Long-acting Somatostatin Analogue Research Articles

Volumetric parameters of 68[Ga]Ga-DOTA-TATE PET/CT in the prediction of response to treatment with long-acting somatostatin analogues in patients with well-differentiated NETs

Volumetric parameters of 68[Ga]Ga-DOTA-TATE PET/CT in the prediction of response to treatment with long-acting somatostatin analogues in patients with well-differentiated NETs

A challenging case of a pituitary macroadenoma and toxic thyroid adenoma with inappropriate TSH secretion.

Thyroid-stimulating hormone-secreting pituitary adenomas (TSHomas) are rare, accounting for less than 1% of all pituitary adenomas. We present a case of hyperthyroidism secondary to a likely TSHoma and coexisting functional thyroid adenoma. Laboratory errors and familial abnormalities in thyroid function tests were ruled out, and a diagnosis of the toxic thyroid adenoma was confirmed on a thyroid uptake scan. However, the triiodothyronine suppression test was contraindicated due to the patient's cardiovascular disease, and the thyrotropin-releasing hormone stimulation test, measurement of glycoprotein hormone alpha-subunit, and genetic testing were unavailable. Magnetic resonance imaging of the brain revealed a suprasellar pituitary macroadenoma measuring 40 mm × 20.3 mm × 17 mm. The patient was initiated on carbimazole; however, thyroid stimulating hormone and thyroxine levels remained elevated. The patient declined trans-sphenoidal surgery and was treated with radioactive iodine to manage the toxic thyroid adenoma, leading to reduced thyroxine levels and symptom improvement. Unfortunately, the patient passed away before long-acting somatostatin analogs became available. This case highlights the diagnostic and therapeutic challenges involved in managing thyrotoxicosis with dual etiology. Hyperthyroidism can have multiple etiologies, which can coexist in the same patient. Persistent discordant thyroid function tests warrant further investigation. The gold standard for diagnosis of TSHomas remains immunohistochemical analysis of the tumor tissue.

Challenging diagnosis of resistance to thyroid hormone in a patient with COVID-19, pituitary microadenoma and unusual response to octreotide long-acting release test.

The resistance to thyroid hormone syndrome (RTHβ) occurs uncommonly and requires a high level of clinical suspicion and specific investigations to reach a precise diagnosis and to avoid unnecessary and potentially harmful therapies. We report a case of a young male patient referred to our unit for SARS-CoV-2 infection and atrial fibrillation with elevated thyroid hormones and non-suppressed thyroid-stimulating hormone (TSH), for which antithyroid therapy was prescribed. A mood disorder was reported in the medical history. The family history was unknown as the patient was adopted. Thyroid-specific antibodies were undetectable, and thyroid ultrasound revealed a normal thyroid gland without nodules. After the resolution of SARS-CoV-2 infection, the diagnostic workup continued, and the pituitary MRI revealed a small area ascribable to a microadenoma. Due to atrial fibrillation, the execution of the T3 test was contraindicated. The octreotide long-acting release (LAR) test showed an initial reduction of free thyroid hormones levels at first administration, which was consistent with the presence of a TSH-secreting pituitary tumour, although an escape from the response was observed after the following two injections of octreotide LAR. Indeed, the genetic investigation revealed a variant in heterozygosity of the THRβ gene (Pro453Ser), thus leading to an RTHβ diagnosis, and, therefore, medical treatment with triiodothyroacetic acid was initiated. After 2 years from the SARS-CoV-2 infection, the patient continues the follow-up at our outpatient clinic, and no other medical interventions are needed. RTHβ is a rare genetic syndrome characterised by discrepant thyroid function tests and by a dissociation between the observed hormone levels and the expected patient signs and symptoms. Features of thyroid hormone deficiency in TR-ß dependent tissues (pituitary gland, hypothalamus, liver and neurosensitive epithelia), as well as thyroid hormone excess in TR-α-dependent tissues (heart, bone, skeletal muscle and brain), may coexist in the same individual. Clinical pictures can be different even when the same variant occurs, suggesting that other genetic and/or epigenetic factors may play a role in determining the patient's phenotype. Differentiating RTHβ from a TSH-secreting pituitary tumour is very difficult, especially when a concomitant pituitary adenoma is detected during diagnostic workup. The injection of long-acting somatostatin analogues can help differentiate the two conditions, but it is important to detect any interference in the dosage of thyroid hormones to avoid an incorrect diagnosis. Genetic testing is fundamental to prevent unnecessary and potentially harmful therapies. Medical treatment with triiodothyroacetic acid was demonstrated to be effective in reducing thyroid hormone excess and controlling symptoms.

Sequencing of Somatostatin-Receptor-Based Therapies in Neuroendocrine Tumor Patients.

Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to somatostatin receptors and are used for palliation of hormonal syndromes and control of tumor growth. The long-acting SSAs octreotide long-acting release and lanreotide are commonly used in the first-line metastatic setting because of their tolerable side effect profile. Radiolabeled SSAs are used both for imaging and for treatment of NETs. 177Lu-DOTATATE is a β-emitting radiolabeled SSA that has been proven to significantly improve progression-free survival among patients with progressive midgut NETs and is approved for treatment of metastatic gastroenteropancreatic NETs. A key question in management of patients with gastroenteropancreatic and lung NETs is the sequencing of 177Lu-DOTATATE in relation to other systemic treatments (such as everolimus) or liver-directed therapies. This question is particularly complicated given the heterogeneity of NETs and the near absence of randomized trials comparing active treatment options. This state-of-the-art review examines the evidence supporting use of somatostatin-receptor-targeted treatments within the larger landscape of NET therapy and offers insights regarding optimal patient selection, assessment of benefit versus risk, and treatment sequencing.

Proton-pump inhibitor-induced bone loss is preventable by concomitant use of a long-acting somatostatin analogue.

Long-term consumption of pump inhibitors causes osteoporosis. Some possible mechanisms are gastrin over-secretion and hypochlorhydria. Octreotide is a somatostatin analog that inhibits the secretion of many hormones such as gastrin. This study aimed to assess the effects of pantoprazole on the bone when used with octreotide in an animal model. Forty-eight male Wistar rats were randomly assigned into 4 groups: A) pantoprazole 3 mg/Kg/day orally; B) Sandostatin LAR 1 mg/month intramuscular injection; C) Pantoprazole and Sandostatin LAR; and D) Control group. After 90 days of the experiment, bone densitometry was done and serum and urine samples were collected for analysis. The results indicated a significant decrease in the global, spine, femur, and tibia bone mineral density (BMD) and bone mineral content (BMC) in the pantoprazole group compared to the control group (P<0.05). There was a significant increase in the levels of PTH, gastrin, and alkaline phosphatase (ALP) in the pantoprazole group compared to the control group (P<0.05). There was no significant difference in the serum levels of gastrin, PTH, ALP, and also BMD in the rats that received sandostatin+ pantoprazole or sandostatin alone, compared to the control group. This study showed that the pantoprazole-induced bone loss, through elevation of serum gastrin and PTH, was preventable by concomitant use of a long-acting somatostatin analog.

Clinical impact of unsuccessful subcutaneous administration of octreotide LAR instead of intramuscular administration in patients with metastatic gastroenteropancreatic neuroendocrine tumors.

Octreotide LAR is a long-acting somatostatin analogue (SSA) used in the management of metastatic gastroenteropancreatic neuroendocrine tumors (GEP NETs). It requires intramuscular (IM) injection. Missed IM injections cause subcutaneous nodules (SCNs) on radiologic images. We reviewed the rates of SCNs in a real-world cohort of GEP NETs receiving octreotide LAR and explored treatment outcomes. Patients commencing octreotide LAR between August 5, 2010 and March 8, 2018 at a single cancer center in Canada were identified from pharmacy records. Patients were included if they had a computed tomography (CT) scan performed at the time of progression and a preceding CT with pelvis included to enable assessment for the presence of nodules. Fisher's exact test was used to examine predictors of SCNs, and Kaplan-Meier curves summarized differences in progression free (PFS) and overall survival (OS) that were compared with log-rank tests. Of 243 patients receiving octreotide LAR, 45 had all required CT images available for central review. SCNs were found in 20/45 (44%) of patients on the last scan showing stable disease before progression and were numerically but not statistically more likely in females (OR: 2.36, 95% CI: 0.66-8.29, p = .23). There was an increased risk of SCNs in patients with a skin-to-muscle distance >38 mm (the length of an octreotide LAR needle) on CT (OR: 5.09, 95% CI: 1.39-16.6, p = .018) and a trend toward increased risk in obese patients (OR: 5.71, 95% CI: 1.26-23.4, p = .061). PFS (HR: 1.01, 95% CI: 0.56-1.78, p = .98) and OS (HR: 0.86, 95% CI: 0.41-1.8, p = .70) was similar between those with/without SCNs. In conclusion, almost half of patients receiving octreotide LAR had SCNs; however, missed administration of SSA did not appear to result in worse survival in this small study. Factors such as sex, younger age skin-to-muscle distance, and obesity may affect SCN development and should be considered when choosing an SSA.

Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days’ supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher’s tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p&lt;.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p&lt;.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Treatment Patterns of Long-Acting Somatostatin Analogs for Neuroendocrine Tumors

Background: Long-acting somatostatin analog therapy (LA-SSA) is recommended as first-line therapy for treatment of unresectable or metastatic neuroendocrine tumors (NETs). Understanding treatment sequencing and dosing patterns of LA-SSA is essential for clinical decision-making to provide value-based management of NETs. Objective: To describe treatment patterns of LA-SSA among patients with NETs and subgroups with carcinoid syndrome (CS) in the United States. Methods: This retrospective study utilized claims data from MarketScan® databases to identify patients with NETs and newly treated with LA-SSA between January 1, 2015, and October 31, 2020. Patients were stratified by index LA-SSA (lanreotide and octreotide long-acting release [LAR]). Reported 28-day doses were based on claim fields for days’ supply/drug quantity or units of service. Dose escalation was defined as increases in quantity or frequency. Continuous variables, categorical variables, and Kaplan-Meier estimated treatment durations were compared using t-tests, chi-square/Fisher’s tests, and log-rank tests, respectively. Results: The study included 241 lanreotide and 521 octreotide LAR patients. Compared with octreotide LAR patients, treatment duration was longer for lanreotide patients (median, 41.3 vs 26.8 months; log-rank p=.004). Fewer lanreotide patients received rescue treatment with short-acting octreotide (7.9% vs 14.4%; p=.011), and a first (6.2% vs 27.3%) and second dose escalation (0.8% vs 5.2%; both p&lt;.05). Among patients with doses reported, fewer lanreotide patients received above-label doses (2.5% [5/202] vs 14.4% [60/416]; p&lt;.001). Among patients who ended treatment during follow-up, fewer lanreotide patients transitioned to another LA-SSA (18.9% [17/90] vs 33.6% [92/274]; p=.008). Similar treatment patterns were observed in CS subgroups. Results for switched treatment patterns were limited due to insufficient sample sizes. Discussion: Real-world treatment patterns of LA-SSA were assessed using more recent administrative claims data. Compared with octreotide LAR patients, lanreotide patients were more likely to remain longer on initial treatment and starting dose without dose escalations and less likely to use rescue treatment and transition to another LA-SSA after discontinuation of the index treatment. Conclusions: Findings from this claims study suggest a potential clinical benefit of lanreotide in NET management.

Use of long-acting somatostatin analogue in a paediatric patient with MEN1 - a case report

Use of long-acting somatostatin analogue in a paediatric patient with MEN1 - a case report

The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

Efficacy, prognosis and influencing factors of transcatheter arterial embolization in the treatment of neuroendocrine neoplasm liver metastases

Objective: To evaluate the efficacy of transcatheter arterial embolization (TAE) in the treatment of neuroendocrine neoplasm liver metastases (NENLM), analyze the prognosis and related factors. Methods: Clinical data of NENLM patients treated with TAE in the First Affiliated Hospital of Nanjing Medical University from January 2018 to March 2022 were retrospectively analyzed. Objective response rate (ORR), disease control rate (DCR), and adverse event rate after TAE were evaluated according to the Response Evaluation Criteria In Solid Tumors and the Common Terminology Criteria for Adverse Events. The prognosis was evaluated by median overall survival (mOS) and median progression-free survival (mPFS). The survival curve was plotted by Kaplan-Meier method. Multivariate Cox regression was used to analyze prognostic factors. Results: A total of 39 NENLM patients were included in this study, aged (53.3±10.3) (23-74) years old, including 23 males and 16 females. Among them, 9 cases had functional neuroendocrine neoplasms. There were 31 cases with primary sites locating in the digestive system, 32 cases with WHO G1 and G2 primary sites, 27 cases with abundant blood supply for liver metastases and 13 cases with liver tumor load >50%. Thirty patients received treatment of long-acting somatostatin analogue(SSA). A total of 123 TAE were performed in 39 cases, with an ORR of 38.5% (15/39) and a DCR of 76.9% (30/39). There were no serious adverse events of level 4-5 during the perioperative period. The median follow-up was 38.7 (95%CI: 31.3-46.1) months, with mOS of 37.3(95%CI: 27.0-47.5) months and mPFS of 12.6 (95%CI: 7.1-18.1) months. Multivariate Cox regression analysis found that the combination of long-term SSA treatment was an influencing factor for overall survival of patients (HR=0.207, 95%CI: 0.076-0.567, P=0.002). Conclusions: TAE can effectively reduce the load of liver metastases in patients with NENLM, and the combination of long-term SSA treatment can improve the ovreall survival of patients.

Effects of somatostatin analogs on uptake of radiolabeled somatostatin analogs on imaging: a systematic review and meta-analysis.

The imaging of somatostatin receptors (SSTRs) plays a significant role in imaging neuroendocrine tumors (NETs). However, there has been no clear definition on whether it is necessary to withdraw somatostatin analogs (SSAs) before SSTRs imaging. We aimed to assess whether nonradioactive SSAs affect the uptake of radiolabeled SSAs on imaging for NETs patients. The databases of PubMed, Embase, and Web of Science (WoS) were searched until March 12, 2022 to identify eligible studies. Maximum standardized uptake values (SUVmax) in tumor and normal tissues were extracted, pooled, and compared before and after SSAs treatment. The change of tumor-to-background/liver ratio was also described. The quality of each study was assessed using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 9 articles involving 285 patients were included and 5 studies using Gallium-68-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe1-Tyr3-Thr8-octreotide (68Ga-DOTATATE) were used for pooled evaluation. We found a significantly decreased SUVmax in the liver (9.56±2.47 vs. 7.62±2.12, P=0.001) and spleen (25.74±7.14 vs. 20.39±6.07, P=0.006) after SSAs treatment whereas no significant differences were observed in the uptake of thyroid, adrenal, and pituitary gland. For either primary tumor sites or metastases, the SUVmax did not change significantly before and after SSAs treatment. The tumor-to-liver/background ratio increased following SSAs therapy. High heterogeneity was observed across the studies, mainly due to inherent diversity of study design, sample size, and scanning technique. Based on current evidence, long-acting SSAs therapy before imaging has no effect on the uptake of radiolabeled SSAs at tumor primary sites and metastatic lesions, but results in a significant reduction of uptake in the liver and spleen. These findings may implicate the unnecessary discontinuation of SSAs before radiolabeled SSAs imaging.

Quantitative uptake in 99m Tc-EDDA/HYNIC-TOC somatostatin receptor imaging - the effect of long-acting release somatostatin analogue therapy.

Withdrawal of long-acting release somatostatin analogue (LAR-SSA) treatment before somatostatin receptor imaging is based on empirical reasoning that it may block uptake at receptor sites. This study aims to quantify differences in uptake of 99m Tc-EDDA/HYNIC-TOC between patients receiving LAR-SSA and those who were not. Quantification of 177 patients (55 on LAR-SSA) imaged with 99m Tc-EDDA/HYNIC-TOC was performed, with analysis of pathological tissue and organs with physiological uptake using thresholded volumes of interest. Standardised uptake values (SUVs) and tumour/background (T/B) ratios were calculated and compared between the two patient groups. SUVs were significantly lower for physiological organ uptake for patients on LAR-SSA (e.g. spleen: SUV max 13.3 ± 5.9 versus 33.9 ± 9.0, P < 0.001); there was no significant difference for sites of pathological uptake (e.g. nodal metastases: SUV max 19.2 ± 13.0 versus 17.4 ± 11.5, P = 0.552) apart from bone metastases (SUV max 14.1 ± 13.5 versus 7.7 ± 8.0, P = 0.017) where it was significantly higher. LAR-SSA has an effect only on physiological organ uptake of 99m Tc-EDDA/HYNIC-TOC, reducing uptake. It has no significant effect on pathological uptake for most sites of primary and metastatic disease. This should be taken into account if making quantitative measurements, calculating T/B ratios or assigning Krenning Scores. There is the potential for improved dosimetric results in Peptide Receptor Radionuclide Therapy by maintaining patients on LAR-SSA.

The Influence of Long-Acting Somatostatin Analogs on 68Ga-DOTATATE Uptake in Patients With Neuroendocrine Tumors.

A high SUVmax tumor-to-liver ratio (TLR) of 68Ga-DOTATATE can be used to select patients with neuroendocrine tumors (NETs) for peptide receptor radionuclide therapy (PRRT). In addition, an SUVmax TLR ≥ 8.1 is associated with increased progression-free survival in NET patients treated with somatostatin analogs (SSAs). To avoid a theoretical interaction, several guidelines recommend performing PET/CT just before the monthly administration of long-acting SSAs. We aimed to investigate the effect of SSA on the SUVmax of 68Ga-DOTATATE in patients with NET and to identify independent predictors for high SUVmax TLR. For this retrospective study, 192 68Ga-DOTATATE PET/CT scans of 165 patients without (n = 115) and with (n = 77) SSA (octreotide or lanreotide) in the 3 months before PET/CT were collected and reviewed. The effect of SSA on SUVmax values was analyzed by a maximum likelihood mixed model. Patients with SSA had a significantly higher median SUVmax TLR than patients without SSA (4.7 [IQR], 3.1-7.7) versus 3.2 [IQR, 2.0-5.4]; P < 0.001). Multivariable logistic regression analysis showed that SSA use was an independent predictor for SUVmax TLR ≥ 8.1 (odds ratio, 2.91; 95% confidence interval, 1.26-6.72; P = 0.012). Our data suggest that higher SSA concentrations do not have a negative effect on 68Ga-DOTATATE uptake in tumor lesions. In addition, we found that only SSA use was associated with SUVmax TLR ≥ 8.1. Our results are consistent with previously conducted studies and in line with the recently published guideline that suggests that the relatively recent use of SSA does not necessitate any delay in 68Ga-DOTATATE PET/CT imaging.

Characteristics and response cutoff of octreotide suppression test in thyrotrophin (TSH)-secreting pituitary adenomas.

Somatostatin analogs are recommended for preoperative therapy in thyrotrophin secreting pituitary adenomas (TSHomas). Octreotide suppression test (OST) was designed to differentiate TSHomas with resistance to thyroid hormones, while its ability to test the sensitivity of SSA has not been fully studied. To test the sensitivity of SSA in TSHomas with OST. We collected 48 pathologically confirmed TSHoma patients with complete 72 h' data of OST into analysis. Octreotide suppression test. Sensitivity timepoint and cutoff of OST. During the entire OST, the TSH descended maximally 89.07% (73.85%, 96.77%), while the FT3 and FT4 declined slowly [43.40% (37.80%, 54.44%) and 26.59% (19.01%, 33.13%), respectively]. The 24th hour was the timepoint wherein the stability occurs for TSH, and the 48th hour for FT3 and FT4 during OST. In the patients who received both short- and long-acting somatostatin analogs (SSA), the 24-h timepoint was the most predictive timepoint for the percentage of TSH decline (Spearman's rank correlation analysis, r = .571, p < .001), while the 72-h timepoint was optimal for predicting the magnitude of TSH decline (Spearman's rank correlation analysis, r = .438, p = .005). In the 24th timepoint, a positive correlation was also observed between TSH suppression rate and the percentage decrease and absolute value decrease of FT3 and FT4. Furthermore, in patients treated with long-acting SSA, the 72-h timepoint was optimal for predicting both the percentage (Spearman's rank correlation analysis, r = .587, p = .01) and magnitude (Spearman's rank correlation analysis, r = .474, p = .047) of TSH decline. The 24th hour was the optimal timepoint with 44.54% (50% of median value of TSH in 72-hOST) decrease of TSH being the observing cutoff. The adverse effect of OST was predominantly occurred in the gastrointestinal system and no severe event occurred during OST. Paradoxical response could occur in OST and it did not influence the effect of SSA as long as sensitivity was confirmed. A high level of hormonal control was achieved in the SSA-sensitive patients. OST can be used as an efficient tool to guide the adequate use of SSA.

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.

Abstract #1402838: Thyroid Stimulating Hormone-Secreting Adenoma: A Rare Case of Hyperthyroidism

TSH-secreting adenomas account for only 0.5 to 3 % of all functioning pituitary tumors. We present this case report to highlight the importance of early diagnosis and prevention of severe complications. A 48-year-old postmenopausal female with a history of hypothyroidism was referred to our clinic for a second opinion. The patient had been stable on levothyroxine for over 10 years. Routine blood work was significant for elevated TSH and free T4. Despite adjustments to her levothyroxine, TSH and free T4 remained elevated. Her prior endocrinologist discontinued the levothyroxine and ordered an MRI brain, which showed an 8mm pituitary adenoma. The patient was referred to a neurosurgeon for evaluation, which then prompted the second endocrinology evaluation. Patient denied any palpitations, weight loss, heat intolerance, headaches, vision changes, or galactorrhea. Lab work repeated off of thyroid supplementation showed persistent elevated TSH at 6.5 mIU/L and free T4 at 2.1 ng/dL. Differential diagnosis included thyroid hormone resistance versus interference to thyroid assays versus TSHoma. The patient tested negative for the thyroid hormone resistance beta mutation, deeming thyroid hormone resistance unlikely. She tested negative for the human anti-mouse antibody, making interference to thyroid assays unlikely. Her alpha subunit level was normal, after which TSHoma was not a certainty. Since the diagnosis was unclear, patient was advised to follow up closely. Repeat MRI showed the tumor was now 1.2cm. Due to the increase in size, she was advised to proceed with trans-sphenoidal surgery (TSS). Pathology stained for TSH, confirming it was a TSH-secreting adenoma. After TSS, TSH normalized and free T4 was low, requiring the patient to be restarted on levothyroxine. TSH-secreting adenomas are quite rare, accounting for less than 1% of all cases of hyperthyroidism. Common clinical features include goiter, visual field defects, headache, menstrual disturbances, and galactorrhea. The presence of high free T4 and T3 and measurable serum TSH in the presence of a macroadenoma on MRI present strong evidence of a TSHoma. Definitive therapy includes transsphenoidal resection. Long-acting somatostatin analogs or dopamine agonists are used to restore euthyroidism prior to surgery. Long-term antithyroid drug therapy or thyroid ablation is not recommended because prolonged decreases in thyroid hormone secretion can stimulate TSH secretion and tumor growth. If TSHomas are left untreated, they can grow aggressively and impinge on nearby structures. Complications include visual field defects due to optic nerve compression, galactorrhea due to pituitary stalk compression, hypopituitarism leading to blood pressure dysregulation and decreased sexual function, and cardiac arrythmias leading to blood clots, stroke, and heart failure. Therefore, when hyperthyroxinemia is present with an elevated TSH, TSHoma should be considered. Even when alpha subunit levels are low or normal, TSHoma is still a possibility. Further investigation and close monitoring should be done to confirm diagnosis and prevent negative outcomes.

Abstract #1398813: A Rare Case of Acromegaly with Negative Immunohistochemical Staining for Growth Hormone

We are presenting a case of mixed prolactin and growth hormone (GH)-pituitary tumor with negative immunostaining for GH. 81-year-old male with history of type 2 diabetes mellitus, hypertension, obstructive sleep apnea, and colon polyps was found to have a pituitary macroadenoma during evaluation of his visual disturbances. Years before the presentation, he noticed his shoe size had increased and his wife observed his jaw becoming more prominent. Physical exam was notable for enlarged nose, mandibular prognathism, and enlarged hands. Pre-operative laboratory results were remarkable for significantly elevated levels of insulin-like growth factor-1 (IGF-1), GH, and prolactin. He underwent transsphenoidal resection (TSPR) of the mass and pathology demonstrated a lactotroph adenoma, negative for GH immunostaining. After surgery he was started on cabergoline 0.5mg PO twice weekly. Three months afterwards his IGF-1 level remained elevated at 415 ng/mL. Acromegaly was confirmed by an elevated GH level of 13.8 ng/mL 2-hours after oral glucose challenge, then a long-acting somatostatin analogue depot was initiated for treatment. In the first year of therapy, he had weight loss and hypoglycemia that required discontinuation of insulin therapy. His IGF-1 and GH levels decreased to within age-appropriate ranges. His prolactin level returned to normal and cabergoline was stopped after a successful discontinuation trial. Clinical suspicion for acromegaly is confirmed by elevated IGF-1 and GH levels. When a GH-secreting pituitary adenoma is resected, immunocytochemistry with GH staining typically supports the diagnosis. It is not common for these tumors to stain negative for GH in the presence of clinical and biochemical acromegaly. The opposite—termed silent somatotroph— is more common and may represent an early stage in the development of a somatotroph adenoma. Failure to provide adequate diagnostic tissue, histopathology misread, or loss of antigenicity during fixation or embedding may be reasons for false negatives. However, it has been suggested that sparse cytoplasmic stores of GH do not parallel the hypersecretion of GH and may reduce staining capacity. Thus, a diagnosis of acromegaly should be made in patients with clinical and biochemical findings, even in the absence of GH immunostaining.

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism.

To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis

Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.