity of RAI in these patients after lenvatinib administration; this suggests that lenvatinib may differ from some other TKI's that enhance RAI sensitivity. Though formal quality of life assessments were not performed, both patients reported tolerating lenvatinib well with standard dose reductions and no significant periods of treatment interruption. They remained very anxious about possible surgical complications. Patient 1 was able to tolerate regular dosing for 14 months and resumed it even when he was not instructed to do so. The tumor mass reduced in size from over 4 cm in longest dimension to 1 cm in size just after 6 months of regular dosing with lenvatinib (Figure 1). Although laryngectomy was offered to the patient for potential cure, he declined given concern for adverse effects related to surgery. Therefore, the degree of anticancer activity was highly effective for this patient for the amount of toxicity faced, even if it was not yet a curative option. The second patient developed metastatic pleural effusion and required frequent dose interruptions due to existing poorly controlled blood pressure. However, even with intermittent or decreased dosing, there were favorable effects. In Patient 2, the pleural effusion completely resolved, resulting in significantly improved quality of life (Figure 2). The side effect of lenvatinib in our patients was similar to that seen in RAI refractory patients.Figure 1. Axial imaging showing tumor response after 6 months of lenvatinib, without prior radioactive iodine.Figure 2. Axial imaging showing dramatic reduction in pleural effusion after 5 months of lenvatinib without prior radioactive iodine.Our patients also demonstrate an interesting aspect about lenvatinib. The dramatic reduction in the volume seen with lenvatinib meant that RAI became an option for therapy. Generally, RAI is effective for low volume DTC that may be localized or metastatic. RAI was initially not recommended for Patient 2 due to the volume of the cancer as well as lack of prior thyroidectomy. However, as the visible burden of disease markedly reduced, both patients received RAI therapy without uptake in their thyroidectomy bed. Lenvatinib is thought to exert its antithyroid cancer effect via VEGF, but it does inhibit MEK as well [10]. MEK inhibitors such as Selumetinib and Trametinib can lead to RAI sensitivity in patients that were previously RAI refractory [11]. It is posited that lenvatinib may lead to enhanced sensitivity to RAI, but in these two patients, this effect is not observed. Whether lenvatinib results in enhanced RAI uptake is currently unclear but the subject of ongoing clinical trials (NCT03506048; PI D Taofeek K/Owonikoko).Lenvatinib generally has a rapid time to tumor response, that is one reason why it may be a particularly effective agent in patients with large tumors that may not respond to RAI. In the SELECT trial, it was shown to have a median time for an objective response of 2 months (95% CI: 1.9–3.5) [2]. The dramatic degree of response seen in our patients suggests that the mechanism of action remains the same in patients with DTC that have never been exposed to RAI.In conclusion, our experience suggests that lenvatinib is effective in DTC that has never been treated with RAI. Early lenvatinib may be a novel approach to convert an unresectable case into one where a more limited surgery is possible, though patients who tolerate lenvatinib well may still remain hesitant to consider any surgery. Lenvatinib reduced the volume of thyroid cancer that had never been treated with RAI to such a degree that subsequent therapy with RAI became possible. In patients who decline surgical resection, have bulky tumors and have other findings suggestive of RAI refractoriness, lenvatinib should not be held for the sole reason that RAI has yet to be administered. The authors caution that these very narrow clinical scenarios detailed in this manuscript should not be used to justify indiscriminate use of lenvatinib in patients who appropriately meet ATA guidelines for surgical resection followed by RAI. Future prospective clinical trials will define lenvatinib's role as a costeffective, safe and efficacious treatment in the general patient population who have not been treated with RAI previously (e.g., NCT03506048).Ethical conduct of researchInformed consent for the use of patient details was obtained from both patients and is present in the medical record. Both patients freely provided this consent to the treating team with the only limitation of no identifiable information being included in the manuscript as well as a request for the final published version. Institutional review board oversight is thus not required as both patients were not treated with research intent. The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Papers of special note have been highlighted as: • of interest; •• of considerable interestReferences1. 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Clin. N. Am. 17(1), 145–155 (2008). Crossref, Medline, Google Scholar5. Vassilopoulou-Sellin R , Schultz PN , Haynie TP . Clinical outcome of patients with papillary thyroid carcinoma who have recurrence after initial radioactive iodine therapy. Cancer 78(3), 493–501 (1996). Crossref, Medline, CAS, Google Scholar6. Shingu K , Kobayashi S , Yokoyama S et al. Effectiveness of preoperative radioactive iodine (131I) therapy for locally advanced papillary thyroid cancer: a case report. Thyroid 8(12), 1113–1116 (1998). Crossref, Medline, CAS, Google Scholar7. Tsuboi M , Takizawa H , Aoyama M , Tangoku A . Surgical treatment of locally advanced papillary thyroid carcinoma after response to lenvatinib: a case report. Int. J. Surg. Case Rep. 41, 89–92 (2017). •• Other examples of preoperative lenvatinib use that was effective.Crossref, Medline, Google Scholar8. Stewart KE , Strachan MWJ , Srinivasan D , MacNeill M , Wall L , Nixon IJ . Tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a case report. Eur. Thyroid J. 8(2), 102–107 (2019). •• Other examples of preoperative lenvatinib use that was effective.Crossref, Medline, CAS, Google Scholar9. Sheu NW , Jiang HJ , Wu CW , Chiang FY , Chiou HC , Hsiao PJ . Lenvatinib complementary with radioiodine therapy for patients with advanced differentiated thyroid carcinoma: case reports and literature review. World J. Surg. Oncol. 17(1), 84 (2019). Crossref, Medline, Google Scholar10. Terezakis SA , Lee KS , Ghossein RA et al. Role of external beam radiotherapy in patients with advanced or recurrent nonanaplastic thyroid cancer: memorial Sloan-kettering cancer center experience. Int. J. Radiat. Oncol. Biol. Phys. 73(3), 795–801 (2009). Crossref, Medline, Google Scholar11. Cortes-Mateus KS , Holub K , Racca F , Grau JJ , Capdevila J . Concurrent palliative external radiotherapy with sorafenib or doxorubicin for bulky differentiated thyroid carcinoma: a case report. Oncol. Lett. 16(3), 4085–4089 (2018). Medline, Google Scholar12. Herle P , Shukla L , Morrison WA , Shayan R . Preoperative radiation and free flap outcomes for head and neck reconstruction: a systematic review and meta-analysis. ANZ J. Surg. 85(3), 121–127 (2015). Crossref, Medline, Google Scholar13. Sokoya M , Bahrami A , Vincent A et al. Preoperative radiation and complication rates after double free flap reconstruction of head and neck cancer. Am. J. Otolaryngol. 39(5), 558–560 (2018). Crossref, Medline, Google Scholar14. Righini CA , Nadour K , Faure C et al. Salvage surgery after radiotherapy for oropharyngeal cancer. Treatment complications and oncological results. Eur. Ann. Otorhinolaryngol. Head Neck Dis. 129(1), 11–16 (2012). Crossref, Medline, Google Scholar15. Danilovic DLS , Castro G Jr , Roitberg FSR et al. Potential role of sorafenib as neoadjuvant therapy in unresectable papillary thyroid cancer. Arch. Endocrinol. Metab. 62(3), 370–375 (2018). Medline, Google Scholar16. Cabanillas ME , Ferrarotto R , Garden AS et al. Neoadjuvant BRAF- and immune-directed therapy for anaplastic thyroid carcinoma. Thyroid 28(7), 945–951 (2018). Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByThe Effect of Lenvatinib in Patients with Thyroid Cancer with Pericardial Metastasis, Which Can Cause Cardiac TamponadeNippon Jibiinkoka Tokeibugeka Gakkai Kaiho(Tokyo), Vol. 124, No. 11Lenvatinib15 February 2020 | Reactions Weekly, Vol. 1791, No. 1 Vol. 6, No. 4 Follow us on social media for the latest updates Metrics History Received 17 June 2019 Accepted 3 October 2019 Published online 7 November 2019 Published in print December 2019 Information© 2019 Saad KhanKeywordsdifferentiated thyroid cancerlenvatinibpapillary thyroid cancerradioactive iodine-naivetyrosine kinase inhibitorEthical conduct of researchInformed consent for the use of patient details was obtained from both patients and is present in the medical record. Both patients freely provided this consent to the treating team with the only limitation of no identifiable information being included in the manuscript as well as a request for the final published version. Institutional review board oversight is thus not required as both patients were not treated with research intent. The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download
International Journal of Endocrine OncologyVol. 6, No. 3 InterviewOpen AccessThe treatment of neuroendocrine prostate cancer; current status and future directionsPasquale RescignoPasquale Rescigno*Author for correspondence: E-mail Address: pasquale.rescigno@icr.ac.ukDivision of Clinical Studies, Prostate Cancer Targeted Therapies Group, Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NGPublished Online:6 Nov 2019https://doi.org/10.2217/ije-2019-0010AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInRedditEmail Pasquale Rescigno is a clinical research fellow at the Royal Marsden Hospital and The Institute of Cancer Research (both London, UK), working under the mentorship of Professor Johann de Bono. Having completed his training in Medical Oncology at the University of Naples Federico II (Naples, Italy), he has been working in London for the last 5 years, aiming to complete his PhD in January 2020. Last year, he was the recipient of an ASCO (American Society of Clinical Oncology) young investigator merit award for his work on SPOP as predictive biomarker of response to abiraterone.Here, he talks to Assistant Editor, Jennifer Straiton, about his work in the field of prostate cancer, the current treatment options for this cancer type and the future of potential treatments in this disease area.Could you describe what you are currently researching?I work in the Prostate Cancer Targeted Therapy Group at the Royal Marsden and run a unit with my colleagues on clinical trials led by Professor de Bono. We work predominantly with experimental drugs, currently focusing on immunotherapies and targeted treatments. An example of the type of trial, we run is the TOPARP-B study on Olaparib which has just been presented at ASCO [1]. Personally, I am working on a Phase II immunotherapy trial of pembrolizumab which I have designed. Professor de Bono gave a presentation at ASCO [2] last year, demonstrating that these drugs can be beneficial in a small subset of patients. When pembrolizumab is given to unselected patients, the response rate is quite low, with approximately 10% or less of the patients included in the trial having a clinical benefit; however, we are now offering this drug to patients selected based on specific biomarkers – mainly looking for patients with defects in the mismatch-repair system. That will be the focus of my work over the next few years though we are also looking for other mechanisms of sensitivity or resistance to immunotherapies. We recently had a publication in the Journal of Clinical Investigation where we explain why we think immunotherapies will be beneficial in this subset of patients [3].The other focus of my work is on agents targeting the Pi3 Kinase-Akt signaling, and we currently have several trials at the Royal Marsden targeting either Pi3 Kinase or Akt. Within the RE-AKT trial, we are trying to determine the efficacy of an AKT inhibitor (AZD5363) when given in combination with enzalutamide for patients with metastatic castration-resistant prostate cancer. This is mainly the kind of work that I do – translational research and clinical study.What are the current therapeutic options for neuroendocrine prostate cancer?To date, neuroendocrine prostate cancer has been historically treated with carboplatin and etoposide. These are the standard options for other neuroendocrine malignancies, and are the treatments that have shown some clinical benefit for prostate cancer patients.A subset of castration resistant prostate cancer acquires histopathological and immunohistochemical evidence of neuroendocrine differentiation and a variety of morphological classifications have been reported to date. However, the term treatment‐related 'neuroendocrine prostate cancer' should be reserved for tumors with absent or minimal androgen‐signaling modulated transcription. Our recent work, published in Proceedings of the National Academy of Sciences [4], where we performed histopathology, whole exome sequencing and RNA-seq for 444 tumor samples shed some light on this matter.What challenges are there in the treatment of prostate cancer?Cancer biology is extremely convoluted; tumor clonality and cancer evolution each represent big challenges. New cancer clones can emerge during the treatment which can induce resistance to anticancer therapies. Prostate cancer has been shown to be quite a heterogeneous disease, and changes can happen over time as cancer cells evolve over the years. If you target a given mutation, this does not mean that that cancer will harbor the same mutation in a months' time, or a years' time. This makes it difficult to study this disease in some patients and asking a patient to undertake multiple biopsies to study his cancer over the years is not a fair solution to the problem. We are investigating the utility of diagnostic leukapheresis in detecting patients' circulating tumor cells for single cell analysis. Liquid biopsies may represent, in the near future, the ideal tool to study cancer evolution without putting patients under stressful and onerous procedures.Genetic targeting and precision medicine can be extremely powerful, as recently showed at ASCO where the work we conducted demonstrated how cancers harboring defects in the BRCA2 gene have 80% of chance to respond to Olaparib [1]. However, in some cases, the cancer can find a way to reverse the mutation, causing resistance to Olaparib and other PARP inhibitors. This reinforces the idea that, even if you target a specific mutation in a successful way, cancers can find a way to elude the treatment pressure, developing new mechanisms of resistance.What options are available for overcoming these challenges?Combinations of drugs targeting different pathways could be an answer to overcoming resistance. However, even if there is a strong rationale for combining drugs, we always have to look at tolerability and patients' compliance, as our primary goal should always be 'do no harm'. If you think about the combination of ipilimumab and nivolumab for example, in a study recently presented at ASCO [5] there were good responses reported in some patients; however, other patients experienced serious reactions and some fatal incidents were also reported while on trial. It is always a balance between the scientific rationale and determining what is tolerable for the patients.I think precision medicine is extremely important, but more evidence is emerging about the relevance of the tumor microenvironment. There are lots of studies about this, each looking at cells like the myeloid derived suppressor cells that can induce an immunosuppressive microenvironment and prevent the immune system attacking the cancer. Modulation of the tumor microenvironment could represent a significant strategy and we have recently showed how the IL-23 pathway could represent a new target of treatment in prostate cancer [6].A new area of interesting prostate cancer is the study of the microbiome. There are now several studies showing that the microbiome can potentially interfere with prostate cancer carcinogenesis. Manipulating the microbiome has been shown to have significant implications in other cancer types. I have seen some work in renal carcinoma on how antibiotics, that affect patients' microbiome, can interfere with responses to immunotherapies. Science is best when we keep an open mind. Looking at experiences in other tumor types may also help us in understanding prostate cancer.Where do you see the field in 5–10 years?There is still a lot to do in the space of prostate cancer, but when it comes to predicting the future, it is impossible to say where it will go; 10 years ago, there were only chemotherapy agents approved for prostate cancer, while now there is a variety of treatments available. If you asked back then whether there would be scope for hormonal agents in prostate cancer, many people would probably have said no because prostate cancer patients would often progress despite treatment with LHRH agonists or bicalutamide defining this condition as hormone refractory. Today, we have several hormonal agents like abiraterone, enzalutamide, apalutamide or darolutamide that are effective in prostate cancer. Again, not long ago, it was thought that based on the knowledge that prostate cancer does not have a lot of associated mutations, there was no space for immunotherapies in this field. Now we know that, even if in a small subset, there are some prostate cancer patients that do respond to immunotherapies.In this respect, the work by Daniel Robinson et al. in 2015 [7] signifies a milestone in prostate cancer research. This work changed the way people thought about prostate cancer and the idea that this is not just one disease but in fact several diseases. It also shows us that, while the androgen receptor pathway is really important in prostate cancer, there are several others meaningful and targetable pathways in prostate cancer.A group of prostate cancers, enriched for histological neuroendocrine features and with high neuroendocrine score, presents alteration in the RB1 gene. RB1 altered cancers are highly aggressive, with poor overall survival and show poor response to hormonal treatments such as abiraterone and enzalutamide. Having identified RB1 as playing a key role in this subset of prostate cancers might allow us to identify novel therapeutic agents in the future.I think we always need to keep an open mind. The most important factor in the field of cancer treatment is the selection of patients within clinical trials, it is important to molecularly characterize prostate cancers because we cannot find a drug that will be suitable for everyone. This is something in a trial that we have learnt in the past from a trial that evaluated the efficacy of satraplatin. This trial failed to show a statistically significant benefit in terms of overall survival, despite satraplatin delaying disease progression in some patients [8]. However, we now know from studies like TOPARP-A [9] and TOPARP-B [1] that cancers harboring defects in genes like BRCA2 and other defects in the DNA repair system known as homologous recombination, are sensitive to Olaparib and are likely to be sensitive to platins. It is likely that a biomarker selection approach would have made the trial with satraplatin a positive trial.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.DisclaimerThe opinions expressed in this interview are those of Pasquale Rescigno and do not necessarily reflect the views of Future Medicine Ltd.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/References1. Mateo J , Porta N , McGovern UB et al. TOPARP-B: a Phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. Presented at: 2019 ASCO Annual Meeting. IL, USA, 31 May–4 June 2019. Crossref, Google Scholar2. De Bono JS , Goh JCH , Ojamaa K et al. KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2018 ASCO Annual Meeting. IL, USA, 1–5 June 2018. Google Scholar3. Rodrigues DN , Rescigno P , Liu D et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J. Clin. Investig. 128(10), 4441–4453 (2018). Crossref, Medline, Google Scholar4. Abida W , Cyrta J , Heller G et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116(23), 11428–11436 (2019). Crossref, Medline, CAS, Google Scholar5. Sharma P , Pachynski RK , Narayan V et al. Initial results from a Phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). Presented at: 2019 ASCO Annual Meeting. IL, USA, 31 May–4 June 2019. Crossref, Google Scholar6. Calcinotto A , Spataro C , Zagato E et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 559(7714), 363–369 (2018). Crossref, Medline, CAS, Google Scholar7. Robinson D , Van Allen EM , Wu YM et al. Integrative clinical genomics of advanced prostate cancer. Cell 161(5), 1215–1228 (2015). Crossref, Medline, CAS, Google Scholar8. Sternberg CN , Petrylak DP , Sartor O et al. Multinational, double-blind, Phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J. Clin. Oncol. 27(32), 5431–5438 (2009). Crossref, Medline, CAS, Google Scholar9. Mateo J , Carreira S , Sandhu S et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373(18), 1697–1708 (2015). Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 6, No. 3 Follow us on social media for the latest updates Metrics Downloaded 507 times History Received 11 July 2019 Accepted 11 July 2019 Published online 6 November 2019 Published in print November 2019 Information© 2019 Pasquale RescignoFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.DisclaimerThe opinions expressed in this interview are those of Pasquale Rescigno and do not necessarily reflect the views of Future Medicine Ltd.Open accessThis work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/PDF download
Pituitary tumors are common intracranial neoplasms associated with significant morbidity due to hormonal dysregulation and neurologic symptoms. Somatic mutations are uncommon in sporadic pituitary adenomas, and only few monogenic conditions are associated with pituitary tumors. However, increasing evidence suggests that aberrant epigenetic modifications are found in pituitary tumors. In this review, we describe these mechanisms, including DNA methylation, histone modification and microRNA expression, and the evidence supporting their dysregulation in pituitary tumors, as well as their regulation of pro-tumorigenic genes. In addition, we provide an overview of findings from preclinical studies investigating the use of histone deacetylase inhibitors to treat pituitary adenomas and the need for further studies involving epigenetic drugs and functional characterization of epigenetic dysregulation.
Aim: The most frequent finding associated with incidental fluorodeoxyglucose (FDG) uptake in sellar region in oncologic F-18 FDG PET/CT is adenoma. However, reports of metastatic involvement exist. We investigated the clinical significance of incidental FDG uptake in this region. Materials & method: 34 patients with several primary tumors who were referred for staging, restaging or treatment response via F-18 FDG PET/CT were included. Images were reviewed and patients with significant FDG uptake in the sellar region were referred. Results: Mean lesion diameter was 11.9 ± 4.9 mm and mean standardized uptake value was 8.2 ± 6.1. Thirteen patients underwent MRI, and the others underwent follow-up F-18 FDG PET/CT. MRI revealed metastatic involvement in nine patients and macro- or micro-adenoma in four. Metastatic patients also had other lesions, yet management did not change. Conclusion: FDG accumulation in the sellar region might be associated with metastasis or adenoma. However, it did not change management. Future studies are warranted.
5-Hydroxyindole acetic acid (5-HIAA) is a surrogate marker for serotonin measurement and one of the first biochemical markers used in neuroendocrine tumors. In this review, we give a brief history of 5-HIAA and its precursor serotonin. We discuss its clinical utility and diagnostic performance in small intestinal neuroendocrine tumor and describe the challenges encountered during its analysis, historically performed in urine. The introduction of blood-based assays will help overcome some of the issues associated with its measurement in urine. The diagnostic performance of serum and plasma 5-HIAA has been shown to be comparable to that of urine 5-HIAA. Thus, analysis in either serum or plasma will provide a practical and convenient alternative to urine.
