Kalyan Mansukhbhai Shekhda

Introduction: Pancreatic neuroendocrine tumors (pNETs) are a recognized feature of tuberous sclerosis complex (TSC). The current evidence suggests that pNETs occurring in TSC may exhibit a different clinical course from sporadic cases, but their natural history remains poorly characterized. Objective: This study aimed to characterize the demographics, clinical presentation, management, and long-term outcomes of TSC-associated-pNETs and to propose possible guidelines for surveillance and management. Materials and Methods: We conducted a multicenter retrospective review of TSC-pNET patients from 6 UK TSC specialist clinics and from 3 NET referral centers, from 2008 to 2024. Data on demographics, tumor characteristics, management, and outcomes, were collected. A systematic review of the literature from 2009 to 2026 on TSC-pNETs was also performed. Results: We identified a total of 26 consecutive cases with the TSC-pNET-association in our cohort: 21 cases of pNETs from TSC specialist clinics (1.1% of the population), and 5 cases of TSC-pNETs from the NET referral centers (0.25% of the population). An additional 80 cases were identified from the published literature. We observed a wide spectrum of clinical phenotypes, with the majority being nonfunctioning pNETs (n = 24; 92%), whereas 2 patients were diagnosed with glucagonomas. Surgical intervention was the mainstay initial treatment, the indication being either functional pNETs, or large or symptomatic nonfunctioning pNETs. Conclusion: TSC-pNETs are rare and mostly nonfunctioning tumors with variable clinical behavior. Due to their uncertain malignant potential, we suggest that baseline pancreatic imaging should be incorporated into TSC surveillance, and we emphasize the need for heightened pNET surveillance and updated management recommendations.

Neuroendocrine tumours (NETs) are heterogeneous, biologically variable tumours arising from the diffuse neuroendocrine system. While more frequently seen in older patients, the incidence and prevalence of NETs in the younger population are increasing. In addition, because of their generally slow progression and favourable prognosis, coupled with widely available effective treatments, survival times even with metastatic tumours may often be prolonged. However, there is a paucity of data on the effect of treatment of NETs on men’s and women’s reproductive and sexual health. In this review, we have evaluated the effects of NET therapies, including somatostatin analogues (SSTAs), molecular targeted therapy (everolimus and sunitinib), peptide receptor radionuclide therapy (PRRT), and chemotherapy, on reproductive and sexual function in patients with NETs. There is a lack of evidence on the detrimental effects of SSTAs on human fertility, and indeed, many patients have conceived successfully after many years of treatment with SSTAs. Even patients who have received SSTAs during pregnancy have generally shown positive maternal and fetal outcomes. While the effects of PRRT and molecular targeted therapy on fertility are as yet poorly defined, chemotherapy has a proven negative impact on fertility; thus, family and pregnancy planning are strongly recommended before the initiation of chemotherapy. Finally, data on the effects of NET treatment on sexual function are very limited; however, neuroendocrine tumours can express oestrogen receptors/progesterone receptors (ER/PR) or testosterone receptors (TR); thus, checking tumour tissue for ER/PR/TR status prior to considering hormonal therapy for sexual dysfunction should be considered but warrants additional studies.

Syndrome of inappropriate antidiuresis (SIAD), the leading cause of hyponatremia, poses treatment challenges. Fluid restriction often proves insufficient. Alternative therapies such as demeclocycline, tolvaptan, and urea are limited to selected cases due to frequent side effects, high cost, and low availability, respectively. This case report explores the potential of empagliflozin as a novel treatment option. A 32-year-old female with SIAD following a traumatic subarachnoid hemorrhage experienced persistent hyponatremia despite fluid restriction and initial treatment with hypertonic saline and tolvaptan. Treatment with severe fluid restriction of 800 milliliters/day (mL/day) for almost a year led to significant impairment in her quality of life. Empagliflozin 25 milligrams/day was then initiated, resulting in sustained normonatremia for 16 months, the longest reported duration to date. This allowed increased fluid intake (1750 mL/day) and improved quality of life. Empagliflozin shows potential for managing chronic SIAD; prospective studies are needed to validate its efficacy and safety.

Mixed neuroendocrine and non-neuroendocrine neoplasms (MiNENs) are rare neoplasms composed of morphologically distinguishable neuroendocrine (NE) and non-neuroendocrine components, each representing at least 30% of the tumor volume. The NE component must be substantiated by immunohistochemistry. MiNENs generally have a poor prognosis, with a more aggressive component dictating overall survival and prognosis. Owing to its rarity, there are no specific validated treatment guidelines available for these tumors, and they are generally treated with surgery if possible. However, surgically unresectable or advanced tumors are generally treated with chemotherapy. We report a case of an elderly woman who was referred to the neuroendocrine tumor (NET) unit following incidental findings of liver lesions found on cardiac magnetic resonance imaging (MRI) performed for an asymptomatic heart murmur. Histology from the liver biopsy revealed MiNEN with up to 60% grade 2 (Ki67: 19%) well-differentiated NET and up to 30% well-differentiated to moderately differentiated adenocarcinoma of possible pancreato-biliary origin; intrahepatic ductal primary could not be excluded. Her 18-fluoro-deoxyglucose positron emission tomography (FDG-PET) revealed no FDG-avid lesions, and a ⁶⁸Gallium 1,4,7,10-tetraazacyclododecane-tetraacetic acid Tyr3-octreotate (⁶⁸ Ga-DOTATATE)-PET scan revealed multiple areas of intensely DOTATATE-avid liver lesions. Due to the absence of any primary imaging findings, the patient was diagnosed with MiNEN of possible pancreato-biliary origin. She was started on lanreotide 120 mg every 28 days for 6 months, with no response to the treatment. Subsequently, the patient was treated with four cycles of ¹⁷⁷Lutetium-DOTATATE (Lutathera®) peptide receptor radionuclide therapy (PRRT). She tolerated the treatment well, with no significant side effects. MRI at the end of treatment revealed a partial response to treatment. PRRT is currently not used in treatment protocols for the management of MiNENs; however, it could be considered a treatment option in patients with MiNENs, where there is a predominant component of well-differentiated NETs with ⁶⁸ Ga-DOTATATE avid lesions.

Since Rudolf Heidenhain first identified neuroendocrine cells in 1870, our understanding of neuroendocrine tumors (NETs) has advanced significantly. The increasing incidence and prevalence of NETs, combined with complete tumor resection being the only curative option, has driven the search for effective treatments. Peptide receptor radionuclide therapy, which combines radioactive elements with octreotide derivatives, has emerged as a promising therapeutic approach. While β-particle emitters are currently used in clinical practice, targeted alpha-particle therapy (TAT) shows particular potential for NET treatment. This review examines the physical and radiobiological characteristics of α- and β-particles, evaluates preclinical and clinical evidence for TAT in somatostatin receptor–expressing NETs, and explores both challenges and future developments in α-particle therapy for NETs.

Introduction: 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) represents a possible therapeutic option for patients with metastatic inoperable phaeochromocytomas (PCC) and paragangliomas (PGL) who demonstrate adequate somatostatin analogue binding on molecular imaging. We describe treatment outcomes in our cohort of patients stratified according to germline pathogenic variants (PV) in succinate dehydrogenase (SDHx) subunit-encoding genes. Methods: In this retrospective analysis, we evaluated 20 patients with metastatic PCC/PGL who underwent two or more cycles of 177Lu-DOTATATE therapy. Clinical, radiological, and biochemical responses were assessed 8–12 weeks after the final PRRT cycle. We describe overall treatment efficacy at follow-up after stratifying according to the presence of germline SDHx PV. Radiological progression was quantified based on the sum of the longest diameter (SLD) of the target lesion. Progression-free survival (PFS) and overall survival were estimated using Kaplan–Meier survival analysis. We also aimed to investigate the impact of PRRT on health-related quality of life (HRQoL), as assessed using the EORTC QLQ-GINET21 questionnaire. Results: After a median follow-up of 29 months, we confirmed stable disease in 12 patients (60%), a partial response in one (5%), and progressive disease in seven patients (35%). The absolute mean difference in SLD was +5 ± 12 mm for bone lesions, −4 ± 6 mm for peritoneal, +8 ± 14 mm for liver lesions and −1 ± 5 mm for lymph nodes (paired t-test P-value 0.273, 0.741, 0.208 and 0.826, respectively). Thirteen patients (65%) had received two or more previous lines of treatment. The overall median PFS for the entire cohort, PGL patients, SDHx positive and negative groups was 24 months (95% CI: 9.9–38.1), 18 months (95% CI: 8.4–27.6), 24 months (95% CI: 11.9–36.0) and 18 months (95% CI: 0–48), respectively. No grade 3/4 cytopenia or nephrotoxicity was observed. Overall, HRQoL improved after PRRT, as evidenced by the progressive decline in overall symptom scores in the QLQ-GINET21. Conclusion: 177Lu-PRRT appears to be an effective therapy with a good safety profile for patients with metastatic PPGL. It also appears to improve HRQoL in patients with metastatic PPGL. Further studies are needed to explore the most effective treatment modalities in this group of patients and their sequencing.

Purpose: To evaluate the added benefit and accuracy of 68Ga-DOTA-TATE PET/CT scans in detecting duodeno-pancreatic neuroendocrine tumours (dpNETs) compared to conventional cross-sectional imaging with CT or MRI scans in patients with multiple endocrine neoplasia type 1 (MEN-1), and whether the results from the 68Ga-DOTA-TATE PET/CT produce a change in management plans for patients with MEN-1 and dpNETs. Methods: A retrospective analysis was performed comparing the initial 68Ga-DOTA-TATE PET/CT to the respective contemporary CT or MRI imaging in patients with MEN-1 under the care of a tertiary neuroendocrine centre. Imaging and electronic patient records were analysed to identify treatment plans and the records of multidisciplinary team discussions. Results: In total, 85% (n = 39/46) of patients with MEN-1 had a 68Ga-DOTA-TATE PET/CT study in the electronic patient record; 23 of those with duodeno-pancreatic lesions detected also had contemporaneous contrast-enhanced CT scans, while 18 had MRI scans. 68Ga-DOTA-TATE PET/CT detected a total of 47 pancreatic lesions compared to 25 on CT, while 68Ga-DOTA-TATE PET/CT detected 32 pancreatic lesions compared to 25 on MRI. There were no duodenal lesions detected on conventional CT or MRI, but in comparison to CT and MRI, 68Ga-DOTA-TATE PET/CT detected eight and one duodenal lesions respectively. While 68Ga-DOTA-TATE PET/CT detected more liver metastases compared to CT (n: 31 vs 21) and similar numbers compared to MRI (n: 11 vs 11), these differences were not statistically significant. As a result of findings on 68Ga-DOTA-TATE PET/CT, a change of management was indicated in 69% (n = 27/39) of patients. Of these, 14 patients were offered somatostatin analogues (SSTA), eight patients were offered surgical intervention, three patients were offered peptide receptor radionuclide therapy, and one patient was offered ablation of liver metastases. Conclusions: In patients with MEN-1, 68Ga-DOTA-TATE PET/CT was shown to detect a greater number of duodeno-pancreatic lesions compared to conventional cross-sectional CT or MRI imaging. Management plans were changed in most patients following their initial 68Ga-DOTA-TATE PET/CT. Therefore, we suggest that somatostatin receptor-targeted PET/CT scans should be an integral part of the investigation of patients with MEN-1 for staging of suspected duodeno-pancreatic NETs.

Objective: To evaluate clinical outcomes, safety and survival measures of octreotide infusion pump (OIP) therapy in patients with metastatic neuroendocrine tumors (NETs) and refractory hormonal syndrome. Design: A retrospective analysis was conducted using data from patients treated with OIP therapy at a single center. Methods: Data on demographics, disease characteristics, biochemical profiles and treatment outcomes were extracted from electronic patient records. Results: Eighteen patients with NETs and debilitating symptoms refractory to maximum approved doses of somatostatin analogs (SSTAs) were included. The cohort comprised 18 patients (12 males (67%) and six females (33%)) with a median age of 64.5 years (IQR: 49.5–71). The most common tumor site was midgut (72.2%), followed by pancreas (22.2%). Refractory carcinoid syndrome was the primary indication for initiation of OIP therapy in 15 patients and VIPoma in three. Most tumors were WHO grade 1 or 2 (89%), and liver metastases were prevalent (94% of patients). At presentation, the median 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) level was 421.5 μmoL/24 h ( n : 8). The mean starting OIP dose was 1,632 ± 522 μg/24 h, escalating to 2,166.7 ± 464 μg/24 h in 66.57% of patients. Symptomatic improvement was observed in 72% of patients, significantly reducing flushing and diarrhea. Patients who did not respond well to OIP therapy had more disease burden and had received more treatment lines before being started on OIP therapy. Conclusion: OIP therapy is an effective treatment option for symptom control in patients with refractory NET-related hormonal syndrome. Randomized controlled trials are warranted to confirm these findings and assess long-term outcomes.

Maturity-onset diabetes of the young (MODY) is often misclassified and can significantly impact the management of these patients and their families. We present three cases initially diagnosed as type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and fasting hyperglycemia, which were later identified as MODY. A 38-year-old Caucasian lady, previously diagnosed with T2DM, was referred to the diabetes antenatal clinic. She was treated with gliclazide and metformin before pregnancy. She required insulin glargine during her pregnancy. Her diabetes autoantibodies were negative. MODY was suspected and genetic testing confirmed HNF1A MODY gene mutation. A 57-year-old Caucasian lady was diagnosed with T1DM at the age of 18 years. Since diagnosis, she was treated with insulin glargine without any short-acting insulin, yet persistently suffered from hypoglycemia. MODY was suspected and genetic testing confirmed HNF4A gene mutation. A 33-year-old South Asian lady was referred to a diabetes clinic for suspected T2DM due to strong family history of T2DM, ethnicity, and persistently elevated fasting blood glucose levels. Her genetic testing confirmed GCK-MODY (Glucokinae-maturity-onset diabetes of the young). MODY represents a group of genetic diabetes that can often go unrecognized due to misdiagnosis. Achieving an accurate diagnosis is important as it guides appropriate treatment strategies, improves patient outcomes, and has an impact on other family members due to the hereditary nature of the condition. Employing a systematic approach is crucial. Our cases highlight that it is never too late to challenge the diabetes classification.