Nonfunctioning Tumors Research Articles

Quantitative Assessment of Visual Field Recovery Following Transspheniodal Pituitary Adenoma Excision and its Time Course

Background: Pituitary adenomas are a significant subset of intracranial tumors, constituting approximately 10-15% of all primary brain tumors. These benign tumors often lead to various clinical symptoms, including hormonal imbalances and visual field defects due to optic chiasm compression. The transsphenoidal approach for pituitary adenoma excision is favored for its minimal invasiveness and favorable outcomes. However, the timeline and extent of visual field recovery post-surgery remain areas of active research. Objective: This study aimed to quantitatively assess and track visual field recovery in patients following transsphenoidal pituitary adenoma excision and to identify factors influencing the recovery process. Methods: This descriptive observational study was conducted at the Department of Neurosurgery, Pakistan Institute of Medical Sciences (PIMS), Islamabad, from June 16, 2023, to March 31, 2024. Forty-six consecutive patients, aged 18-70 years, who underwent transsphenoidal pituitary adenoma excision and had documented visual field impairments, were included. Exclusion criteria were previous pituitary surgery, pre-existing visual field abnormalities not attributable to pituitary adenoma, and inability to perform visual field testing. Preoperative visual field measurements were taken within two weeks before surgery using Humphrey visual field testing. Postoperative evaluations were performed immediately after surgery (within 48 hours), and at one month, two months, and three months. Visual field indices, including mean deviation (MD) and pattern standard deviation (PSD), were recorded. Data were analyzed using SPSS version 25, with descriptive statistics for patient demographics and tumor characteristics, and inferential statistics (Student's t-test and chi-square test) for comparing visual field indices. Results: The study included 23 male and 23 female patients, with a mean age of 52.3 years (SD ± 8.7). Tumor size averaged 2.7 cm (SD ± 0.9). Non-functioning tumors comprised 65.2% of cases. Preoperative hormonal dysfunction was present in 39.1% of patients. Preoperative visual field indices showed a mean MD of -5.2 dB (SD ± 2.1). Visual field improvement was noted postoperatively, with mean MD values of -4.0 dB (SD ± 1.8) at 48 hours, -3.5 dB (SD ± 1.7) at one month, -2.8 dB (SD ± 1.5) at two months, and -2.2 dB (SD ± 1.3) at three months. Endoscopic surgery was performed in 82.6% of cases, with a gross total resection rate of 69.6%. Postoperative complications included CSF leaks (13%) and hypopituitarism (26.1%). Conclusion: The study demonstrated significant visual field recovery in patients following transsphenoidal pituitary adenoma excision, with notable improvements observed within the first three months post-surgery. These findings support the efficacy of the transsphenoidal approach in improving visual outcomes and highlight the importance of early intervention and comprehensive postoperative monitoring.

Are comorbidities of patients with adrenal incidentaloma tied to sex?

A recent cross-sectional study showed that both comorbidities and mortality in patients with adrenal incidentaloma (AI) are tied to sex. However, few longitudinal studies evaluated the development of arterial hypertension, hyperglycemia, dyslipidemia and bone impairment in patients with AI. The aim of this study is to analyze the impact of sex in the development of these comorbidities during long-term follow-up. We retrospectively evaluated 189 patients (120 females, 69 males) with AI, from four referral centers in Italy and Croatia. Clinical characteristics, comorbidities and cortisol after 1-mg dexamethasone suppression test (1-mg DST) were assessed at baseline and at last follow-up visit (LFUV). Median follow-up was 52 (Interquartile Range 25-86) months. The rates of arterial hypertension and hyperglycemia increased over time both in females (65.8% at baseline versus 77.8% at LFUV, p=0.002; 23.7% at baseline versus 39.6% at LFUV, p<0.001; respectively) and males (58.0% at baseline versus 69.1% at LFUV, p=0.035; 33.8% at baseline versus 54.0% at LFUV, p<0.001; respectively). Patients were stratified in two groups using 1.8 µg/dl as cut-off of cortisol following 1-mg DST: non-functional adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS). In the NFAT group (99 patients, females 62.6%), at baseline, we did not observe any difference in clinical characteristics and comorbidities between males and females. At LFUV, males showed a higher frequency of hyperglycemia than females (57.6% versus 33.9%, p=0.03). In the MACS group (89 patients, females 64.0%), at baseline, the prevalence of hypertension, hyperglycemia and dyslipidemia was similar between sexes, despite females were younger (60, IQR 55-69 versus 67.5, IQR 61-73, years; p=0.01). Moreover, females presented higher rates of bone impairment (89.3% versus 54.5%, p=0.02) than males. At LFUV, a similar sex-related pattern was observed. Patients with AI frequently develop arterial hypertension and hyperglycemia and should be periodically checked for these comorbidities, regardless of sex. In patients with MACS, the lack of difference between sexes in the frequency of cardiometabolic comorbidities despite that females are younger, and the higher frequency of bone impairment in females, suggest a sex-specific effect of cortisol.

Paraganglioma of the Thyroid Gland

Paragangliomas (PGs) are rare neuroendocrine tumor. Primary PGs are rare to be in the thyroid gland, and most of them present slowly. Enlarging thyroid nodules over several years, and most of the time, it is a nonfunctional tumor. We are presenting a rare thyroid neoplasm diagnosis as primary thyroid PG. Due to rare presentation and occurrence, thyroid PGs are frequently mistaken for other common thyroid neoplasms. It is mandatory to increase awareness of its rare expression in the thyroid and its characteristic features to prevent diagnostic and therapeutic pitfalls.

Cardiovascular disease and gender differences in non-functioning pituitary tumors: preliminary data of a prospective study

Cardiovascular disease and gender differences in non-functioning pituitary tumors: preliminary data of a prospective study

TGFBR3L gene expression and relevance for the gonadotroph non-functioning pituitary neuroendocrine tumours

TGFBR3L gene expression and relevance for the gonadotroph non-functioning pituitary neuroendocrine tumours

The novel SST3 agonist ITF2984 exerts antimitotic and proapoptotic effects in human non-functioning pituitary neuroendocrine tumor (NF-PitNET) cells

The novel SST3 agonist ITF2984 exerts antimitotic and proapoptotic effects in human non-functioning pituitary neuroendocrine tumor (NF-PitNET) cells

The incidence of cancers in patients with non-functional adrenal tumors: a swedish population-based national cohort study

The incidence of cancers in patients with non-functional adrenal tumors: a swedish population-based national cohort study

A clinicopathological study of non-functioning pituitary neuroendocrine tumours using the World Health Organization 2022 classification.

The 2022 World Health Organization (WHO) classification of pituitary neuroendocrine tumour (PitNET) supersedes the previous one in 2017 and further consolidates the role of transcription factors (TF) in the diagnosis of PitNET. Here, we investigated the clinical utility of the 2022 WHO classification, as compared to that of 2017, in a cohort of patients with non-functioning PitNET (NF-PitNET). A total of 113 NF-PitNET patients who underwent resection between 2010 and 2021, and had follow-up at Queen Mary Hospital, Hong Kong, were recruited. Surgical specimens were re-stained for the three TF: steroidogenic factor (SF-1), T-box family member TBX19 (TPIT) and POU class 1 homeobox 1 (Pit-1). The associations of different NF-PitNET subtypes with tumour-related outcomes were evaluated by logistic and Cox regression analyses. Based on the 2022 WHO classification, the majority of NF-PitNET was SF-1-lineage tumours (58.4%), followed by TPIT-lineage tumours (18.6%), tumours with no distinct lineage (16.8%) and Pit-1-lineage tumours (6.2%). Despite fewer entities than the 2017 classification, significant differences in disease-free survival were present amongst these four subtypes (Log-rank test p=0.003), specifically between SF-1-lineage PitNET and PitNET without distinct lineage (Log-rank test p<0.001). In multivariable Cox regression analysis, the subtype of PitNET without distinct lineage (HR 3.02, 95% CI 1.28-7.16, p=0.012), together with tumour volume (HR 1.04, 95% CI 1.01-1.07, p=0.017), were independent predictors of a composite of residual or recurrent disease. The 2022 WHO classification of PitNET is a clinically useful TF and lineage-based system for subtyping NF-PitNET with different tumour behaviour and prognosis.

Surgical resection of double advanced pancreatic neuroendocrine tumors with multiple renal cell carcinoma associated with von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease, an autosomal dominant genetic disorder caused by a germline mutation, is associated with non-functional and slow-growing pancreatic neuroendocrine tumor (PNET) and kidney cancer. We describe the case of a 46year-old man with a 35mm mass in the pancreatic head causing stricture of the bile duct and main pancreatic duct, a 55mm mass in the pancreatic tail causing obstruction of the splenic vein (SV), and multiple masses of > 36mm on both kidneys. We performed a two-stage resection. First, a total pancreatectomy with superior mesenteric vein (SMV) resection and reconstruction and retroperitoneoscopic right partial nephrectomy (NP) for five lesions was performed, followed by retroperitoneoscopic left partial NP of the five lesions 6months later. Postoperative histopathological examination revealed NET G2 in the pancreatic head with SMV invasion and somatostatin receptor type 2A (SSTR2A) positivity, NET G2 in the pancreatic tail showed SV invasion and negative SSTR2A, and multiple clear cell renal cell carcinomas (RCC) were also noted. Multiple liver recurrences occurred 22months after primary surgery. The patient remains alive 41months after primary surgery. Kidney cancer generally determines VHL prognosis; however, we experienced dual-advanced PNETs with a more defined prognosis than multiple RCC associated with VHL.

Inflammation-based scores in patients with pheochromocytoma.

Pheochromocytoma is associated with systemic inflammation, but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and haematological parameters - as a surrogate of inflammation - in patients with pheochromocytoma and the influence of preoperative α-blockade treatment. We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age 53 years, 64.7% females) and two control groups matched for age, sex, and body mass index (BMI): 68 patients with non-functioning adrenocortical tumors (NFAT) and 53 with essential hypertension (EAH). The complete blood count (CBC) and several inflammation-based scores [Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic-Immune-Inflammation Index (SII), Prognostic-Nutrition Index (PNI)] were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n=26) and before and after preoperative α-blockade treatment (n=29). A higher inflammatory state, as indicated by both CBC and inflammation-based scores, was observed in patients with pheochromocytoma compared to NFAT and EAH. Plasma metanephrine levels showed a positive correlation with NLR (r=0.4631), PLR (r=0.3174), SII (r=0.3709), and a negative correlation with LMR (r=0.4368) and PNI (r=0.3741), even after adjustment for age, sex, ethnicity, BMI and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (p=0.001), PLR (p=0.003), SII (p=0.004) and a concomitant increase in LMR (p=0.0002). Similarly, α-blockade treatment led to a reduction in NLR (p=0.007) and SII (p=0.03). Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade.

Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

MiRNA Signatures Related to Invasiveness and Recurrence in Patients With Non-Functioning Pituitary Neuroendocrine Tumors.

This preliminary study aimed to analyze and identify differentially expressed miRNAs in Bulgarian patients with non-functioning pituitary neuroendocrine tumors (NFPitNET). The relationship between deregulated miRNAs and tumor invasiveness, recurrence, and size was determined. Twenty patients with NFPitNET were selected and fresh pituitary tumor tissues were collected. RNA containing miRNAs were isolated using miRNAeasy mini kit and analyzed by quantitative real-time polymerase chain reaction (PCR) using LNA miRNA Cancer-Focus PCR Panel (Qiagen). Three miRNAs (miR-210-3p, miR-149-3p, and miR-29b-3p) were deregulated in invasive compared to non-invasive NFPitNETs. Differential expression of four-miRNA signatures - miRNA-17, miR-19, miR-106a, and miR-20, correlated with patient recurrence. This prospective pilot study selected a unique miRNA expression profile, that correlates with invasiveness and recurrence in non-functioning pituitary neuroendocrine tumors. Moreover, some of the selected miRNAs are reported for the first time in patients with this disease, shedding light on the molecular mechanisms involved in pituitary pathogenesis. The identified miRNAs demonstrate potential as biomarkers, deserving further investigation in a larger cohort to validate their clinical applicability.

Prevalence and Incidence of Fractures in Patients With Nonfunctional Adrenal Tumors

It is unclear whether nonfunctional adrenal tumors (NFATs) are associated with fractures. To analyze fracture frequencies in individuals with NFATs. A national retrospective cohort study was conducted in patients with NFATs diagnosed in Sweden between January 1, 2005, and December 31, 2019, and control participants without adrenal tumors followed up until death or the end of 2019. Individuals with a diagnosis of adrenal hormonal excess or previous malignant tumors were excluded. Sensitivity analyses were performed in subgroups of individuals with a combination of gallbladder, biliary tract, and pancreas diseases (for whom it was assumed that controls would also have undergone computed tomography) and 3- and 12-month survival free of malignant tumors after the NFAT diagnosis. The data were analyzed from September to November 2023. Diagnosis of NFATs. Main study outcomes were prevalence and incidence of fractures after adjustment for sex, age, and comorbidities. Secondary outcomes were fragility fractures, fractures with fall on the same level, and fracture locations (distal arm and vertebral and hip fractures). Fracture incidence after adrenalectomy was also studied. Among 20 390 patients, 12 120 (59.4%) were women, and the median (IQR) age was 66 (57-73) years; among 125 392 controls, 69 994 (55.8%) were women, and the median (IQR) age was 66 (57-73) years. Previous fractures were more common in patients diagnosed with NFATs compared with controls (4310 of 20 390 [21.1%] vs 20 323 of 125 392 [16.2%]; odds ratio [OR], 1.39; 95% CI, 1.34-1.45; adjusted OR [AOR], 1.27; 95% CI, 1.23-1.33). During the follow-up period (median [IQR], 4.9 [2.2-8.2] years), incident fractures were more common in patients with NFATs (3127 of 20 390 [15.3%] vs 16 086 of 125 392 [12.8%]; hazard ratio [HR], 1.40; 95% CI, 1.34-1.45; adjusted HR [AHR], 1.27; 95% CI, 1.22-1.33). An association between NFATs and vertebral fractures was found (AOR, 1.51; 95% CI, 1.33-1.72; AHR, 1.83; 95% CI, 1.60-2.09). In men younger than 50 years, NFATs were associated with fractures (AOR, 1.45; 95% CI, 1.21-1.74; AHR, 1.48; 95% CI, 1.20-1.82). There was no association among individuals who had undergone adrenalectomy (AHR, 1.12; 95% CI, 0.90-1.38). The association between NFATs and fractures remained significant and of similar magnitude in all sensitivity analyses. In this cohort study, NFATs were associated with fractures, particularly among younger men; thus, patients with NFATs should have bone health evaluation with appropriate treatment and monitoring, especially in younger men.

Mesenchymal Stem Cells Induce an Immunosuppressive Microenvironment in Pituitary Tumors.

The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSCs) and immune cells, among others. MSC have been isolated from different tumors and they favor tumor cell growth; however, their role in pituitary tumors (PTs) remains unknown. Herein we report the presence of MSCs in 2 adrenocorticotropin (ACTH)-secreting PTs causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF), and 2 nontumoral pituitary glands (MS). We have analyzed the transcriptomic profiles by RNA sequencing and compared MSCs in terms of their immunosuppressive effects against lymphoid T-cell and macrophage populations by means of cocultures and flow cytometry. Our transcriptomic analysis revealed molecular differences between MSCs derived from nontumoral pituitaries and MSCs derived from PTs. Two distinct subpopulations of MSC emerged: one displaying immunosuppressive properties and the other with increased proproliferative capabilities, regardless of their origin. MSCs derived from ACTH- and nonfunctioning PTs, but not those derived from nontumoral glands, significantly inhibited the proliferation of activated T cells, favored the generation of regulatory T cells, and promoted M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony-stimulating factor (M-CSF) and interleukin-10. Importantly, MSC derived from ACTH-PTs showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. This study demonstrates the presence of at least 2 MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSCs may have important implications in PT growth.

ABCD1 as a Novel Diagnostic Marker for Solid Pseudopapillary Neoplasm of the Pancreas.

The diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) can be challenging due to potential confusion with other pancreatic neoplasms, particularly pancreatic neuroendocrine tumors (NETs), using current pathological diagnostic markers. We conducted a comprehensive analysis of bulk RNA sequencing data from SPNs, NETs, and normal pancreas, followed by experimental validation. This analysis revealed an increased accumulation of peroxisomes in SPNs. Moreover, we observed significant upregulation of the peroxisome marker ABCD1 in both primary and metastatic SPN samples compared with normal pancreas and NETs. To further investigate the potential utility of ABCD1 as a diagnostic marker for SPN via immunohistochemistry staining, we conducted verification in a large-scale patient cohort with pancreatic tumors, including 127 SPN (111 primary, 16 metastatic samples), 108 NET (98 nonfunctional pancreatic neuroendocrine tumor, NF-NET, and 10 functional pancreatic neuroendocrine tumor, F-NET), 9 acinar cell carcinoma (ACC), 3 pancreatoblastoma (PB), 54 pancreatic ductal adenocarcinoma (PDAC), 20 pancreatic serous cystadenoma (SCA), 19 pancreatic mucinous cystadenoma (MCA), 12 pancreatic ductal intraepithelial neoplasia (PanIN) and 5 intraductal papillary mucinous neoplasm (IPMN) samples. Our results indicate that ABCD1 holds promise as an easily applicable diagnostic marker with exceptional efficacy (AUC=0.999, sensitivity=99.10%, specificity=100%) for differentiating SPN from NET and other pancreatic neoplasms through immunohistochemical staining.

Risk Factors for Isolated Sphenoid Sinusitis after Endoscopic Endonasal Transsphenoidal Pituitary Surgery.

(1) Background: Transsphenoidal pituitary surgery can be conducted via microscopic or endoscopic approaches, and there has been a growing preference for the latter in recent years. However, the occurrence of rare complications such as postoperative sinusitis remains inadequately documented in the existing literature. (2) Methods: To address this gap, we conducted a comprehensive retrospective analysis of medical records spanning from 2018 to 2023, focusing on patients who underwent transsphenoidal surgery for pituitary neuroendocrine tumors (formerly called pituitary adenoma). Our study encompassed detailed evaluations of pituitary function and MRI imaging pre- and postsurgery, supplemented by transnasal endoscopic follow-up assessments at the otolaryngology outpatient department. Risk factors for sinusitis were compared using univariate and multivariate logistic regression analyses. (3) Results: Out of the 203 patients included in our analysis, a subset of 17 individuals developed isolated sphenoid sinusitis within three months postoperation. Further scrutiny of the data revealed significant associations between certain factors and the occurrence of postoperative sphenoid sinusitis. Specifically, the classification of the primary tumor emerged as a notable risk factor, with patients exhibiting nonfunctioning pituitary neuroendocrine tumors with 3.71 times the odds of developing sinusitis compared to other tumor types. Additionally, postoperative cortisol levels demonstrated a significant inverse relationship, with lower cortisol levels correlating with an increased risk of sphenoid sinusitis postsurgery. (4) Conclusions: In conclusion, our findings underscore the importance of considering tumor classification and postoperative cortisol levels as potential predictors of postoperative sinusitis in patients undergoing transsphenoidal endoscopic pituitary surgery. These insights offer valuable guidance for clinicians in identifying at-risk individuals and implementing tailored preventive and management strategies to mitigate the occurrence and impact of sinusitis complications in this patient population.

499 Silent Corticotroph Staining Pituitary Neuroendocrine Tumors: Prognostic Significance in Radiosurgery

INTRODUCTION: There is conflicting evidence on the significance of adrenocorticotrophic hormone (ACTH) staining in the prognosis of nonfunctioning pituitary neuroendocrine tumors (NFpitNETs). METHODS: This retrospective, multicenter study included patients managed with SRS for NFpitNET residuals. The patients were divided into two cohorts: 1) silent corticotroph (SC) for NFpitNETs with positive ACTH immunostaining and 2) non-SC NFpitNETs. Rates of local tumor control, as well as the incidence of post-treatment pituitary and neurological dysfunction were documented. Factors associated with radiological and clinical outcomes were also analyzed. RESULTS: The cohort included 535 patients from fourteen centers with 84 (15.7%) patients harboring silent corticotroph NFpitNETs (SCs). At last follow-up, local tumor progression occurred in 11.9% of patients in the SC compared to 8.1% of patients in the non-SC cohort (p = 0.27). No statistically significant difference was noted in new-onset hypopituitarism rates (10.7% vs 15.4%, p = 0.25) or visual deficits (3.6% vs 1.1%, p = 0.088) between the two cohorts at last follow-up. When controlling for residual tumor volume, maximum dose, and patient age and gender, positive ACTH immunostaining did not have a significant correlation with local tumor progression (HR = 1.69, 95% CI = 0.8 - 3.61, p = 0.17). CONCLUSIONS: In contemporary radiosurgical practice with a single fraction dose of 8-25 Gy (median 15 Gy), ACTH immunostaining in NFpitNETs did not appear to confer a significantly reduced rate of local tumor control after SRS.

Endoscopic Ultrasound (EUS) guided Radiofrequency Ablation (RFA) in Treatment of Functional &amp; Non-Functional Pancreatic Neuroendocrine Tumors

Endoscopic Ultrasound (EUS) guided Radiofrequency Ablation (RFA) in Treatment of Functional &amp; Non-Functional Pancreatic Neuroendocrine Tumors

Prognostic significance of systemic immune-inflammation index in patients with nonfunction pancreatic neuroendocrine tumor undergoing surgical resection.

The purpose of our study was to investigate the clinical significance and prognostic role of the systemic immune-inflammation index (SII) in patients who underwent surgical resection for nonfunctioning pancreatic neuroendocrine tumors (pNETs). We conducted a retrospective analysis of 364 patients with nonfunctioning pNETs. The association between the SII level and clinical parameters was investigated. The receiver operating characteristic (ROC) curve was used to calculate the optimal SII value. Cox proportional hazard analysis was performed to evaluate the prognostic factors. Our study included 364 patients with nonfunctioning pNETs who underwent surgery. The median age was 51.0 (43.0, 59.3), and 164 (45.1%) were male. The optimal threshold of SII determined by ROC analysis was 523.95. Higher SII levels were significantly associated with older age (p = 0.001), sex (p = 0.011), tumor size (p = 0.032), and tumor grade (p = 0.002). Recurrence was observed in 70 (19.2%) patients following a median follow-up of 98 months. Univariate analysis showed that higher SII (p < 0.0001), tumor size >4 cm (p = 0.015), and G2/G3 grade (p = 0.002) were significantly associated with disease-free survival (DFS). Multivariate analysis revealed that higher SII (HR: 7.35; 95% CI: 3.44, 15.70; p < 0.0001) and G2/G3 grade (HR: 3.11; 95% CI: 1.42, 6.82; p = 0.005) remained significantly associated with tumor recurrence. Furthermore, 46 (12.6%) patients died during the follow-up. Higher SII (HR: 8.43; 95% CI: 3.19, 22.72; p < 0.0001) and G2/G3 grade (HR: 3.16; 95% CI: 1.01, 9.86; p = 0.048) were independent predictors of overall survival (OS) by multivariate analysis. In conclusion, our study revealed that a higher SII level was associated with tumor-related features (larger tumor size and advanced grade) and subsequent shorter DFS and OS in patients with nonfunctioning pNETs. These results indicated that the SII could serve as an efficient prognostic biomarker for nonfunctioning pNETs.

The Novel SSTR3 Agonist ITF2984 Exerts Antimitotic and Proapoptotic Effects in Human Non-Functioning Pituitary Neuroendocrine Tumor (NF-PitNET) Cells.

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984's antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (-40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.