Letter to the Editor Re: Clinical and molecular features of treatment-related neuroendocrine prostate cancer In their review article regarding the clinical and molecular features, and possible mechanisms of neuroendocrine differ- entiation (NED) in prostate cancer, Akamatsu et al. described in an exhaustive and at the same time clear form the current state-of-the-art the studies dealing with this topic. 1 In their article, the authors outlined the definition and classification of treatment-related neuroendocrine prostate cancer (t-NEPC), their clinical features, all the possible genomic and molecular characteristics, and novel therapeutic targets and biomarkers for t-NEPC. In our opinion, however, the excellent article refrained from the chance to use somatostatin receptor (SSTR) imaging to show the onset of NED in prostate can- cer. In the past three decades, nuclear medicine imaging has been widely used to study SSTR in neuroendocrine tumors and tumors with NED. The first human nuclear medicine in vivo study of SSTR overexpression in t-NEPC studied 31 patients with 111 In-pen- tetreotide scintigraphy. 2 Almost all (94%) of the patients enrolled had at least one localization visualized, and nearly 40% of the metastases detected by bone scan were in vivo, as evidenced by SSTR imaging. With the development of clini- cal positron-emission tomography (PET), Luboldt et al. stud- ied the usefulness of 68 Ga-DOTATOC, a somatostatin 2 and 5 receptor analog, in t-NEPC. 3 However, just 30% of focal metastases showed SSTR overexpression. The authors con- cluded that 68 Ga-DOTATOC might show the presence of SSTRs in t-NEPC, but the receptor concentration is so weak, and suggested testing a radiopharmaceutical with a different receptor affinity. Five years later, another study took up Luboldt’s suggestion, and described the biodistribution and results of the PET examination carried out in t-NEPC patients with 68 Ga-DOTANOC, a compound with a difference in SSTR affinity (DOTATOC binds to SSTRs 2 and 5, whereas DOTANOC binds to 2, 3 and 5). Some degree of SSTR overexpression was shown in two of the six patients studied. The authors concluded that from this very preliminary and small cluster of patients, the positivity to PET SSTRs exami- nation was too weak to hypothesize a therapy. 4 The study that surely reported the most striking results in the study of SSTRs by nuclear medicine procedures was reported in 2017 by Gofrit et al. 5 A total of 12 patients with t-NEPC were studied with 68 Ga-DOTATATE PET/computed tomography. This radiopharmaceutical technology is a further evolution of SSTR analog compounds used in nuclear medicine, character- ized by a narrower affinity with the receptor subclasses; that is, it binds only to SSTRs type 2, but with a 10-fold higher affinity compared with 68 Ga-DOTATOC. Significant uptakes were seen in six patients, and all patients had at least one 68 Ga-DOTATATE-positive metastasis. Despite the relatively poor number of t-NEPC patients studied for SSTRs as a tissue maker of NED differentiation, we believe that this opportunity should not be ruled out a priori. These comments are only meant to supplement the precious and clear information pro- vided by Akamatsu et al., and to suggest a possible way to show NED in t-NEPC in vivo with a non-invasive procedure. Giordano Savelli M.D., 1 Alberto Zaniboni M.D. 2 and Antonella Stefanelli M.D. 1 1 Division of Nuclear Medicine, and 2 Department of Medical Oncology, Poliambulanza Hospital, Brescia, Italy giordano.savelli@poliambulanza.it Conflict of interest None declared. References 1 Akamatsu S, Inoue T, Ogawa O, Gleave ME. Clinical and molecular features of treatment-related neuroendocrine prostate cancer. Int. J. Urol. 2018; 25: 345–51. 2 Nilsson S, Reubi JC, Kalkner KM et al. Metastatic hormone-refractory pro- static adenocarcinoma expresses somatostatin receptors and is visualized in vivo by [111In]-labeled DTPA-D-[Phe1]-octreotide scintigraphy. Cancer Res. 1995; 1: 5805s–10s. 3 Luboldt W, Z€ophel K, Wunderlich G et al. Visualization of somatostatin receptors in prostate cancer and its bone metastases with Ga-68-DOTATOC PET/CT. Mol. Imaging Biol. 2010; 12: 78–84. 4 Savelli G, Muni A, Falchi R et al. Somatostatin receptors over-expression in castration resistant prostate cancer detected by PET/CT: preliminary report of in six patients. Ann. Transl. Med. 2015; 3: 145. 5 Gofrit ON, Frank S, Meirovitz A et al. PET/CT with 68 Ga-DOTA-TATE for diagnosis of neuroendocrine: differentiation in patients with castrate-resistant prostate cancer. Clin. Nucl. Med. 2017; 42:1–6. © 2018 The Japanese Urological Association 1 International Journal of Urology (2018) doi: 10.1111/iju.13832