Scientific letter
Stage IV mixed adenoneuroendocrine carcinoma of sigmoid colon in complete response after immunotherapy. Closer to curing neuroendocrine neoplasms?
Carcinoma mixto adenoneuroendocrino de sigma estadio IV en respuesta completa con inmunoterapia. ¿Hacia la curación de las neoplasias neuroendocrinas?
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Closer to curing neuroendocrine neoplasms?" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figura 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1649 "Ancho" => 2925 "Tamanyo" => 524468 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A) Pólipo sigmoideo LST-G Is/IIa NICE 2. B) Hallazgos radiológicos compatibles con un carcinoma neuroendocrino (CNE) de sigma estadio IV. C) Resultados de la secuenciación genómica. 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Closer to curing neuroendocrine neoplasms?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "262" "paginaFinal" => "263" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "César Gutiérrez Pérez, Inmaculada Rodríguez Ledesma, Carmen Blanco Abad, Juan Luis Catoya Villa, Irene Chivato Martín-Falquina, Alicia Cuenca Zarzuela, Guillermo Crespo Herrero" "autores" => array:7 [ 0 => array:4 [ "nombre" => "César" "apellidos" => "Gutiérrez Pérez" "email" => array:1 [ 0 => "cesargutierrezperez@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Inmaculada" "apellidos" => "Rodríguez Ledesma" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Carmen" "apellidos" => "Blanco Abad" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Juan Luis" "apellidos" => "Catoya Villa" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Irene" "apellidos" => "Chivato Martín-Falquina" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "Alicia" "apellidos" => "Cuenca Zarzuela" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 6 => array:3 [ "nombre" => "Guillermo" "apellidos" => "Crespo Herrero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Oncología Médica, Hospital Universitario de Burgos, Burgos, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Aparato Digestivo, Hospital Universitario de Burgos, Burgos, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicios de Radiodiagnóstico, Hospital Universitario de Burgos, Burgos, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Carcinoma mixto adenoneuroendocrino de sigma estadio IV en respuesta completa con inmunoterapia. ¿Hacia la curación de las neoplasias neuroendocrinas?" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1649 "Ancho" => 2925 "Tamanyo" => 524468 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A) Sigmoid polyp LST-G Is/IIa NICE 2. B) Radiological findings compatible with stage IV sigmoid neuroendocrine carcinoma (NEC). C) Genomic sequencing results. D) Sustained complete radiological response.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We present the case of a 62-year-old man assessed by colonoscopy after a positive result in the faecal occult blood test performed as part of the colorectal cancer screening programme. A 50-mm LST-G Is/IIa NICE 2 polyp was found in the sigmoid colon (30 cm from the anal margin) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A), resected by piecemeal endoscopic mucosectomy, with a diagnosis of high-grade-mixed adenoneuroendocrine large cell carcinoma on adenomatous polyp with severe dysplasia. Computed tomography (CT) was performed, showing abdominal lymphadenopathy and bone and liver metastases (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>B). Octreotide scintigraphy revealed the absence of somatostatin receptors.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">Once the tumour study was completed, the patient was started on treatment with cisplatin-etoposide, while the absence of potential therapeutic molecular targets was confirmed by genomic sequencing: microsatellite stability (MSS), low tumour mutational burden (TMB), with three mutations/megabase, and pathogenic alterations in the KRAS, APC, RB1, SOX9 and TP53 genes (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>C). After five cycles of cytostatic treatment, a reassessment CT scan revealed new liver lesions, and an application was made for compassionate use of ipilimumab and nivolumab. After six months of immunotherapy, with partial radiological response in the first cycles, positron emission tomography showed the absence of pathological uptake in liver and bone, and an apparent decrease in lymph node metastases, but with a single lymph node progression in the region of the coeliac trunk. Resection of the only existing lymphadenopathy was performed, showing infiltration by high-grade large cell neuroendocrine carcinoma (NEC), plus sigmoidectomy to ensure healing, the result of which was ypT0ypN0. Weeks later, the patient started maintenance treatment with nivolumab until completing two years of immunotherapy.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Forty months after diagnosis, our patient is in excellent general condition and there is no evidence of cancerous disease at present (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>D).</p><p id="par0020" class="elsevierStylePara elsevierViewall">Neuroendocrine neoplasms (NET) are a heterogeneous group of rare tumours. Based on morphological and cell proliferation criteria, they are classified as well-differentiated and poorly-differentiated. The former over-express somatostatin receptors, which facilitates diagnosis and targeted treatment; in contrast, poorly-differentiated NEC exhibit more aggressive tumour behaviour and, as reflected in our patient, lack somatostatin receptors.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The present case is morphologically defined as a mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN), the most aggressive component being a high-grade large cell NEC with a high proliferation index (Ki67 100%). Treatment is based on combining platinum salts with etoposide.</p><p id="par0030" class="elsevierStylePara elsevierViewall">As there is no standard second-line treatment for NEC, and response rates with conventional chemotherapy regimens are below 10%,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> we resorted to immunotherapy. Compassionate use approval was initially sought for ipilimumab and nivolumab based on efficacy data in terms of objective response rate (ORR) published in the DART clinical trials SWOG 1609<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> and CA209-538,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> with ORR of 44% and 31% respectively in high-grade NEC. Despite the initial response to immunotherapy, single lymph node progression in the coeliac trunk led to the disease being treated surgically, and finally to a sustained complete response with nivolumab.</p><p id="par0035" class="elsevierStylePara elsevierViewall">High levels of PD-L1, MSI or elevated TMB are considered predictive biomarkers of response to immunotherapy, but their clinical effectiveness is still unknown. Focusing on NEC, the association has been shown between high-grade NEC and high levels of TMB, as well as the expression of an increased number of PD-L1 receptors in these tumours.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However, no biomarkers predictive of response to immunotherapy were identified in our patient.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In conclusion, even considering the excellent objective response, the evidence on the benefits of immune-mediated therapy in NET is not sufficiently robust. This case calls for the study of the molecular basis of immunotherapy and its potential applications in NET and other orphan tumours for effective therapeutic alternatives.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1649 "Ancho" => 2925 "Tamanyo" => 524468 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A) Sigmoid polyp LST-G Is/IIa NICE 2. B) Radiological findings compatible with stage IV sigmoid neuroendocrine carcinoma (NEC). C) Genomic sequencing results. D) Sustained complete radiological response.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:4 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Design and validation of the GI-NEC score to prognosticate overall survival in patients with high-grade gastrointestinal neuroendocrine carcinomas" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Lamarca" 1 => "T. Walter" 2 => "M. Pavel" 3 => "I. Borbath" 4 => "P. Freis" 5 => "B. Nuñez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1093/jnci/djw277" "Revista" => array:4 [ "tituloSerie" => "J Natl Cancer Inst" "fecha" => "2017" "volumen" => "109" "paginaInicial" => "djw277" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S.P. Patel" 1 => "M. Othus" 2 => "Y.K. Chae" 3 => "F.J. Giles" 4 => "D.E. Hansel" 5 => "P.P. 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