Basal and Calcium-Stimulated Procalcitonin for the Diagnosis of Medullary Thyroid Cancers: Lights and Shadows

BackgroundProcalcitonin (proCt) was recently proposed as an alternative or in addition to calcitonin (Ct) in medullary thyroid cancer (MTC) diagnostics.MethodsSerum basal Ct (bCt) and proCt (bproCt) levels were measured before surgery from a consecutive series of patients with (n=43) and without (n=75) MTC, retrospectively collected in Padua. Serum bproCt, bCt and stimulated proCt and Ct (sproCt and sCt) were measured in another consecutive series of 33 patients seen at three tertiary-level institutions undergoing a calcium stimulation test prior to surgery, 20 of them with a final diagnosis of MTC, and 13 with non-MTC nodular disease.ResultsMedian bproCt levels were higher in MTC than in non-MTC. A positive correlation was found for bproCt with bCt (P<0.01, R2 = 0.75), and with tumor size (P<0.01, R2 = 0.39). The cut-off for bproCt differentiating between MTC and non-MTC patients was >0.07 ng/ml (sensitivity: 85.7%, specificity: 98.9%, positive predictive value [PPV]: 98.2%, negative predictive value [NPV]: 90.6%, P<0.01). While bproCt was >0.07 ng/ml in 38/39 (97.4%) patients with MTC >10 mm, it was above said cut-off only in 15/23 (65.2%) patients with tumors ≤10 mm. A sproCt >0.19 ng/ml was able to identify MTC [sensitivity: 90.0%, specificity:100.0%, PPV: 100.0%, NPV: 86.7% (P<0.01)].ConclusionsOur data suggest that bproCt can be a good adjunct to Ct for MTC diagnostic purposes. In consideration of its high specificity, it can be used in combination with Ct in MTC diagnostics, particularly in the case of mildly elevated basal Ct levels.

The insulinoma as a diagnostically and therapeutically challenging neoplasm

Introduction and purpose An insulinoma is the most common neuroendocrine tumor of a pancreas. This tumor produces insulin, which in excess causes hypoglycemic attacks, provoked by hunger or physical effort. Delays in diagnostic processes of the insulinoma are associated with the misattribution of symptoms to cardiac, psychiatric or neurological disorders. Thus, the suitable diagnostic procedures play a significant role as they ensure quick introduction of treatment. The purpose of this work is to evaluate advances in demanding diagnostically and therapeutically insulinoma. A brief description of the state of knowledge The used method was a literature review. The basic and the most common method of treating the insulinoma is a surgery. Due to this, finding precise location of the tumor preoperatively is crucial. In the diagnostics of the insulinoma both basic CT and MRI contrast enhanced and an endoscopic ultrasound, a selective arterial calcium stimulation test and the latest molecular imaging are used. In treatment process not only traditional surgical excisions were performed, but also laparoscopic and robotic surgeries turned out to be success. Conclusions Summing up, the insulinoma is a neoplasm with a wide range of therapeutic and diagnostic solutions, thanks to the progress that has been made in recent years. Although there are many difficulties on a diagnostic path of the insulinoma, new solutions and appropriate aproach make this process easier. Nevertheless, doctor’s diagnostic vigilance is essential, because consideration in the differential diagnosis the insulinoma is an essential step and without this step any further actions can be taken.

Basal and Calcium-Stimulated Procalcitonin for the Diagnosis of Medullary Thyroid Cancer: Lights and Shadows

Background: procalcitonin (proCt) was recently proposed as an alternative or in addition to calcitonin (Ct) in medullary thyroid cancer (MTC) diagnostics. Methods: serum basal Ct (bCt) and proCt (bproCt) levels were measured before surgery from a consecutive series of patients with (n=43) and without (n=75) MTC, retrospectively collected in Padua. Serum bproCt, bCt and stimulated proCt and Ct (sproCt and sCt) were measured in another consecutive series of 33 patients seen at three tertiary-level institutions underwent a calcium stimulation test prior to surgery, 20 of them with a final diagnosis of MTC, and 13 with non-MTC nodular disease. Results: median bproCt levels were higher in MTC than in non-MTC. A positive correlation was found for bproCt with bCt (P<0.01, R2=0.75), and with tumor size (P<0.01, R2=0.39). The cut-off for bproCt differentiating between MTC and non-MTC patients was >0.07 ng/ml (sensitivity: 85.7%, specificity: 98.9%, positive predictive value [PPV]: 98.2%, negative predictive value [NPV]: 90.6%, P<0.01). While bproCt was >0.07 ng/ml in 38/39 (97.4%) patients with MTC >10 mm, it was only above said cut-off in 15/23 (65.2%) patients with tumors ≤10 mm. A sproCt >0.19 ng/ml was able to identify MTC (sensitivity: 90.0%, specificity:100.0%, PPV: 100.0%, NPV: 86.7% [P<0.01]). Conclusions: proCt cannot replace Ct as the standard of care in the MTC diagnosis, because it often fails to identify a small MTC. That said, it has a very high specificity and can be used in combination with Ct in MTC diagnostics, particularly in the case of mildly elevated basal Ct levels.

Calcitonin Stimulation Tests: Rationale, Technical Issues and Side Effects: A Review

Calcitonin (CT) stimulation tests have great value and could help to: differentiate thyroid causes of elevated CT apart from non-thyroid sources, determine whether the patients with slightly elevated basal CT could/could not be candidates for surgery, and indicate the right moment for prophylactic thyroidectomy in children with MEN syndromes when with normal basal CT. This triggered the requests for development of CT stimulation tests, taking into consideration their safety and aimed us to write a systematic review of literature regarding the rationale, technical issues, and side effects of CT stimulating tests used for diagnosis of MTC. After a thorough review of the literature, we classified the reported side effects by severity, as defined by United States Food and Drug Administration. A statistical analysis was performed using IBM SPSS Statistics version 20. Various side effects were noticed during stimulation tests that differ by intensity, duration and severity, depending on types of substances and protocols used. The side effects after pentagastrin test were significantly more severe than those reported after calcium stimulation test (p=0.0396). There are also significant gender-specific differences in side effects induced by stimulation tests. In conclusion, we recommend performing Ca CT stimulation test when needed, considering preventive evaluation of some clinical, instrumental, and biochemical aspects of each patient. Precise instructions should be followed before a stimulation test and furthermore continuous cardiac monitoring is essential during and after the test to minimize the possibility of a serious event.

Canagliflozin: A New Therapeutic Option in Patients That Present Postprandial Hyperinsulinemic Hypoglycemia after Roux-en-Y Gastric Bypass: A Pilot Study

<b><i>Introduction:</i></b> Roux-en-Y gastric bypass (RYGB) is the most common surgical procedure for morbid obesity. However, it can present serious late complications, like postprandial hyperinsulinemic hypoglycemia (PHH). Recent data suggested an increase in intestinal SGLT-1 after RYGB. However, there is no data on the inhibition of SGLT-1 to prevent PHH in patients with prior RYBG. On this basis, we aimed to evaluate (a) the effect of canagliflozin 300 mg on the response to 100 g glucose overload (oral glucose tolerance test [OGTT]); (b) the pancreatic response after intra-arterial calcium stimulation in the context of PHH after RYGB. <b><i>Materials and Methods:</i></b> This is a prospective pilot study including patients (<i>n</i> = 21) with PHH after RYGB, matched by age and gender with healthy controls (<i>n</i> = 5). Basal OGTT and after 2 weeks of daily 300 mg of canagliflozin was performed in all cases. In addition, venous sampling after intra-arterial calcium stimulation of the pancreas was performed in 10 cases. <b><i>Results:</i></b> OGTT after canagliflozin showed a significant reduction of plasma glucose levels (minute 30: 161.5 ± 36.22 vs. 215.9 ± 58.11 mg/dL; minute 60: 187.46 ± 65.88 vs. 225.9 ± 85.60 mg/dL, <i>p</i> &#x3c; 0.01) and insulinemia (minute 30: 95.6 ± 27.31 vs. 216.35 ± 94.86 mg/dL, <i>p</i> = 0.03; minute 60: 120.85 ± 94.86 vs. 342.64 ± 113.32 mIU/L, <i>p</i> &#x3c; 0.001). At minute 180, a significant reduction (85.7%) of the rate of hypoglycemia was observed after treatment with canagliflozin (<i>p</i> &#x3c; 0.00001). All cases presented normal pancreatic response after intra-arterial calcium administration. <b><i>Conclusion:</i></b> Canagliflozin (300 mg) significantly decreased glucose absorption and prevented PHH after 100 g OGTT in patients with RYGB. Our results suggest that canagliflozin could be a new therapeutic option for patients that present PHH after RYGB.

The Role of Glucagon-Like Peptide 1 Receptor PET/CT With Ga-68-NODAGA-exendin in Localising an Insulinoma: Lessons From a Clinical Case

We present a clinical case highlighting the diagnostic challenges in a patient with an insulinoma. A 57-year-old lady initially presented with sweating on waking. Investigation documented a fasting blood glucose of 2 mmol/L (3.9-5.4) and the presence of anti-endomysial antibodies. On the basis of a diagnosis of Coeliac disease, the patient was commenced on a gluten free diet with apparent resolution of symptoms for 9 years. Subsequently, she re-presented with recurrent episodes of confusion which resolved with a ‘sugary’ drink. Consequently, she underwent a prolonged supervised fast: glucose 1.9 mmol/L (neuroglycopaenic symptoms), insulin 76 pmol/L (&lt;20), c-peptide 763 nmol/L (&lt;200) and β-hydroxybutyrate (BHB) 131 μmol/L (&lt;2700). A diagnosis of endogenous hyperinsulinaemic hypoglycaemia resulted in radiological investigation (CT thorax/ abdomen/pelvis, MRI pancreas and endoscopic ultrasound [EUS] of pancreas) with no tumor identified. Due to persisting symptoms, in addition to dietary changes, diazoxide and octreotide were commenced. She was referred for a second opinion where a repeat 72-hour fast (at the time of hypoglycaemia symptoms) showed: glucose 2.3 mmol/L, Insulin 51 pmol/L, C-Peptide 513 pmol/L, BHB 1580 μmol/L and proinsulin 31 pmol/L (&lt;10). Insulin antibody and sulphonylurea screens were negative. Her symptoms resolved after carbohydrate ingestion. Further imaging including a Ga-68-DOTATATE PET/CT, selective arterial calcium stimulation and hepatic venous sampling failed to localise an insulinoma. Despite pharmacological treatment hypoglycaemia continued to impede the patient’s quality of life and both octreotide and diazoxide were stopped due to side effects and minimal benefit. A glucagon-like peptide 1 receptor (GLP-1R) PET/CT scan with Ga-68-NODAGA-exendin-4 was performed and revealed uptake in a lesion in the ventral pancreatic body, suggestive of an insulinoma. A further EUS showed a corresponding 10 mm calcified area in the pancreatic body. The surgeon was unable to identify the tumor intra-operatively (macroscopically and ultrasound guided) and therefore performed a distal pancreatectomy which encompassed a 13 mm tumor. Histopathology demonstrated a 13 mm well differentiated, Grade 1 pancreatic neuroendocrine tumor (Ki67 1%) staining positively for AE1/AE3, synaptophysin, chromogranin and insulin (GLP-1R and pro-insulin staining awaited). Post-operatively, there was complete resolution of hypoglycaemia. In summary the learning points are the 9-year interval between initial presentation and confirmation of the diagnosis and the challenge of tumor localisation. There is no published evidence about gluten free diets reducing hypoglycaemia in insulinomas, but our patient described symptomatic improvement. GLP-1R are expressed in &gt;90% of insulinomas and this case underlines the utility of GLP-1R PET/CT in insulinoma localisation.

Selective Intra-Arterial Calcium Stimulation Venous Sampling Test for Preoperative Localization of Occult Neuroendocrine Tumors: Recall for an Old Technique

Background Surgical resection is the curative treatment for neuroendocrine tumors (NETs). Noninvasive imaging is unreliable in localizing NETs measuring less than 2 cm. This study investigates the safety and efficacy of the selective intra-arterial calcium stimulation venous sampling test (SACST) for preoperative localization of functional NETs within the pancreas. Methods This retrospective analysis of the patients referred for localization of radiologically occult functional NETs from 2004 to 2019 was performed at a single institution. The technical success, diagnostic accuracy, and complications of the test were evaluated. Results Twenty-three patients underwent SACST. The SACST was technically successful in 100% of the patients. Lesions were successfully localized in 19 (83%) patients. Tumor blush was seen in one patient. The mean ± standard deviation of maximal dimension of the resected tumor was 2.0 ± 1.9 cm. Sensitivity, specificity, positive predictive value, and negative predictive value of the SACST for localization of all lesions were 1.0, 0.57, 0.84, and 1.0, as well as 1.0, 0.57, 0.80, and 1.0 for insulinomas, respectively. Conclusion SACST is a feasible, safe, well-tolerated, and effective procedure to preoperatively localize radiologically occult NETs within the pancreas.

Insulinoma of Pancreatic Head Localized by Intra-Arterial Calcium Stimulation with Hepatic Venous Sampling

Hypoglycemia is a common medical emergency. Insulinoma, a rare pancreatic endocrine tumour is the most common cause of hypoglycemia in patients without systemic illness. Most insulinomas are small, solitary and benign, which can be treated effectively by surgical removal of the tumour. Diagnosis is based on clinical features, laboratory tests and radiological investigation to localize the tumour. However, small size of this tumour leads to difficulty in localization of the disease, especially in occult insulinoma. Intra-arterial calcium stimulation with hepatic venous sampling can be utilised for preoperative localization of the tumour. We hereby present a case of a 33-year-old woman presenting with history of recurrent hypoglycemic symptoms and morbid obesity. A thorough history, clinical examination and laboratory investigation including prolonged fasting test were conducted and diagnosis of insulinoma was made. Intra-arterial calcium stimulation with hepatic venous sampling was carried out and revealed localization of insulinoma at pancreatic head. Bangladesh Journal of Medical Science Vol.20(1) 2021 p.216-219

Successful surgical treatment of a patient with primary insulinoma of the liver

Insulinoma is the most frequent functional neuroendocrine tumor of the pancreas, which causes organic hyperinsulinism with severe hypoglycemia. There are no cases of primary insulinoma of the liver described. A 63-year-old female was admitted to our center presenting symptoms of severe hypoglycemia due to confirmed endogenic hyperinsulinism. None of the performed diagnostic procedures could reveal a pancreatic tumor. However, a pathologic mass in the sixth segment of the liver was detected. We performed arterial calcium stimulation that showed increased levels of insulin and c-peptide in almost all stimulated arteries. The highest and most prolonged peaks were detected at the points of the common hepatic artery and the right hepatic artery. After the surgical removal of the liver tumor, the blood glucose level was stabilized within the normal range. Post-operative pathomorphological investigation confirmed the diagnosis of a neuroendocrine tumor. The long-term survival results show correct treatment tactics without any signs of disease recurrence.

Calcium Stimulation Test for Insulinoma Localization in an End-stage Renal Disease Patient on Diazoxide

Insulinomas are rare, and even rarer in patients with end-stage renal disease (ESRD). Clear criteria for the biochemical diagnosis of insulinomas in patients with renal failure have not been established, and hypoglycemia is often attributed to the renal disease itself, frequently leading to a delay in diagnosis. We describe a case of a patient who presented with asymptomatic recurrent hypoglycemia during hemodialysis. Disease progression and biochemical testing strongly suggested an insulinoma. Computed tomography (CT) of the abdomen and pelvis, 111In-pentetreotide scintigraphy and endoscopic ultrasound did not localize a pancreatic tumor. A calcium stimulation test was performed while the patient was taking diazoxide due to severe hypoglycemia with fasting for a couple of hours without treatment. The test showed a marked increase in insulin after calcium infusion in the dorsal pancreatic artery, localizing the tumor to the body and tail of the gland. Exploratory surgery easily identified a tumor at the body of the pancreas and pathology confirmed an insulin-secreting pancreatic neuroendocrine tumor. On follow-up, there was resolution of the hypoglycemia. We review the challenges of diagnosing an insulinoma in ESRD and describe a successful intra-arterial calcium stimulation test done in an ESRD patient while continuing diazoxide.