How Many Times Can One Go Back to the Drawing Board before the Accurate Diagnosis and Surgical Treatment of Glucagonoma?

Glucagonomas are neuroendocrine tumors (NETs) that arise from the alpha cells of the pancreatic islets. They are typically slow-growing tumors associated with abnormal glucagon secretion, resulting in one or more non-specific clinical features, such as necrolytic migratory erythema (NME), diabetes, diarrhea, deep vein thrombosis, weight loss, and depression. Here, we report the case of a 44-year-old male with a history of diabetes mellitus, presenting with a pruritic and painful disseminated cutaneous eruption of erythematous plaques, with scales and peripheral pustules, misdiagnosed as disseminated pustular psoriasis and treated for 2 years with oral retinoid and glucocorticoids. During this period, the patient complained of weight loss of 32 kg and diarrhea and developed deep vein thrombosis. These symptoms, together with an inadequate response to therapy of the skin lesions, led to the reassessment of the initial diagnosis. Laboratory tests confirmed elevated plasma glucagon levels (>1000 pg/mL) and computed tomography (CT) scans revealed a 35/44 mm tumor in the pancreatic tail. Due to considerable disease complications and the COVID-19 pandemic, the surgical removal of the tumor was delayed for nearly 2 years. During this time, somatostatin analogue therapy efficiently controlled the glucagonoma syndrome and likely prevented tumor progression. As in other functional pancreatic NETs, the early clinical recognition of hormonal hypersecretion syndrome and the multidisciplinary approach are the keys for best patient management.

Necrolytic migratory erythema: an important visual cutaneous clue of glucagonoma

Objective: Glucagonoma is an extremely rare neuroendocrine tumor that arises from pancreatic islet alpha cells. Although glucagonoma is usually accompanied by a variety of characteristic clinical symptoms, early diagnosis is still difficult due to the scarcity of the disease. Methods: In this study, we present the cumulative experiences, clinical characteristics and treatments of seven patients diagnosed with glucagonoma during the past 10 years at the First Affiliated Hospital of Xi’an Jiaotong University. Results: The seven patients in our cohort consisted of six females and one male with an average diagnosis age of 40.1 years (range 23-51). The average time from onset of symptoms to diagnosis of glucagonoma was 14 months (range 2-36 months). All the patients visited dermatology firstly for necrolytic migratory erythema (NME) 7/7 (100%), other presenting symptoms included: diabetes mellitus (DM) 4/7 (57%), stomatitis 2/7 (28%), weight loss 4/7 (57%), anemia 4/7 (57%), diarrhea 1/7 (14%), DVT1/7 (14%). Plasma glucagon levels were increased in all patients (range 216.92–3155 pg/mL), and declined after surgery. Imaging studies revealed that four of seven patients had liver metastasis. Six of seven patients received surgical resection, and all of them received somatostatin analogue therapy. Symptoms improved significantly in 6 out of 7 patients. Three of seven patients died of this disease by the time of follow-up. Conclusion: Our data suggest that if persistent NME is associated with DM and high glucagon levels, timely abdominal imaging should be performed to confirm glucagonoma. Once diagnosed, surgery and somatostatin analogues are effective for symptom relief and tumor control.

Self-Administration of Long-Acting Somatostatin Analogues in NET Patients—Does It Affect the Clinical Outcome?

Background and Objectives: Long-acting somatostatin analogues (SSA) (octreotide LAR and lanreotide Autogel) are recommended as first line treatment of locally advanced or metastatic well-differentiated neuroendocrine tumors (NETs) with a good expression of somatostatin receptor (SSTR). Both of these SSAs are usually administered via injections repeated every 4 weeks. The purpose of the study was to compare the route of SSA administration (injection performed by professional medical staff and self-administration of the drug) with progression-free survival. Materials and methods: 88 patients in 2019 and 96 patients in 2020 with locally advanced or metastatic well-differentiated NETs were included in the study. All patients had a good expression of SSTR type 2 and had been treated for at least 3 months with a stable dose of long-acting somatostatin analogue every 4 weeks. All of them had received training on drug self-injections from professional NET nurses at the beginning of the COVID-19 epidemic. Results: The rate of NET progression in the study group in 2020 was higher than in 2019 29.1% vs. 18.1% (28 vs. 16 cases), p = 0.081. Conclusions: The method of administration of long-acting SSA injection performed by professional medical staff vs. self-injection of the drug may significantly affect the risk of NET progression. The unequivocal confirmation of such a relationship requires further observation.

Improved Personalised Neuroendocrine Tumours’ Diagnosis Predictive Power by New Receptor Somatostatin Image Processing Quantification

Although neuroendocrine tumours (NETs) are intensively studied, their diagnosis and consequently personalised therapy management is still puzzling due to their tumoral heterogeneity. In their theragnosis algorithm, receptor somatostatin scintigraphy takes the central place, the diagnosis receptor somatostatin analogue (RSA) choice depending on laboratory experience and accessibility. However, in all cases, the results depend decisively on correct radiotracer tumoral uptake quantification, where unfortunately there are still unrevealed clues and lack of standardization. We propose an improved method to quantify the biodistribution of gamma-emitting RSA, using tissular corrected uptake indices. We conducted a bi-centric retrospective study on 101 patients with different types of NETs. Three uptake indices obtained after applying new corrections to areas of interest drawn for the tumour and for three reference organs (liver, spleen and lung) were statistically analysed. For the corrected pathological uptake indices, the results showed a significant decrease in the error of estimating the occurrence of errors and an increase in the diagnostic predictive power for NETs, especially in the case of lung-referring corrected index. In conclusion, these results support the importance of corrected uptake indices use in the analysis of 99mTcRSA biodistribution for a better personalised diagnostic accuracy of NETs patients.

Pharmacological Characterization of Veldoreotide as a Somatostatin Receptor 4 Agonist

Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein‒coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (Emax, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (Emax, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5.

Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review

Introduction: Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1 (MEN1) where patients display a 70% lifelong risk of developing a pancreatic NENs (pNENs). To date, specific personalized treatment for pNENs in patients with MEN1 are lacking. The aim of this study was to systematically analyze the efficacy and safety of somatostatin analogue (SSA) treatment in patients affected by MEN1-related pNENs. Materials and Methods: We performed a systematic review of the literature, searching for peer-reviewed articles on SSA (octreotide or lanreotide) treatment in MEN1 associated with pNENs. Results: We selected 20 studies with a pooled population of 105 MEN1 patients with pNENs. Females were 58.5%, median age was 44 years (18–73). TNM stage at diagnosis was stage I-II in 84.8% and stage IV in 15.2%. The overall response rate (SD+PR+CR) was achieved in 88.3% of cases, with stable disease in 75.6% and objective response in 12.7% of patients. The safety profile was favorable with both SSA agents. Conclusions: SSAs appear to be an effective and safe treatment option for MEN1-related pNEN, either at localized or advanced stages.

Impact of Different Modalities of Treatment of Hepatorenal Syndrome as Midodrine, Somatostatin analogue, Albumin infusion and Tapping of Ascites on Renal Artery Resistive Index by Doppler ultrasound

Background Liver cirrhosis is a major cause of morbidity and mortality worldwide, mainly due to complications of portal hypertension. Ascites formation in patients with Kristeen E. cirrhosis, portal hypertension, or both usually results from hyperdynamic circulatory Zaki dysfunction. Aim of the Work to investigate the effect and prognostic value of treatment of hepatorenal syndrome in patients with liver cirrhosis and massive ascites by LVP, somatostatin analogue and midodrine intake and its effect on renal resistive index. Patients and Methods This study was carried on 40 patients divided into 4 groups where 10 patients (G1) received midodrine therapy and albumin infusion, 10 patients (G2) had tapping of ascites with albumin infusion, 10 patients (G3) received octreotide therapy and albumin infusion and the last 10 patients (G4) received octreotide, midodrine and albumin infusion. All patients were subjected to careful history taking and thorough clinical examination. Before and after intervention, patients had laboratory investigation including complete blood picture, liver function tests, renal function test and ascitic fluid analysis in addition to renal artery Doppler imaging. Results The study revealed considerable decline in RI in G1 (midodrine group), the change fell short of statistical significance. However, our study showed significant effect of midodrine administration on renal functions as expressed by serum creatinine, blood urea and creatinine clearance. In G3 (octreotide group), the effect of treatment on renal artery RI was minimal. The other group that perceived significant decline in renal artery resistive index was G4 (midodrine and octreotide group). Conclusions LVP and midodrine combination administration resulted in significant decrease in creatinine clearance. Renal artery resistive index has significant correlation with creatinine clearance in studied group and can be used as non-invasive tool.

Efficacy and Safety of CyberKnife Stereotactic Radiosurgery in Acromegaly

Aims Objective: Active acromegaly is associated with increased mortality. While surgery is the mainstay of treatment, it is not always curative. In selected cases, CyberKnife stereotactic radiosurgery (CK SRS) can be used as adjuvant treatment in patients with persistent disease. Method Methodology: Biochemical response was measured using serum IGF-1 levels, calculated as a percentage of the upper limit of normal (% ULN). Levels were recorded prior to treatment, at 6-12 months post-treatment and at the most recent follow-up. Anterior pituitary hormone deficits were assessed before and after treatment. Tumour size was followed-up using MRI. Results 10 patients (7 male, mean age 36 yrs [+/- 12.6, SD]) with acromegaly were treated with CK SRS. 9 were treated following failure to attain biochemical remission with TSS. 1 had primary CK SRS. 2 had previous conventional fractionated external beam radiotherapy. Median tumour diameter was 6 mm (IQR 5.2-10.5 mm), with cavernous sinus invasion in 2 cases. The dose was 20-24Gy/1#. 4 patients were on dopamine agonist, 4 on somatostatin analogue and 2 on pegvisomant. Mean follow-up 31.6 months (+/- 13.5 months, SD). Median IGF-1 % ULN was 146% pre-treatment (IQR 126.5-208.5), 109% at 6-12 months (IQR 76.5-131%) and 71% (IQR 59-91%) at last follow-up. Mean radiological follow-up 16.6 months (+/- 15.9 months, SD). No cases showed tumour enlargement. One patient developed secondary hypothyroidism. Side-effects: headache (7 patients), blurred vision (1 patient), fatigue/nausea (1 patient). No new visual fields defects, cranial nerve palsies, cerebrovascular events or secondary tumours. Conclusion Conclusions: CK SRS appears safe and effective in selected patients with acromegaly, when there is failure to attain biochemical cure with surgery and in patients intolerant or resistant to medical treatment.