Advances in the treatment of gastroenteropancreatic neuroendocrine neoplasms with somatostatin analogs

Neuroendocrine neoplasms (NENs) include well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Somatostatin receptors (SSTRs) are highly expressed on NETs cells, and somatostatin analogs (SSAs) could bind to SSTRs with high affinities, regulating cell proliferation and hormone secretion. As many clinical trials have demonstrated the antiproliferative efficacy and safety of SSAs in metastatic gastroenteropancreatic NETs (GEP-NETs), SSAs have been recommended by multiple NEN guidelines as the first-line therapy of GEP-NETs. In recent years, more and more researches have been exploring new therapeutic possibilities of SSA in GEP-NETs, such as high-dose SSA as second-line therapy, SSA in metastatic GEP-NETs with Ki-67 > 10%, SSA as adjuvant therapy for postoperative pancreatic NETs patients, and combinations of SSA with chemotherapy or targeted therapy. In this review, we summarized the latest published or released researches and discussed new application attempts of SSA in GEP-NETs.

Review of recent advances in medical treatment for neuroendocrine neoplasms:somatostatin analogs and chemotherapy

Neuroendocrine neoplasms(NENs)are a heterogeneous group of rare tumours often producing high levels of hormones and causing symptoms.There are a number of different types of NENs.They usually arise as advanced and low/intermediate grade only in a minority of cases,as high grade.Treatment depends on which type and may include surgery,interventional radiology,and systemic treatment,including chemotherapy,somatostatin analogs,interferonα2b,peptide receptor radionuclide therapy,and only for pancreatic neuroendocrine tumors,molecular targeted agents,including everolimus and sunitinib.The aim of the article is to review the medical approaches with somatostatin analogs and chemotherapy.The treatment of NENs is mainly based on their biological characteristics of aggressiveness and functional features,such as symptoms and endocrine markers.

Advancements in medical treatment for pancreatic neuroendocrine tumors:A beacon of hope

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors(pan-NETs),emphasizing tailored approaches for specific subtypes.Cytoreductive surgery and somatostatin analogs(SSAs)play pivotal roles in managing tumors,while palliative options such as molecular targeted therapy,peptide receptor radionuclide therapy,and chemotherapy are reserved for SSA-refractory patients.Gastrinomas,insul-inomas,glucagonomas,carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies.Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research.This review underscores the evolving landscape of pan-NET treatment,offering renewed hope and improved outcomes for patients facing this complex disease.

Regression of liver metastases of occult carcinoid tumor with slow release Lanreotide therapy

Few clinical studies have demonstrated an anti-proliferative activity of somatostatin (SST) analogs in carcinoids. We report the case of a woman with liver metastases of neuroendocrine tumor and no evidence of the primary tumor. The liver metastases were characterized by high proliferation index, immunoreactiviy for somatostatin receptor (SSTR)-l, 2, 3 and 5 and positive octreoscan. Urinary 5-hydroxyindolacetic acid, serum serotonin and chromogranin A were elevated. Slow release lanreotide (SR-LAN) therapy for 3 mo controlled clinical and biochemical signs of carcinoid tumor and caused a clear-cut reduction in the diameter of two liver metastases and disappearance of another lesion, with further reduction after 6 and 18 mo. We demonstrated a clear-cut long-lasting anti-proliferative effect of SR-LAN on liver metastases of occult carcinoid with high proliferation index and immunoreactivity for SSTR-1, 2, 3, and 5. Immunohistochemistry for SSTRs could be a suitable method for the selection of patients with metastatic carcinoid that may benefit from SST analog therapy.

New therapeutic approaches to metastatic gastroenteropancreatic neuroendocrine tumors:A glimpse into the future

Neuroendocrine(NE) gastroenteropancreatic tumors are a heterogeneous group of neoplasias arising from neuroendocrine cells of the embryological gut. Their incidence have increased significantly over the past 3 decades probably due to the improvements in imaging and diagnosis. The recent advances in molecular biology have translated into an expansion of therapeutic approaches to these patients. Somatostatin analogs, which initially were approved for control of hormonal syndromes, have recently been proven to inhibit tumor growth. Several new drugs such as antiangiogenics and others targeting mammalian target of rapamycin pathways have been approved to treat progressive pancreatic neuroendocrine tumors(NETs) although their role in nonpancreatic is still controversial. The treatment of NETs requires a coordinated multidisciplinary approach. The management of localized NETs primarily involves surgical resection followed by surveillance. However, the treatment of unresectable and/or metastatic disease may involve a combination of surgical resection, systemic therapy, and liver-directed therapies with the goal of alleviating symptoms of peptide release and controlling tumor growth. This article will review the current therapeutic strategies for metastatic gastroenteropancreatic NETs and will take a glimpse into the future approaches.

Molecular factors,diagnosis and management of gastrointestinal tract neuroendocrine tumors:An update

The prevalence of gastrointestinal neuroendocrine tumors(GI-NETs) is increasing,and despite recent advances in their therapy,it remains inadequate in patients with advanced well-differentiated neuroendocrine tumors.These tumors present many challenges concerning the molecular basis and genomic profile,pathophysiology,clinicopathological features,histopathologic classification,diagnosis and treatment.There has been an ongoing debate on diagnostic criteria and clinical behavior,and various changes have been made over the last few years.Neuroendocrine carcinoma of the gastrointestinal system is a rare but highly malignant neoplasm that is genetically distinct from gastrointestinal system neuroendocrine tumors(NETs).The diagnosis and management have changed over the past decade.Emerging novel biomarkers and metabolic players in cancer cells are useful and promising new diagnostic tools.Progress in positron emission tomography-computerized tomography and scintigraphy with new radioactive agents(^(64)Cu-DOTATATE or ^(68)Ga-DOTATATE) replacing enough octreoscan,has improved further the current diagnostic imaging.Promising results provide targeted therapies with biological agents,new drugs,chemotherapy and immunotherapy.However,the role of surgery is important,since it is the cornerstone of management.Simultaneous resection of small bowel NETs with synchronous liver metastases is a surgical challenge.Endoscopy offers novel options not only for diagnosis but also for interventional management.The therapeutic option should be individualized based on current multidisciplinary information.

Recent trends in the treatment of well-differentiated endocrine carcinoma of the small bowel

Well-differentiated endocrine carcinomas of the small bowel are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that may cause carcinoid syndrome. However, many are clinically silent until late presentation with major effects. Initial treatment aims to control carcinoid syndrome with somatostatin analogs. Even if there is metastatic spread, surgical resection of the primitive tumor should be discussed in cases of retractile mesenteritis, small bowel ischemia or subocclusive syndrome in order to avoid any acute complication, in particular at the beginning of somatostatin analog treatment. The choice of treatment depends on the symptoms, general health of the patient, tumor burden, degree of uptake of radionuclide, histological features of the tumor, and tumor growth. Management strategies include surgery for cure (which is rarely achieved) or for cytoreduction, radiological interventions (transarterial embolization or radiofrequency ablation), and chemotherapy (interferon and somatostatin analogs). New biological agent and radionuclide targeted therapies are under investigation. Diffuse and non-evolving lesions should also be simplymonitored. Finally, it has to be emphasized that it is of the utmost importance to enroll these patients with a rare disease in prospective clinical trials assessing new therapeutic strategies.

Treatment of Zollinger-Ellison Syndrome

In this article, we have reviewed the main therapeutic measures for the treatment of Zollinger-Ellison syndrome （ZES）. Review of the literature was based on computer searches （Pub-Med, Index Medicus） and personal experiences. We have evaluated all the measures now available for treating patients with sporadic gastrinomas or gastrinomas associated with Multiple Endocrine Neoplasia Type 1, （MEN 1） including medical therapy such as antisecretory drugs and somatostatin analogs （SST）, chemotherapy and chemoembolization, and surgical procedures. In ZES patients, the best therapeutic procedure is surgery which, if radical, can be curative. Medical treatment can be the best palliative therapy and should be used, when possible, in association with surgery, in a multimodal therapeutic approach.

EFFECT OF PREOPERATIVE USE OF LONG-ACTING OCTREOTIDE ON GROWTH HORMONE SECRETING PITUITARY ADENOMA AND TRANSSPHENOIDAL SURGERY

Objective To investigate whether somatostatin analog octreotide long acting release (LAR) shrinks growth hormone (GH) secreting adenomas, and improves the results of subsequent transsphenoidal surgery. Methods Seventeen previously untreated active acromegalic patients with pituitary adenomas were treated with LAR (30 mg intramuscular injection every 28 days) for 3 months prior to transsphenoidal surgery. Clinical reaction, mean GH secretion, and tumor volume were measured under basal conditions and after LAR treatment. Results Presurgical treatment improved acromegaly symptoms and induced a significant reduction of GH under the 5 ng/mL limit in microadenoma (P < 0.05), while only 18.2% (2/11) in macroadenoma. Meanwhile, tumor shrinkage occurred in 58.8% (10/17) patients, with 1 case in the microadenoma group. All marked shrinkage (> 25%) occurred in the macroadenoma group. Statistical analysis showed tumor shrinkage caused by LAR was greater in macroadenoma group than that in microadenoma group (P < 0.05). During operation, adenoma was soft in 15 cases, with the exception of 2 cases in which the soft tumor was divided by fibrous septa, but all tumor removal was smooth. Conclusions A short term administration of preoperative LAR may induce a significant decrease in GH-secretion level and adenoma volume. Presurgical use of octreotide LAR improves surgical results especially in macroadenomas.

Primary testicular neuroendocrine tumor with liver lymph node metastasis: A case report and review of the literature

BACKGROUND Primary testicular neuroendocrine tumors(TNETs)are sporadic,accounting for only 0.23%of all testicular tumors.Few cases have been reported in the literature,and no uniform treatment protocol exists.We report a case of a primary TNET with liver lymph node metastasis diagnosed at the age of 24 years and discuss its clinicopathological features,diagnosis,differential diagnosis,treatment,and prognosis.CASE SUMMARY We report the case of a 24-year-old patient with a primary TNET with liver lymph node metastasis.The patient was found to have a right testicular swelling of about 3 cm×4 cm in size with unclear borders and no testicular pressure pain seven years ago without any examination or treatment.One month ago,an ultrasound examination was performed for persistent enlargement of the right testis,which showed an occupying lesion of the right testis approximately 110 mm×102 mm×82 mm in size.Magnetic resonance imaging scan of the testis(plain scan)showed that the right testis was an occupying lesion with inhomogeneous density and mixed signal,the boundary was still clear,and the possibility of seminoma was considered;chest X-ray and computed tomography did not show any apparent abnormalities.The patient underwent radical orchiectomy,and the pathological examination suggested a right TNET with a typical carcinoid tumor histological type.One month after the surgery,the patient received nine cycles of lanreotide chemotherapy at a dose of 90 mg/mo without adverse effects.No distant lymph node or other organ metastases were detected at follow-up.He is in good physical condition and attends regular follow-up visits.CONCLUSION Neuroendocrine tumors are rare in clinical practice,and the diagnosis mainly relies on the characteristics of microscopic tumor cells and immunohistochemical features.Treatment involves radical orchiectomy.If it is accompanied by distant lymph node metastasis and the metastatic lesion can be resected,it should be surgically removed;if it cannot be resected,growth inhibitor analog octreotide or lanreotide chemotherapy can be administered to obtain good results,with close postoperative follow-up to prevent recurrence and metastasis.

Personalized treatment of well-differentiated gastric neuroendocrine tumors based on clinicopathological classification and grading:A multicenter retrospective study

Background:The incidence of well-differentiated gastric neuroendocrine tumors(G-NET)is increasing annually,and while they have a good prognosis and low mortality rate,their high recurrence rate makes treatment options controversial.This study aims to determine the relationship between individualized treatment plans and the recurrence of G-NET.Methods:We performed a multicenter,retrospective study of 94 patients with highly differentiated G-NET and treated at Peking Union Medical College Hospital,Yantai Yuhuangding Hospital,and Beijing Zhong-Neng-Jian Hospital from November 2015 to September 2023.Risk factors for recurrence of G-NETs were investigated using chi-squared test and multifactorial logistic regression analysis.Results:After a median follow-up of 49 months,the overall recurrence rate among the 94 G-NET patients was 14%(13/94).The recurrence rates of endoscopic mucosal resection(EMR),endoscopic submucosal dissection(ESD),somatostatin analog(SSA)therapy,and surgery were 43%(6/14),10%(5/49),5%(1/22),and 11%(1/9),respectively.Post-treatment recurrence rates were significantly different(P=0.014)among four treatments(EMR,ESD,SSA,and surgery),and further subgroup comparisons revealed lower recurrence rates in the ESD and SSA groups than in the EMR group.From the second month onward,SSA therapy considerably reduced the gastrin levels from 1081.0(571.5,2472.8)pg/mL to 461.5(255.3,795.0)pg/mL(Z=-3.521,P<0.001).Both chi-squared test and multifactorial logistic regression analysis suggested that among the clinicopathological parameters studied,only the pre-treatment gastrin level(P=0.018 and 0.005)and the type of treatment(P=0.014 and 0.017)were significantly associated with G-NET recurrence.Conclusions:Individualized treatment strategies may reduce the risk of relapse after G-NET treatment.Long-term SSA therapy may be a secure and efficacious treatment option for type 1 G-NET with more than six lesions,and it substantially decreases the incidence of post-treatment recurrence.

Advances in the treatment of gastroenteropancreatic neuroendocrine neoplasms with somatostatin analogues

Neuroendocrine neoplasms(NENs)include well-differentiated neuroendocrine tumors(NETs)and poorly-differentiated neuroendocrine carcinomas(NECs).Somatostatin receptors(SSTRs)are highly expressed on NETs cells,and somatostatin analogs(SSAs)could bind to SSTRs with high affinities,regulating cell proliferation and hormone secretion.As many clinical trials have demonstrated the antiproliferative efficacy and safety of SSAs in metastatic gastroenteropancreatic NETs(GEP-NETs),SSAs have been recommended by multiple NEN guidelines as the first-line therapy of GEP-NETs.In recent years,more and more researches have been exploring new therapeutic possibilities of SSA in GEP-NETs,such as high-dose SSA as second-line therapy,SSA in metastatic GEP-NETs with Ki67>10%,SSA as adjuvant therapy for postoperative pancreatic NETs patients,and combinations of SSA with chemotherapy or targeted therapy.In this review,we summarized the latest published or released researches and discussed new application attempts of SSA in GEP-NETs.

Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma

Background： Thyrotropin-secreting pituitary adenomas （TSHomas） are a rare cause of hyperthyroidism. Somatostatin （SST） analogs work by interacting with somatostatin receptors （SSTRs）. This study aimed to evaluate short-term preoperative octreotide （OCT） use in TSHoma patients and to investigate SSTR2 and SSTR5 expression and observe structural changes in tumor tissue. Methods： We reviewed records and samples from eight TSHoma patients treated between July 2012 and July 2015. We tested immunohistochemically for SSTR2/5 expression and examined TSHoma cells for morphological changes. Signed rank sum test was used to compare the efficacy of short-term preoperative OCT treatment. Results： OCT treatment （median time： 7.9 days, range： 3-16 days; median total dose： 1.8 mg, range： 0.94.2 mg） led to significant decrease in all patients＇ thyroid hormone levels （FT3 [nmol/L]： 8.33 [7.02, 12.29] to 4.67 [3.52, 5.37] [P = 0.008]; FT4 [pmol/L]： 25.36 [21.34, 28.99] to 16.66 [14.88, 21.49] [P = 0.016]; and TSH [gU/ml]： 5.80 [4.37, 6.78] to 0.57 [0.19, 1.24] [P = 0.008]）. All the eight tumor specimens expressed high SSTR2 protein levels; 5/8 expressed high SSTRS, but 3/8 that expressed low SSTR5 presented a significantly higher TS H suppression rate （P = 0.036）. Electron microscopy showed subcellular level impairments, including clumped nuclear chromatin and reduced cytoplasmic volume. Golgi complexes were observed in the OCT-treated TSHoma specimens. Conclusions： OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.

Surgical treatment of non-functioning pancreatic neuroendocrine tumors:current controversies and challenges

There has been a rising trend in the incidence and prevalence of non-functioning pancreatic neuroendocrine tumors(NFPanNETs).While a significant number of the newly diagnosed NFPanNETs are asymptomatic,a majority of patients will present with liver metastasis(LM)at the time of diagnosis.Surgical resection remains the only curative treatment,especially for localized NFPanNETs.While a majority of small NFPanNETs are indolent,some are not.This heterogeneity in tumor biology presents the surgeon with the unique challenge of determining which patient will benefit from surgery,given the morbidity of pancreatic surgery.There has been a recent push for a more aggressive approach to the care of these patients,given the emergence of data supporting such measures.However,the risk of over or under treatment has generated immense debate amongst experts in the field.The heterogeneity of current practice guidelines and institutional practices around the world is a reflection of the disparate opinion on the management of NFPanNET.In this review,we set out to examine the evidence regarding some of the most controversial and challenging aspects of the surgical treatment of NFPanNET.We evaluate the following questions;should patients with small NFPanNETs≤2 cm in size be resected;should patients with metastatic NFPanNETs undergo surgical debulking,and should there be resection of the primary tumor in the setting of non-resectable metastatic disease?Although there are currently no Level 1 data to answer these questions conclusively,we believe that the current literature supports a more aggressive approach to the management of NFPanNET.