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A minimally invasive partial pancreatectomy was performed through a novel laparoscopic lateral flank approach in sternal-oblique recumbency in four clinical cases presented with an insulinoma. All four cases were female castrated dogs of older age (range 7-9 years) and different breeds (Wire haired dachshund, German shepherd, Jack Russel terrier, and Boxer), and all presented with episodic weakness, tremors, and/or seizures. The diagnosis was based on plasma glucose level below reference range with concomitant increased or normal insulin level. A laparoscopic approach was considered based on triple-phase contrast-enhanced computed tomography findings of the abdomen, revealing a pancreatic mass situated in the right pancreatic limb or left pancreatic limb without suspicion of metastasis. Laparoscopic procedures were performed without any major complications, and peri-operative glycemia increased to (supra-)normal levels in all cases. Histopathologic reports qualified the masses as neuroendocrine carcinomas, and in conjunction with the clinical picture, this neoplasia was further defined as insulinoma. Post-operative care in an intensive care unit was of short duration, and all animals were discharged being clinically normal and normoglycemic in between 1.5 and 2.5-day post-surgery. At short-term follow-up, no dogs showed clinical abnormalities, all recovered well from the surgical procedure, and blood glucose levels remained in the normal range. During long-term follow-up, 2 cases remained clinically normal at the time of writing, 564 and 1,211 days after surgery, 1 dog had recurrence of hypoglycemic episodes after 246 days and was euthanized after 673 days of surgery due to progressing disease, and 1 dog was euthanized after 1,028 days of surgery due to reasons unrelated to the insulinoma. Survival times ranged from 599 to 1,232 days after diagnosis. Considering the highly metastatic nature and difficulty of full laparoscopic staging of insulinoma patients, thoro

Introduction: Pheochromocytoma is a neuroendocrine tumor that originates in the neural crest and is characterized by the production of catecholamines. Objective: organize the diagnostic approach to a rare pathology. Clinical Case: A 58-year-old male patient who went to the emergency department with a 4-hour history of nausea and vomiting on four occasions involving food, reported progressive asthenia. During the anamnesis, the patient reports diffuse pain in the abdominal area that radiates to the lumbar area without the presence of fever. Symptoms are exacerbated, requiring hospitalization. Blood count: Hemoglobin 13.6, hematocrit 39%, leukocytes 11,200, neutrophils 10,420. Blood count without alterations. During hospitalization, symptoms persisted, so an abdominal ultrasound was performed with notable findings of a mass of approximately 6 centimeters located adjacent to the inner edge of the upper third of the left kidney, a right kidney with normal characteristics. To rule out metastasis of neoplasia, an abdominal CT scan with contrast is performed, which reports a multilobulated left adrenal mass that presents heterogeneous internal content with a solid area compatible with Pheochromocytoma or primary adrenal tumor. Conclusions: Pheochromocytoma is a pathology that should be suspected in the presence of an adrenal mass and changes associated with increased secretion of catecholamines. Surgical treatment should be performed immediately., Introducción: El feocromocitoma es un tumor neuroendocrino que se origina en la cresta neural y se caracteriza por la producción de catecolaminas. Objetivo: organizar el abordaje diagnóstico de una patología poco frecuente. Caso Clínico: Paciente masculino de 58 años que acude al servicio de emergencias por cuadro de 4 horas con náuseas y vómitos por cuatro ocasiones de contenido alimentario, refiere astenia progresiva. Durante anamnesis paciente refiere dolor difuso en zona abdominal que se irradia zona lumbar sin presencia de fiebre, sintomatología se exacerba por lo que se requiere hospitalización. Hemograma: Hemoglobina 13.6, hematocrito 39%, leucocitos 11.200, neutrófilos 10420. hemograma sin alteraciones. Durante hospitalización sintomatología persiste por lo que se procede a realizar ecografía abdominal con hallazgos destacables de masa de aproximadamente en 6 centímetros localizada adyacente a borde interno del tercio superior de riñón izquierdo, riñón derecho de características normales. Para descartar metástasis de neoplasia se procede Tomografía abdominal con contraste la misma que reporta masa suprarrenal izquierda multilobulada que presenta contenido interno heterogéneo con área sólida compatible para Feocromocitoma o tumor suprarrenal primario. Conclusiones: El feocromocitoma es una patología que debe sospecharse ante la presencia de una masa suprarrenal y cambios asociados al aumento de la secreción de catecolaminas. El tratamiento quirúrgico debe realizarse inmediatamente.

Neuroendocrine tumors generally originate in the digestive tract or pancreas, developing liver metastases throughout their evolution. The presence of a primary neuroendocrine tumor of the liver is still controversial and there are very few cases. We present a case of a primary neuroendocrine tumor of the liver confirmed by anatomo-pathological study and images. The patient underwent two major liver resections, lastly preserving only segment IV., Los tumores neuroendocrinos generalmente se originan en el tracto digestivo o páncreas, desarrollando metástasis hepática a lo largo de su evolución. La presencia de un tumor neuroendocrino primario de hígado es motivo de controversia y de muy escasa casuística. Presentamos el caso de un tumor neuroendocrino primario de hígado confirmado por estudio anatomo-patológico e imágenes. La paciente fue sometida a dos resecciones hepáticas mayores, preservando sólo el segmento IV

BACKGROUND: This post-hoc retrospective study describes long-term patient-reported outcomes (PROs) for REarranged during Transfection (RET)-altered non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC), non-MTC thyroid cancer (TC), and tumor agnostic (TA) patients (Data cut-off: January 2023) from the LIBRETTO-001 trial. PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30). Patients with MTC also completed a modified version of the Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). The proportion of patients with improved, stable, or worsened status after baseline was reported. PROs were summarized at 3 years (cycle 37) post-baseline for the NSCLC and MTC cohorts, and at 2 years (cycle 25) post-baseline for the TC and TA cohorts. Time-to-event outcomes (time to first improvement or worsening and duration of improvement) were reported. RESULTS: The baseline assessment was completed by 200 (63.3%), 209 (70.8%), 50 (76.9%), and 38 (73.1%) patients in the NSCLC, MTC, TC, and TA cohorts, respectively. The total compliance rate was 80%, 82%, 70%, and 85%, respectively. Approximately 75% (NSCLC), 81% (MTC), 75% (TC), and 40% (TA) of patients across all cohorts reported improved or stable QLQ-C30 scores at year 3 (NSCLC and MTC) or year 2 (TC and TA) with continuous selpercatinib use. Across cohorts, the median time to first improvement ranged from 2.0 to 19.4 months, the median duration of improvement ranged from 1.9 to 28.2 months, and the median time to first worsening ranged from 5.6 to 44.2 months. The total compliance rate for the mSTIDAT was 83.7% and the proportion of patients with MTC who reported diarrhea on the mSTIDAT was reduced from 80.8% at baseline to 35.6% at year 3. CONCLUSIONS: A majority of patients with RET-driven cancers improved or remained stable on most QLQ-C30 domains, demonstrating favorable health-related quality

N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.

The hypothalamic paraventricular nucleus (PVN) is a highly complex brain region that is crucial for homeostatic regulation through neuroendocrine signaling, outflow of the autonomic nervous system, and projections to other brain areas. In the past years, single-cell datasets of the hypothalamus have contributed immensely to the current understanding of the diverse hypothalamic cellular composition. While the PVN has been adequately classified functionally, its molecular classification is currently still insufficient. To address this, we created a detailed atlas of PVN transcriptomic cell types by integrating various PVN single-cell datasets into a recently published hypothalamus single-cell transcriptome atlas. Furthermore, we functionally profiled transcriptomic cell types, based on relevant literature, existing retrograde tracing data, and existing single-cell data of a PVN-projection target region. Finally, we validated our findings with immunofluorescent stainings. In our PVN atlas dataset, we identify the well-known different neuropeptide types, each composed of multiple novel subtypes. We identify Avp-Tac1, Avp-Th, Oxt-Foxp1, Crh-Nr3c1, and Trh-Nfib as the most important neuroendocrine subtypes based on markers described in literature. To characterize the preautonomic functional population, we integrated a single-cell retrograde tracing study of spinally projecting preautonomic neurons into our PVN atlas. We identify these (presympathetic) neurons to cocluster with the Adarb2+ clusters in our dataset. Further, we identify the expression of receptors for Crh, Oxt, Penk, Sst, and Trh in the dorsal motor nucleus of the vagus, a key region that the pre-parasympathetic PVN neurons project to. Finally, we identify Trh-Ucn3 and Brs3-Adarb2 as some centrally projecting populations. In conclusion, our study presents a detailed overview of the transcriptomic cell types of the murine PVN and provides a first attempt to resolve functionality for the identifi, Pattern Recognition and Bioinformatics

High-grade neuroendocrine neoplasms are a rare disease entity and account for approximately 10% of all neuroendocrine neoplasms. Because of their rarity, there is an overall lack of prospectively collected data available to advise practitioners as to how best to manage these patients. As a result, best practices are largely based on expert opinion. Recently, a distinction was made between well-differentiated high-grade (G3) neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas, and with this, pathologic details, appropriate imaging practices and treatment have become more complex. In an effort to provide practitioners with the best guidance for the management of patients with high-grade neuroendocrine neoplasms of the gastrointestinal tract, pancreas, and gynecologic system, the North American Neuroendocrine Tumor Society convened a panel of experts to develop a set of recommendations and a treatment algorithm that may be used by practitioners for the care of these patients. Here, we provide consensus recommendations from the panel on pathology, imaging practices, management of localized disease, management of metastatic disease and surveillance and draw key distinctions as to the approach that should be utilized in patients with well-differentiated G3 neuroendocrine tumors vs poorly differentiated neuroendocrine carcinomas.

BackgroundTo date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation.MethodsPatients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy.Primary endpointobjective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated.ResultsPart A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours.DiscussionTreatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs.Clinical trial registrationClinicalTrials.gov NCT03136055.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma that affects sun-damaged skin. Histologically, the tumor consists of round cells with fine chromatin positive for cytokeratin 20 in ~90% of cases. Rare cases of MCC can regress spontaneously and present as nodal metastasis. Nodal MCC of unknown primary can cause a potential pitfall as they can be misinterpreted as other neuroendocrine carcinomas such as small cell carcinoma. We report a case of nodal MCC with an atypical immunohistochemistry pattern presented as bilateral axillary lymphadenopathy in a 90-year-old man with a remote history of a skin lesion that healed spontaneously leaving a scar.

Background: Over the last few decades of treatment, the outcomes for at least some subsets of neuroendocrine neoplasms (NENs) have improved. However, the identification of new vulnerabilities for this heterogeneous group of cancers remains a priority. Methods: Using two libraries of compounds selected for potential repurposing, we identified the inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylases (HDAC) as the agents with the highest activity. We validated the hits in an expanded set of neuroendocrine cell lines and examined the mechanisms of action. Results: In Kelly, NH-6, and NCI-H82, which are two neuroblastoma and one small cell lung cancer cell lines, respectively, metabolic studies suggested that cell death following NAMPT inhibition is the result of a reduction in basal oxidative phosphorylation and energy production. NAMPT is the rate-limiting enzyme in the production of NAD+, and in the three cell lines, NAMPT inhibition led to a marked reduction in the ATP and NAD+ levels and the catalytic activity of the citric acid cycle. Moreover, comparative analysis of the mRNA expression in drug-sensitive and -insensitive cell lines found less dependency of the latter on oxidative phosphorylation for their energy requirement. Further, the analysis of HDAC and NAMPT inhibitors administered in combination found marked activity using low sub-lethal concentrations of both agents, suggesting a synergistic effect. Conclusion: These data suggest NAMPT inhibitors alone or in combination with HDAC inhibitors could be particularly effective in the treatment of neuroendocrine neoplasms.

Purpose The interactions between the administration of cold somatostatin analogs (cSAs) and their radiolabeled counterpart remain unclear, and discontinuation before imaging is still advised as a precaution. The aim of this systematic review is to evaluate the consequences of cSA administration on tumoral and surrounding healthy organs' uptake at somatostatin receptor (SSTR) imaging with SPECT or PET. Methods After registration of the study on Prospero (CRD42022360260), an electronic search of PubMed and Scopus databases was performed. Inclusion criteria were as follows: human patients referred for SSTR imaging for oncological purposes; at least 1 examination performed either before cSA administration or after a long-enough withdrawal of cSA treatment; at least 1 examination was performed under cSA treatment. Included articles were independently appraised by 2 authors using the standardized protocol provided by the Quality Assessment of Diagnostic Accuracy Studies. Discrepancies were solved by consensus. Results A total of 12 articles were included, 4 using 111In-pentetreotide and 8 using 68Ga-DOTA peptides. Administration of cSAs consistently resulted in decreased spleen and liver uptake (6.9% to 80% for spleen, 10% to 60% for liver) and increased tumor-to-background or tumor-to-healthy organ ratios. After cSA treatment, tumor uptake alone was unchanged or moderately decreased. Similar results were noted whether patient was octreotide-naive. Conclusion Impairment in SSTR imaging quality after cSA administration has not been demonstrated. On the contrary, the administration of cSAs seems to improve the contrast between tumoral lesions and the surroundings.

Introduction: Craniopharyngioma is a rare, low-grade tumor located in the suprasellar region of the brain, near critical structures like the pituitary gland. Here, we concurrently investigate the status of clinical and genomic data in a retrospective craniopharyngioma cohort and survey-based data to better understand patient-relevant outcomes associated with existing therapies and provide a foundation to inform new treatment strategies. Methods: Clinical, genomic, and outcome data for a retrospective cohort of patients with craniopharyngioma were collected and reviewed through the Children's Brain Tumor Network (CBTN) database. An anonymous survey was distributed to patients and families with a diagnosis of craniopharyngioma to understand their experiences throughout diagnosis and treatment. Results: The CBTN repository revealed a large proportion of patients (40 - 70%) with specimens that are available for sequencing but lacked relevant quality of life (QoL) and functional outcomes. Frequencies of reported patient comorbidities ranged from 20 to 25%, which is significantly lower than historically reported. Survey results from 159 patients/families identified differences in treatment considerations at time of diagnosis versus time of recurrence. In retrospective review, patients and families identified preference for therapy that would improve QoL, rather than decrease risk of recurrence (mean 3.9 vs. 4.4 of 5) and identified endocrine issues as having the greatest impact on patients' lives. Conclusions: This work highlights the importance of prospective collection of QoL and functional metrics alongside robust clinical and molecular correlates in individuals with craniopharyngioma. Such comprehensive measures will facilitate biologically relevant therapeutic strategies that also prioritize patient needs.

[EN] The purpose of the EANM Dosimetry Committee is to provide recommendations and guidance to scientists and clinicians on patient-specific dosimetry. Radiopharmaceuticals labelled with lutetium-177 (177Lu) are increasingly used for therapeutic applications, in particular for the treatment of metastatic neuroendocrine tumours using ligands for somatostatin receptors and prostate adenocarcinoma with small-molecule PSMA-targeting ligands. This paper provides an overview of reported dosimetry data for these therapies and summarises current knowledge about radiation-induced side effects on normal tissues and dose-effect relationships for tumours. Dosimetry methods and data are summarised for kidneys, bone marrow, salivary glands, lacrimal glands, pituitary glands, tumours, and the skin in case of radiopharmaceutical extravasation. Where applicable, taking into account the present status of the field and recent evidence in the literature, guidance is provided. The purpose of these recommendations is to encourage the practice of patient-specific dosimetry in therapy with 177Lu-labelled compounds. The proposed methods should be within the scope of centres offering therapy with 177Lu-labelled ligands for somatostatin receptors or small-molecule PSMA.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. We previously demonstrated that depletion of the mitochondrial molecular chaperone, mortalin, can effectively suppress human MTC cells in culture and in mouse xenografts, by disrupting mitochondrial bioenergetics and subsequently inducing apoptosis and RET downregulation. Similar effects were induced by MKT-077, a water-soluble rhodocyanine dye analog known to inhibit mortalin, but with notable toxicity in animals. These observations led us to evaluate recently developed MKT-077 analogs that exhibited higher selectivity to HSP70 proteins and improved bioavailability. We validated the MTC cell-suppressive effects of mortalin depletion in three-dimensional cultures of the human MTC lines, TT, and MZ-CRC-1, and then evaluated different MKT-077 analogs in two- and three-dimensional cell cultures, to show that the MKT-077 analogs, JG-98 and JG-194, effectively and consistently inhibited propagation of TT and MZ-CRC-1 cells in these cultures. Of note, these compounds also effectively suppressed the viability of TT and MZ-CRC-1 progenies resistant to vandetanib and cabozantinib. Moreover, JG-231, an analog with improved microsomal stability, consistently suppressed TT and MZ-CRC-1 xenografts in mice. These data suggest that mortalin inhibition may have therapeutic potential for MTC.

Though relatively rare in dogs, prostate cancer (PCa) is the most common non-cutaneous cancer in men. Human and canine prostate glands share many functional, anatomical and physiological features. Due to these similarities, canine PCa has been proposed as a model for PCa in men. PCa is typically androgen-dependent at diagnosis in men and for this reason, androgen deprivation therapies (ADT) are important treatments for advanced PCa in men. In contrast, there is some evidence that PCa is diagnosed more commonly in castrate dogs, at which point, limited therapeutic options are available. In men, a major limitation of current ADT is that progression to a lethal and incurable form of PCa, termed castrate-resistant prostate cancer (CRPC), is common. There is, therefore, an urgent need for a better understanding of the mechanism of PCa initiation and progression to CRPC to enable the development of novel therapeutic approaches. This review focuses on the functional, physiological, endocrine and histopathological similarities and differences in the prostate gland of these species. In particular, we focus on common physiological roles for androgen signalling in the prostate of men and dogs, we review the short- and longer-term effects of castration on PCa incidence and progression in the dog and relate how this knowledge may be relevant to understanding the mechanisms of CRPC in men.

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve the quality of life in patients with advanced prostate cancer. However, resistance to antiandrogens occurs frequently through mechanisms that are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital role in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. My research has focused on understanding the potential role of the Wnt5a/FZD2-mediated non-canonical Wnt pathway in enzalutamide-resistant prostate cancer. My study has found that Wnt5a and FZD2 are upregulated upon the development of enzalutamide resistance and that their overexpression correlates with higher Gleason score, biochemical recurrence and metastatic status, and with shortened disease-free survival duration. Importantly, blocking the Wnt5a/FZD2 signal transduction not only diminished the activation of non-canonical Wnt signaling but also suppressed the expression and function of constitutively activated androgen receptor (AR) and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays a critical role in promoting enzalutamide resistance and that targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.Treatment-emergent neuroendocrine prostate cancer often occurs after AR-tarted therapies. Thus, my research further investigated the emergence of neural lineage features in enzalutamide-resistant prostate cancer. Ninety-five-gene signature of neural lineage (NLS) was identified from C4-2B MDVR and neuroendocrine prostate cancer patient databases. These NLS genes positively correlate with conventional NE markers such

Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.

The molecular mechanisms underlying the conspecific cue-mediated larval settlement in Crassostrea gigas is not yet fully understood. In this study, we described and compared the transcriptomes of competent pediveligers (Pedi) and conspecific cue-induced postlarvae (PL). A total of 2383 candidate transcripts were identified: 740 upregulated and 1643 downregulated transcripts, after settlement. Gene Ontology analysis revealed active chitin binding, calcium ion binding, and extracellular region processes in both stages. Results showed that the differential expression trend of six candidate transcripts were consistent between the quantitative real-time PCR and transcriptome data. The differential transcript expression related to shell formation showed closely linked dynamics with a gene regulatory network that may involve the interplay of various hormone receptors, neurotransmitters, and neuropeptide receptors working together in a concerted way in the Pedi and PL stages. Our results highlight the transcriptome dynamics underlying the settlement of oysters on conspecific adult shells and demonstrate the potential use of this cue as an attractant for wild and hatchery-grown oyster larval attachment on artificial substrates. It also suggests the possible involvement of an ecdysone signal pathway that may be linked to a neuroendocrine-biomineralization crosstalk in C. gigas settlement., Diversity, 14 (7), art. no. 559; 2022

The molecular mechanisms underlying the conspecific cue-mediated larval settlement in Crassostrea gigas is not yet fully understood. In this study, we described and compared the tran-scriptomes of competent pediveligers (Pedi) and conspecific cue-induced postlarvae (PL). A total of 2383 candidate transcripts were identified: 740 upregulated and 1643 downregulated transcripts, after settlement. Gene Ontology analysis revealed active chitin binding, calcium ion binding, and extracellular region processes in both stages. Results showed that the differential expression trend of six candidate transcripts were consistent between the quantitative real-time PCR and transcriptome data. The differential transcript expression related to shell formation showed closely linked dynam-ics with a gene regulatory network that may involve the interplay of various hormone receptors, neurotransmitters, and neuropeptide receptors working together in a concerted way in the Pedi and PL stages. Our results highlight the transcriptome dynamics underlying the settlement of oysters on conspecific adult shells and demonstrate the potential use of this cue as an attractant for wild and hatchery-grown oyster larval attachment on artificial substrates. It also suggests the possible in-volvement of an ecdysone signal pathway that may be linked to a neuroendocrine-biomineralization crosstalk in C. gigas settlement., Annals of Transplantation, 27, art. no. e936371; 2022

Sinonasal malignancies constitute 3% of head and neck cancers, with squamous cell carcinoma (SCC) the most common histology. Neuroendocrine carcinomas (NEC) are rare, with a subset showing neuroendocrine carcinoma and a non-neuroendocrine component. The pathogenesis of these combined tumors is largely unknown, and TP53 driver mutations may play a role. A database search for combined NEC was performed across two institutions (UNM and UCSF) spanning 15 years. Excluding NUT midline carcinoma, 3 cases met inclusion criteria. All were morphologically NEC + SCC and underwent a comprehensive immunohistochemical evaluation. Tumors demonstrated two components histologically: moderately to poorly differentiated SCC and high-grade NEC. Divergent differentiation was confirmed with lineage-specific markers. Only one patient received neoadjuvant chemotherapy prior to surgery, with a remarkable response (a marked decrease in the size of the primary lesion and resolution of liver metastases). Immunohistochemical staining for p53 was increased in 2 of 3 cases (both components), suggesting a role in the carcinogenesis of these tumors. Aberrant expression of beta-catenin was not identified. One case tested positive for p16, which can be seen in high grade NECs due to inactivation of Rb gene. Additionally, both cases with a small cell NEC component expressed PD-L1, suggesting that immunotherapy may be an effective treatment. Findings in this study support the role of p53 mutation in a subset of combined NEC + SCC of the sinonasal tract. Recognition of this rare entity is essential for optimal management of these aggressive neoplasms.

Neuroendocrine tumors are neoplasms that usually have a malignant clinical behavior. They arise from enterochromaffin-like and/or gastrin-producing cells. According to their anatomical location they can be classified as foregut tumors (affecting stomach, duodenum, lungs and pancreas), midgut tumors (affecting distal portion of the duodenum) and hindgut tumors (affecting transverse colon to rectum). Carcinoid syndrome, occurring in half of the cases at the time of diagnosis, is characterized by episodes of diarrhea, tachycardia, hypotension, flushing (due to telangiectasia), and heart valve disease depending on their severity. On the other hand, the carcinoid crisis, a rare complication that is related to episodes of shock, occur as a consequence of the release of vasoactive amines into the systemic circulation after a triggering event. Here we describe a case of a male patient with a history of neuroendocrine neoplasm, who after embolization of hepatic metastatic lesions presented a carcinoid crisis, ending with a vasodilatory shock, refractory to conventional treatment including octreotide and vasopressors, which resulted in the death of the patient. A discussion of the clinical report and a review of the available literature are presented, including the epidemiology, pathogenesis, diagnosis, clinical manifestations and treatment of this entity., Los tumores neuroendocrinos son neoplasias que suelen tener un comportamiento clínico maligno, son provenientes de células entero cromafines y/o células productoras de gastrina. Según su origen anatómico, se clasifican en tumores del intestino anterior (comprometen estómago, duodeno, pulmones y páncreas), intestino medio (parte distal del duodeno) e intestino posterior (colon transverso hasta el recto). El síndrome carcinoide, presente en la mitad de los casos al momento del diagnóstico, se caracteriza por desencadenar episodios de diarrea, taquicardia, hipotensión, rubor (por el desarrollo de telangiectasias), y según la gravedad, valvulopatías cardiacas. Por otro lado, la crisis carcinoide, una complicación infrecuente, está relacionada con episodios de choque, que cuando ocurren son consecuencia de la liberación en la circulación sistémica de aminas vasoactivas, posterior a un evento desencadenante. A continuación, se presenta el caso de un paciente masculino con antecedente de un tumor neuroendocrino de intestino delgado, quien luego de ser llevado a embolización de metástasis hepáticas, presentó una crisis carcinoide, y finalmente un choque distributivo refractario a tratamientos convencionales, incluyendo octreotide y vasopresores, que culminó con la muerte del paciente. Se realiza la discusión del caso clínico y la presentación de la literatura disponible, donde se describe la epidemiología, patogénesis, diagnóstico, clínica y tratamiento de esta entidad.

Resistance to androgen receptor (AR) targeted therapies remains as the main reason for most prostate cancer related deaths. Lineage plasticity resulting in altered, treatment insensitive prostate tumor cell phenotypes such neuroendocrine differentiated prostate cancer is a common manifestation within resistant tumors upon AR-targeted therapies. The mechanisms responsible for lineage plasticity in prostate cancer remain incompletely understood. Here we demonstrate that the enzalutamide resistant MDVR cell line possesses lineage plastic characteristics associated with overexpression of the Wnt transporter Wntless (WLS). Furthermore, we present evidence that overexpression of WLS is common in varying cell line models of lineage plastic prostate cancer, is higher in neuroendocrine patient samples, and positively correlates with the neuroendocrine marker SYP in clinical data. Targeting WLS in lineage plastic cellular models reduces viability and represses lineage plasticity associated gene expression. Our study provides insight into the importance of WLS to the development of lethal resistant prostate cancer and provides a potential target for the treatment of advanced disease.

Purpose: Grade 3 neuroendocrine tumor (NET G3) is a novel pathologic category within gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NENs) but its clinical behavior and therapeutic management still remain challenging. Prognostic and predictive factors aiding NET G3 management are needed. Patients and methods: We performed a retrospective analysis from 2015 to 2020 of all patients with > 20% Ki-67, well-differentiated NETs evaluated within our NEN-dedicated multidisciplinary team. We divided the sample according the timing of NET G3 diagnosis, the radiotracers distribution and Ki-67. We analyzed the correlation between these NET G3 features and clinical outcomes. Results: Among 3238 multidisciplinary discussion reports, we selected 55 patients, 48 from GEP and 7 from an occult GEP origin. In 45 patients, NET G3 diagnosis occurred at the beginning of clinical history (upfront-NET G3), whereas in 10, during the NET G1-G2 clinical history (late-NET G3). Patients with ≤ 30% (34/55) vs. > 30% Ki-67 (21/55) had a better overall survival (OS) (p = 0.042); patients with a homogeneous vs. inhomogeneous/negative 68Gallium(68Ga)-DOTA-Peptide Positron Emission Tomography (PET)/computed tomography (CT) showed a trend to a better OS, and a significant better progression-free survival (PFS) (p = 0.033). A better OS was observed for negative/inhomogeneous vs. homogeneous 18-fluorodeoxyglucose (18FDG)-PET/CT (p = 0.027). A trend to a better OS was reported in late- vs. upfront-NET G3, while the latter showed a significantly better response rate (RR) (p = 0.048). Conclusion: Our findings suggested that Ki-67 cutoff, functional imaging and the timing to NET G3 diagnosis may help clinicians in more accurate selection of NET G3 management. Prospective studies are needed.

Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.

Affective immunology of the skin is a growing area; however, established protocols for measuring individual differences in cutaneous inflammation are lacking. To address this, we present a preliminary validation of Precision Implementation of Minimal Erythema Dose (PI-MED) testing as a method for measuring cutaneous inflammation. PI-MED is a recently adapted protocol, optimized for reproducibility and individual differences research, that uses ultraviolet (UV) light to evoke cutaneous erythema, or inflammatory skin reddening. PI-MED's novel UV dosage schedule produces standardized erythema responses across different skin pigmentation types and shows strong internal consistency within person and good test-retest reliability across 8-10 weeks. In line with predictions, increased PI-MED erythema was associated with heightened anhedonia, across several measures, beyond influences of non-affective covariates. While future work should further refine the dosage schedule for the lightest and darkest skin types, overall, evidence supports PI-MED as a protocol for inducing and measuring individual differences in cutaneous inflammation. Further, PI-MED-induced erythema can expand psychoneuroimmunology research by offering a complementary assessment for general inflammatory tone. This work adds to a growing body of evidence demonstrating a distinct relationship between inflammation and anhedonia.

Objective: To study associations between maternal stress during pregnancy and reproductive function in young men.Design: A cohort study nested in a population-based birth cohort.Setting: Not applicable.Patients: Young men (n = 1,052; response rate, 19%) participated in the Fetal Programming of Semen Quality cohort from 2017 to 2019. They were recruited from pregnancies in the Danish National Birth Cohort (1996-2001). The men completed an online questionnaire, clinical examination, and collection of blood and semen samples.Exposures: Information on maternal life and emotional stresses was available from a telephone interview covering the interval from the beginning of pregnancy to approximately gestational week 30.Main Outcome Measure(s): We applied negative binomial, linear, and logistic regression to examine associations between life and emotional stress scores (range, 0-18) and reproductive function. The primary outcomes were measures of semen quality, and the secondary outcomes included reproductive hormone levels and testicular volume.Result(s): Overall, we observed no negative associations between maternal life or emotional stress and male reproductive function. Maternal emotional stress was associated with higher total sperm count (16% difference; 95% confidence interval [CI], 1-33), serum estradiol (11% difference; 95% CI, 2-21), and calculated free testosterone (b = 17.8; 95% CI, 1.26-34.3). The results were robust to inverse probability weighting introduced to account for selection.Conclusion(s): Although our findings may appear reassuring, further efforts to validate the measures of stress during pregnancy and improve our understanding of the full spectrum of fetal stress exposures and consequences for health later in life are needed. ((C) 2022 by American Society for Reproductive Medicine.)

BACKGROUNDThe capacity of posttraumatic stress disorder (PTSD) to occur with delayed onset has been documented in several systematic reviews and meta-analyses. Neurobiological models of PTSD may provide insight into the mechanisms underlying the progressive increase in PTSD symptoms over time as well as into occasional occurrences of long-delayed PTSD with few prodromal symptoms.AIMTo obtain an overview of key concepts explaining and types of evidence supporting neurobiological underpinnings of delayed PTSD.METHODSA scoping review of studies reporting neurobiological findings relevant to delayed PTSD was performed, which included 38 studies in the qualitative synthesis.RESULTSNeurobiological mechanisms underlying PTSD symptoms, onset, and course involve several interconnected systems. Neural mechanisms involve the neurocircuitry of fear, comprising several structures, such as the hippocampus, amygdala, and prefrontal cortex, that are amenable to time-dependent increases in activity through sensitization and kindling. Neural network models explain generalization of the fear response. Neuroendocrine mechanisms consist of autonomic nervous system and hypothalamic-pituitary-adrenocortical axis responses, both of which may be involved in sensitization to stress. Neuroinflammatory mechanisms are characterized by immune activation, which is sometimes due to the effects of traumatic brain injury. Finally, neurobehavioral/contextual mechanisms involve the effects of intervening stressors and mental and physical disorder comorbidities, and these may be particularly relevant in cases of long-delayed PTSD.CONCLUSIONThus, delayed PTSD may result from multiple underlying neurobiological mechanisms that may influence the likelihood of developing prodromal symptoms preceding the onset of full-blown PTSD.

Neuroendocrine tumors (NETs) are more commonly slow-growing, therefore patients often receive chronic systemic therapies for tumor growth control and preservation of quality of life. Metronomic chemotherapy (mCT) is in line with this goal as it leads to stabilization of tumor growth over time without severe systemic toxicity. This is a retrospective analysis of patients with metastatic NETs receiving metronomic capecitabine (mCAP) or temozolomide (mTEM), at a NET-referral center. The aims of the study were to explore activity and safety of mCT and relationships between some characteristics of the patient population and clinical outcomes. Among a total of 67 patients with metastatic well or moderately differentiated (W/M-D) NETs, mostly gastroenteropancreatic (GEP) and nonfunctioning, 1.2 years (95% CI: 0.8–1.8) median progression-free survival (mPFS), and 3.0 years (95% CI: 2.3–4.9) median overall survival (mOS) were observed. Disease control rate was 85%. Grade 3 adverse events occurred in 15% of patients in mCAP and 13% in mTEM, and were mostly hematological and gastrointestinal. At univariate and multivariate analysis none of the variables analyzed (treatment regimen, sex, age at diagnosis, site of primary tumor and metastases, number of previous mCT lines, baseline tumor status before mCT, Ki67 value) were significantly correlated to OS and PFS. Our retrospective study suggested that mCAP and mTEM can be active and well tolerated in patients with metastatic W/M-D NETs, irrespective of the primary site, site of metastases, line of treatment and baseline tumor status.

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib.

Pulmonary carcinoid tumors are uncommon neuroendocrine tumors that rarely metastasize to the skin. We report the case of a 71-year-old woman with a longstanding history of primary atypical pulmonary carcinoid tumor who presented with a new tender cutaneous nodule. Immunostaining of the nodule was consistent with metastatic atypical carcinoid tumor of the skin including positive staining for neuroendocrine markers chromogranin and synaptophysin. Dermatologists should consider cutaneous neuroendocrine metastasis when evaluating new nodules in patients with stable pulmonary carcinoid tumors or in those with concomitant concerning respiratory symptoms.

Neuroendocrine conditions (illnesses impacting the relationship between the nervous system and hormone function) are complex, often manifesting as overlapping layers of physical, cognitive, and emotional symptoms. As such, these conditions are highly specialized and often difficult to diagnose, treat, and receive adequate social support for. This project is a mixed-methods investigation of neuroendocrine support groups on Facebook, wherein I examine the difficulty of identifying and finding help for these nebulous neuroendocrine experiences as they slip fluidly between chemical, emotional, cognitive, situational, and social planes. Drawing on autoethnographic accounts of my own patient experience, ethnographic observations of Facebook support communities, and in-depth interviews with patient advocates and Facebook group administrators, I ask how people make sense of the embodied hormonal experiences that biomedicine might not provide satisfying answers for, and how neuroendocrine patients utilize online communities to help parse mind-body experiences that are deeply felt but also invisible, mysterious, and easily misunderstood.Part One — Facts — focuses on evidence and medical legitimacy: how people use Facebook support communities to plug the informational gaps in their own diagnosis and treatment paths, and the effects of these informational exchanges on patients and their social networks. Part Two — Feelings — focuses on the slipperiness between cognitive, emotional, and interpersonal experiences of neuroendocrine illness, and how patients conceptualize or compartmentalize their experiences to suit their individual needs. I suggest that facts and feelings are equally malleable — bended toward a variety of strategic, emotional, and social ends.

Though relatively rare in dogs, prostate cancer (PCa) is the most common non-cutaneous cancer in men. Human and canine prostate glands share many functional, anatomical and physiological features. Due to these similarities, canine PCa has been proposed as a model for PCa in men. PCa is typically androgen-dependent at diagnosis in men and for this reason, androgen deprivation therapies (ADT) are important treatments for advanced PCa in men. In contrast, there is some evidence that PCa is diagnosed more commonly in castrate dogs, at which point, limited therapeutic options are available. In men, a major limitation of current ADT is that progression to a lethal and incurable form of PCa, termed castrate-resistant prostate cancer (CRPC), is common. There is, therefore, an urgent need for a better understanding of the mechanism of PCa initiation and progression to CRPC to enable the development of novel therapeutic approaches. This review focuses on the functional, physiological, endocrine and histopathological similarities and differences in the prostate gland of these species. In particular, we focus on common physiological roles for androgen signalling in the prostate of men and dogs, we review the short- and longer-term effects of castration on PCa incidence and progression in the dog and relate how this knowledge may be relevant to understanding the mechanisms of CRPC in men.

About 1-3% of all new cases of lung cancer are large cell neuroendocrine carcinoma (LCNEC). This is an aggressive form of lung cancer; patients with metastatic disease have an average of 4-9 months to live after diagnosis. The treatment for them currently consists of chemotherapy as we also use for other forms of lung cancer. This dissertation studied similarities and differences between LCNEC and other forms of (lung) cancer. Through more clarity about these similarities and differences, it can be better predicted to which type of treatment LCNEC patients will respond well. Also, different subgroups of LCNEC are distinguished. Patients in these subgroups may also benefit from a slightly different treatment. LCNEC appears to be a form of lung cancer with unique characteristics, but also with a clear overlap with other forms of lung cancer.

We report the impact of 177Lu-DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors often find burdensome. Methods: All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial (177Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], n = 117; high-dose octreotide LAR, n = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Results: Patients (intent-to-treat) who received 177Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For 177Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 d per 4 wk, respectively, compared with 0.99, 1.44, and 2.54 d for high-dose octreotide LAR. The mean differences were 3.11 d (95% CI, 1.35–4.88; P = 0.0007) for abdominal pain, 3.11 d (1.18–5.04; P = 0.0017) for diarrhea, and 1.98 d (0.08–3.88; P = 0.0413) for flushing, favoring 177Lu-DOTATATE. A positive repeated-measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. Conclusion: In addition to efficacy and quality-of-life benefits, symptom diaries from NETTER-1 demonstrated that treatment with 177Lu-DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut neuroendocrine tumors, compared with high-dose octreotide LAR, supporting a beneficial effect of 177Lu-DOTATATE on health-related quality of life., Title in Web of Science: Symptom Diaries of Patients with Midgut Neuroendocrine Tumors Treated with Lu-177-DOTATATE

BackgroundPrimary small cell carcinoma of the pancreas (SCCP) is a rare malignant neuroendocrine carcinoma (NEC). Typically, it presents with lymphovascular invasion as well as metastasis at the time of diagnosis which portends a dismal prognosis. Treatment is typically based on therapy used for other aggressive NECs such as small cell lung cancer. Although multimodal surgery, radiation and chemotherapy may improve prognosis, the outcome generally remains poor.Case presentationHere we present a primary SCCP managed with neoadjuvant multi-agent chemotherapy combined with radiotherapy and surgery CONCLUSIONS: Multi-disciplinary therapy resulted in an ongoing 28 + month radiographic complete response and overall survival.

We report the impact of 177Lu DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors (NETs) often find burdensome. Methods: All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial (177Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], n = 117; high-dose octreotide LAR, n = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Results: Patients (intent-to-treat) who received 177Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For 177Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 days per 4 weeks, respectively, compared with 0.99, 1.44, and 2.54 days for high-dose octreotide LAR. The mean differences were 3.11 days (95% confidence interval, 1.35-4.88; P = 0.0007) for abdominal pain, 3.11 days (1.18-5.04; P = 0.0017) for diarrhea, and 1.98 days (0.08-3.88; P = 0.0413) for flushing, favoring 177Lu-DOTATATE. A positive repeated measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. Conclusion: In addition to efficacy and quality of life benefits, symptom diaries from NETTER-1 demonstrated that treatment with 177Lu DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut NETs, compared with high-dose octreotide LAR, supporting a beneficial effect of 177Lu DOTATATE on HRQoL.

BackgroundRectal neuroendocrine tumors comprise 20% of neuroendocrine tumors in the alimentary tract, but there is controversy surrounding the optimal management of this disease. The purpose of this study is to better define treatment for patients with rectal neuroendocrine tumors.MethodsUsing the National Cancer Database, we analyzed patients with rectal neuroendocrine tumors between 2004 and 2015. Patients with metastatic disease and missing treatment data were excluded. We examined overall survival stratified by tumor size, treatment type, and presence of positive lymph nodes using Kaplan-Meier analysis with log-rank test. Cox proportional hazard regression model was performed to identify factors associated with overall survival.ResultsIn total, 17,448 patients with rectal neuroendocrine tumors were identified; 16,531 of these patients met inclusion criteria. The majority of patients had tumors ≤ 10 mm (9216 patients, 79.8%), and approximately 90% underwent local excision. The probability of 5-year overall survival was significantly higher for patients with smaller tumors (≤ 10 mm: 94.1% 11-20 mm: 85.7%, > 20 mm: 71.8%; p < 0.001) and those with no positive lymph nodes (91.4% versus 53.3%, p < 0.001). The probability of 5-year overall survival differed based on treatment modality (local excision: 93.6%, radical resection: 79.1%, observation alone: 77.1%; p < 0.001). On multivariable Cox regression, when compared to local excision, radical resection was not associated with a difference in overall survival but observation alone was associated with significantly worse OS (HR = 2.750, p < 0.001).ConclusionsThere is a significant difference in overall survival between patients who underwent local excision versus observation alone. Excision of the tumor should be offered to all patients with rectal neuroendocrine tumors who are appropriate surgical candidates, regardless of the tumor size.

Care of infants is a hallmark of mammals. Whereas parental care by mothers is obligatory for offspring survival in virtually all mammals, fathers provide care for their offspring in only an estimated 5%-10% of genera. In these species, the transition into fatherhood is often accompanied by pronounced changes in males behavioral responses to young, including a reduction in aggression toward infants and an increase in nurturant behavior. The onset of fatherhood can also be associated with sensory, affective, and cognitive changes. The neuroplasticity that mediates these changes is not well understood; however, fatherhood can alter the production and survival of new neurons; function and structure of existing neurons; morphology of brain structures; and neuroendocrine signaling systems. Although these changes are thought to promote infant care by fathers, very little evidence exists to support this hypothesis; in most cases, neither the mechanisms underlying neuroplasticity in fathers nor its functional significance is known. In this paper, we review the available data on the neuroplasticity that occurs during the transition into fatherhood. We highlight gaps in our knowledge and future directions that will provide key insights into how and why fatherhood alters the structure and functioning of the male brain.

Grade 3 (G3) neuroendocrine tumors (NETs) are a novel category among digestive neuroen-docrine neoplasms, characterized by Ki-67 >20% and a well-differentiated morphology, presenting high intra-tumor heterogeneity. We aimed to explore the role of dual-tracer PET imaging (68 Gallium (Ga)-DOTATOC and18 Fluorodeoxyglucose (FDG)) as overall survival (OS) predictor in NET G3 patients. We performed a retrospective analysis in NET G3 patients treated at our institution between 2003 and 2021. Accordingly, 30 NET G3 patients were analyzed.68 Ga-DOTA-TOC and18 F-FDG uptake were assessed by tumor/non-tumor (T-nonT) ratio. We reported a slightly better OS for patients with ≥75% concordance between68 Ga-DOTA-TOC and18 F-FDG PET/CT (p = 0.42). Among patients with discordant functional imaging, we reported a better 5-y OS rate for patients with a prevalent68 Ga-DOTATOC vs.18 F-FDG PET/CT (p = 0.016). In positive18 F-FDG PET/CT cases, we reported a better OS for <4 vs. ≥4 T/non-T ratio (p = 0.021). Among upfront-NET G3 patients with concordant exams, 5-y OS rate was 83.3% (95% CI: 27.3–97.5). Among patients with discordant exams, 5-y OS rate was 81.3% (52.5–93.5), 100% for those with prevalent receptor expression, and 50% (11.1–80.4) for those with prevalent18 F-FDG uptake. Our findings suggest that dual-tracer PET/CT can be considered as a predictor of patient outcome, able to stratify NET G3 patients with poorer prognosis.

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease., SCOPUS: re.j, info:eu-repo/semantics/published

Many physiological systems rely on hormones to communicate and time cellular and tissue-level functions. Most endocrine systems are dynamic and governed by complex regulatory systems and/or feedback mechanisms to generate precise patterns and modes of hormone release in order to optimize control of physiological and cellular processes. This Special Issue focuses on hormone release patterns (ultradian, infradian, pulsatile, circadian), with a special emphasis on the hypothalamic-pituitary axis as well as melatonin release, and how these patterns of hormone secretion change during life stages and disease.

The master regulator of neuroendocrine differentiation, achaete-scute complex homolog 1 (ASCL1) defines a subgroup of lung adenocarcinoma. However, the mechanistic role of ASCL1 in lung tumorigenesis and its relation to the immune microenvironment is principally unknown. Here, the immune landscape of ASCL1-positive lung adenocarcinomas was characterized by immunohistochemistry. Furthermore, ASCL1 was transduced in mouse lung adenocarcinoma cell lines and comparative RNA-sequencing and secretome analyses were performed. The effects of ASCL1 on tumorigenesis were explored in an orthotopic syngeneic transplantation model. ASCL1-positive lung adenocarcinomas revealed lower infiltration of CD8+, CD4+, CD20+, and FOXP3+ lymphocytes and CD163+ macrophages indicating an immune desert phenotype. Ectopic ASCL1 upregulated cyclin transcript levels, stimulated cell proliferation, and enhanced tumor growth in mice. ASCL1 suppressed secretion of chemokines, including CCL20, CXCL2, CXCL10, and CXCL16, indicating effects on immune cell trafficking. In accordance with lower lymphocytes infiltration, ASCL1-positive lung adenocarcinomas demonstrated lower abundance of CXCR3-and CCR6-expressing cells. In conclusion, ASCL1 mediates its tumor-promoting effect not only through cell-autonomous signaling but also by modulating chemokine production and immune responses. These findings suggest that ASCL1-positive tumors represent a clinically relevant lung cancer entity.

[11C]5-Hydroxy-tryptophan ([11C]5-HTP) is a Positron Emission Tomography marker for serotonergic biosynthesis and degradation, with use in imaging of neuroendocrine tumors and recently also the endocrine pancreas in diabetes. In order to further develop [11C]5-HTP as a quantitative in vivo tool for understanding the mechanisms of serotonin signaling in human pancreas, we aimed to develop a kinetic modeling approach sensitive for changes in serotonin biosynthesis, retention and degradation. Cynomolgus monkeys were examined by [11C]5-HTP PET/CT, either at baseline (n=9) or following intravenous pretreatment with 3 mg/kg carbidopa (Dopa Decarboxylase inhibitor, n=3) or 2 mg/kg clorgyline (Monoamine Oxidase-A inhibitor, n=5). The dynamic tissue uptake was analysed by a 2-tissue compartment model including an efflux mechanism from the second tissue compartment (2TC kloss), which theoretically reproduces the known processing of 5-HTP in neuroendocrine cells. The 2TC kloss model could accurately describe all three modes of tissue kinetics depending on the pretreatment regiment. Rate constant k3 (corresponding to DDC activity) and the macro-parameter Flux (Ki) was decreased (P<0.05) by carbidopa pretreatment, while k2 (corresponding to cellular washout of intact [11C]5-HTP) was increased (P<0.05). The efflux parameter kloss (corresponding to MAO-A activity) was decreased (P<0.05) by pretreatment of clorgyline, while the macro-parameter Flux/Efflux ratio (Ki/kloss) was increased (P<0.0001). We present a compartment model analysis method that can quantitatively assess in vivo pharmacological interactions with several of the key enzymatic steps of the serotonergic biosynthesis in pancreas.

Purpose Ectopic Cushing’s syndrome (ECS) caused by an ACTH secreting neuroendocrine neoplasm (NEN) is a rare and challenging condition. We aimed to detect predictive and prognostic parameters for ECS patients identified from a retrospective, comprehensive cohort of NENs treated at a tertiary referral center. Methods Medical records of 886 patients with NENs were reviewed. We identified 51 patients with ECS (33 females/18 men); mean age 52 ± 15 years (SD). Clinical parameters including symptoms, biochemical markers, and survival were extracted and further analyzed. Results The primary tumor was located in the thorax (n = 28) or pancreas (n = 15) or was of unknown primary origin (n = 8). In 30 patients, tumor and ECS were diagnosed simultaneously. In 12 patients, the NEN diagnosis preceded ECS development, with a median time of 43.5 months (range: 9–96), and 10 of these showed radiological tumor progression at ECS diagnosis. Twenty-one patients had multiple hormone secretion, which correlated with shorter overall survival (OS), p = 0.012 (HR 2.4 (95% CI 1.2–4.9)), as did high morning cortisol, p = 0.037 (HR 2.3 (1.0–5.2)), higher tumor grade, p = 0.044 (HR 2.3 (1.0–5.1)), and diabetes, p = 0.050 (HR 2.4 (1.0–6.0)). Conclusions Multiple hormone secretion, high morning cortisol, higher tumor grade, and diabetes were correlated with shorter OS. Development of ECS in patients with a non-functioning NEN may indicate tumor progression. Multiple hormone secretion should be considered as a bad prognostic sign in ECS patients and should lead to intensified clinical management.

Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.