Octreotide-conjugated silver nanoparticles for active targeting of somatostatin receptors and their application in a nebulized rat model

Drug uptake and distribution through cell–receptor interactions are of prime interest in reducing the adverse effects and increasing the therapeutic effectiveness of delivered formulations. This study aimed to formulate silver nanoparticles (AgNPs) conjugated to somatostatin analogs for specific delivery through somatostatin receptors (SSTRs) expressed on cells and by nebulizing the prepared AgNPs formulations into lung cells for in vivo application. AgNPs were prepared using the citrate reduction method, yielding AgNPs–CTT, which was further chemically conjugated to octreotide (OCT) to form AgNPs–OCT through an amide linkage. The AgNPs–OCT formulation was coated using alginate to yield a carrier, AgNPs–OCT–Alg, feasible for drug delivery through nebulization. AgNPs were uniform in size with an acceptable range of zeta potential. Furthermore, the concentrations of AgNP formulations were found safe for the model cell lines used, and cell proliferation was significantly reduced in a dose-dependent manner (p < 0.05). In the healthy lung tissues, AgNPs–OCT–Alg accumulated at a concentration of 0.416 ± 5.7 mg/kgtissue, as determined via inductively coupled plasma optical emission spectrometry. This study established the accumulation of AgNPs, specifically the AgNPs–OCT–Alg, in lung tissues, and substantiated the active, specific, and selective targeting of SSTRs at pulmonary sites. The anticancer efficacy of the formulations was in vitro tested and confirmed in the MCF-7 cell lines. Owing to the delivery suitability and cytotoxic effects of the AgNPs–OCT–Alg formulation, it is a potential drug delivery formulation for lung cancer therapy in the future.

[177Lu]Lu-DOTA-TATE versus standard of care in adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs): a cost-consequence analysis from an Italian hospital perspective

Purpose To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs). Methods We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin. Results In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus. Conclusions [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1–G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making.

Modern principles of diagnosis and treatment of patients with neuroendocrine carcinoma of the prostate

Background. Prostate cancer (PCa) is well-known as the 2nd leading cause of death from malignant neoplasms among the males from developed countries. One of the variants of the disease - neuroendocrine carcinoma of the prostate (NECP) -manifests itself as the form of castration-resistant PCa. Distinctive manifestations of NECP include a low level of serum prostate specific antigen (PSA), a high potential rate of metastasis, and resistance to hormone replacement therapy. There are very few medical publications on the possibilities of diagnosis and therapy of this type of tumor.The objective of the study is to review the current foundations of pathogenesis, methods of diagnosis and treatment of patients with NECP.Materials and methods. The data of modern medical literature from the PubMed/Crossref archives, from the Elsevier and Scopus databases for 1991-2020 were studied. The materials on the epidemiology and pathogenesis of NECP, as well as the methods of diagnosis and treatment of patients with this pathology are summarized. A comparative analysis of the levels of neuroendocrine markers in castration-resistant and localized forms of PCa was carried out. The schemes of combination therapy of NECP with the use of somatostatin analogs are considered.Results. The detection rate of NECP is reduced due to the blurred clinical picture and morphological characteristics similar to poorly differentiated carcinoma. The basis for the diagnosis of NECP is the determination of the levels of neuronal markers - chromogranin A, neuron-specific enolase, and a number of potentially mitogenic hormones, including PTHrP, NT, serotonin, bombesin, calcitonin, and thyroid-stimulating hormone. The worst prognosis was observed in patients with initially high levels of chromogranin A, which emphasizes the high significance of this indicator for monitoring NECP. The drug of choice in the treatment of patients with this pathology is the somatostatin analogue octreotide-depot, the use of which in combination with hormone replacement therapy leads to stabilization of PCa in 50 % of cases. During therapy with an analogue of somatostatin alone or in cases of tumor progression against the background of chemotherapy, a decrease in PSA level is noted in 50-60 % of cases, and PSA level stabilization - in 41.7-53.3 %.Conclusion. We founded an insufficient number of randomized clinical trials of NECP, therefore, the prognosis of the development of this pathology remains completely unclear. The use of somatostatin analogues, along with targeted therapy, is the main choice of therapy for NECP, but requires further study in the program of randomized trials. If a positive result is obtained, it will be possible to use somatostatin analogs more widely to improve the quality and increase the life expectancy of patients with NECP.

Multicenter Analysis of Presacral Neuroendocrine Neoplasms—Clinicopathological Characterization and Treatment Outcomes of a Rare Disease

Background and AimsNeuroendocrine neoplasms (NENs) of the presacral space are an extremely rare disease entity with largely unknown outcome and no established standard of care treatment. Therefore, we wanted to analyze clinical presentation, histopathological findings, treatment outcomes, and prognosis in a multicentric patient cohort.MethodsWe searched local databases of six German NEN centers for patients with presacral NEN. Retrospective descriptive analyses of age, sex, stage at diagnosis, symptoms, grade, immunohistochemical investigations, biomarkers, treatment, and treatment outcome were performed. Kaplan–Meier analysis was used to determine median overall survival.ResultsWe identified 17 patients (11 female, 6 male) with a median age of 50 years (range, 35–66) at diagnosis. Twelve cases presented initially with distant metastases including bone metastases in nine cases. On pathological review the majority of patients had well-differentiated G2 tumors. Immunohistochemical profile resembled rectal NENs. All but one patient had non-functioning tumors. Somatostatin receptor imaging was positive in 14 of 15 investigated cases. Eight patients were treated surgically including palliative resections; 14 patients received somatostatin analogs with limited efficacy. With 14 PRRTs completed, 79% showed clinical benefit, whereas only one patient with neuroendocrine carcinoma (NEC) responded to chemotherapy. Treatment with everolimus in three patients was not successful, whereas cabozantinib resulted in a disease stabilization in a heavily pretreated patient. During a median observation period of 44.5 months, 6 patients died. Median overall survival was not reached.ConclusionPresacral NEN are histopathologically similar to rectal NENs. Presacral NEN should be considered as possible primary in NEN of unknown primary. The majority of tumors is non-functioning and somatostatin receptor positive. PRRT demonstrated promising activity; tyrosine kinase inhibitors warrant further investigations. Further molecular characterization and prospective evaluation of this rare tumor entity are needed.

ADVANCES IN THE NEUROSURGICAL AND COMBINED TREATMENT OF PATIENTS WITH ACROMEGALY

Aim. The study was carried out to identify and analyze the factors of a positive outcome of surgical and radiation treatment of acromegaly. Methods. The work was performed on clinical material and summarizes treatment results of 256 patients (90 males and 166 females). 86% of patients underwent surgical treatment, 14% of patients received radiation therapy during 2002–2018. Significance of factors of a positive outcome of treatment was carried out using the RStudio program. Results. The results of the study revealed that: 1. Significant factors (p <0.05) of a positive outcome of surgical treatment of acromegaly are somatostatin analogs (SSA) therapy before surgery, a small tumor size (microadenomas), and the absence of extrasellar tumor spread. 2. The most significant factor in achieving remission of acromegaly after non-radical adenomectomy is postoperative therapy with SSA (p <0.05). 3. Aggressive pituitary tumors invading surrounding structures, high baseline IGF-1 levels, unfavorable histological findings, macroadenomas, growth hormone levels above 10 μg/L before therapy, and extrasellar tumor spread were associated with less favorable outcomes of acromegaly radiation therapy (RT) (p <0.05). The most significant factor in achieving remission of acromegaly is SSA therapy after RT (p <0.05). Conclusion. Surgical treatment is the optimal primary treatment for acromegaly. Drug therapy with SSA is effective and the preferred treatment after non-radical surgery.

Somatostatin analog therapy effectiveness on the progression of polycystic kidney and liver disease: A systematic review and meta-analysis of randomized clinical trials

Background Uncertainty underlies the effectiveness of somatostatin analogues for slowing the progression of polycystic kidney or liver disease. Methods Eligible studies included randomized controlled trials (RCTs) evaluating somatostatin analog as therapy for patients with polycystic kidney disease (PKD) or polycystic liver disease (PLD) compared to placebo or standard therapy. Two reviewers independently screened studies identified from databases (MEDLINE, EMBASE, Cochrane Database), clinical trial registries, and references from pertinent articles and clinical practice guidelines. Outcome measurements were changes in total liver volume (TLV), total kidney volume (TKV), and estimated glomerular filtration rate (eGFR). Results Of 264 nonduplicate studies screened, 10 RCTs met the inclusion criteria. The body of evidence provided estimates warranting moderate confidence. Meta-analysis of 7 RCTs including a total of 652 patients showed that somatostatin analogs are associated with a lower %TLV growth rate compared to control (mean difference, -6.37%; 95% CI -7.90 to -4.84, p<0.00001), and with a lower %TKV growth rate compared to control (mean difference, -3.66%; 95% CI -5.35 to -1.97, p<0.0001). However, it was not associated with a difference in eGFR decline (mean difference, -0.96 mL/min./1.73m2; 95% CI -2.38 to 0.46, p = 0.19). Conclusions Current body of evidence suggests that somatostatin analogs therapy slows the increase rate of TLV and TKV in patients with PKD or PLD compared to control within a 3-year follow-up period. It does not seem to have an effect on the change in eGFR. Somatostatin analogs therapy can be a promising treatment for ADPKD or ADPLD, and we need to continue to research its effectiveness for ADPKD or ADPLD.

Thyreotroop adenoom van de hypofyse: een zeldzame oorzaak van hyperthyreoïdie

TSH-secreting pituitary adenoma: a rare cause of hyperthyroidism Central hyperthyroidism is noted in a 35-year-old man with recurrent panic attacks. Thyroid-stimulating hormone-secreting pituitary adenoma (TSH-secreting adenoma) is found to be the underlying etiology. A pituitary adenomectomy is carried out, with regression of the symptoms and hyperthyroidism. TSH-secreting adenomas are rare and cause hyperthyroidism due to autonomous TSH secretion. In addition to hyperthyroidism, dysfunction of other pituitary axes and neurological problems due to local compression may also be present. Biochemically, TSH adenoma is characterized by elevated levels of thyroid hormones without suppression of the TSH concentration. After analytical interference has been ruled out, additional biochemical and radiological investigations are necessary in the differential diagnosis and to establish diagnostic certainty. Neurosurgical resection is the cornerstone of the treatment, although radiotherapy and somatostatin analogs may also be considered.

Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Patients’ satisfaction with long-acting injectable somatostatin analog therapy for neuroendocrine tumors

Background Long-acting somatostatin analogs (LA SSAs) are approved and recommended for the treatment of patients with advanced neuroendocrine tumors (NETs). Given the long duration of therapy and differences in administration routes, it is important to understand patients’ experiences with receiving LA SSA injections. Methods We conducted a serial survey, informed by qualitative interviews with eight patients treated with LA SSAs and two nurses who administer LA SSA injections, among patients undergoing LA SSA treatment over a 28-day period (administered at baseline and 14 days and 28 days after injection). Eligible patients, recruited by the Carcinoid Cancer Foundation, self-reported having received an LA SSA injection for physician-diagnosed NET within the 5 days before the survey. Results 202 patients completed the survey at baseline (82 receiving lanreotide and 120 receiving octreotide), 148 at day 14, and 124 at day 28. Patients reported consistently high satisfaction levels with their most recent LA SSA injection (91.1% at baseline, 85.1% at day 14, and 85.5% at day 28); 68.8% reported that their injection experience differed based on the nursing staff administering the injection. Conclusions Satisfaction with LA SSA injections is high among patients in this population, and specific experiences with LA SSA injections varied based on the nursing staff administering the injection. Evaluations of patients’ experiences and satisfaction with treatment are increasingly important as patients take more active roles in decision-making for their treatment pathways.