Purpose:Thyroid nodules with indeterminate cytology are often referred for diagnostic surgery. This systematic review evaluated diagnostic markers in fine-needle aspiration cytology samples of indeterminate nodules to improve differentiation between benign and malignant nodules. Methods:We searched MEDLINE, Embase, and the Cochrane Library from 1995 to 2025. The literature was screened, and data were extracted from the included studies. The quality of studies was assessed with QUADAS-2. We performed split component meta-analysis of diagnostic accuracy using R-studios and the SCS meta-function (split component synthesis). Results:Forty-one relevant studies were identified, of which 23 eligible studies were included in the meta-analysis. Data on Galectin-3, HBME-1, and BRAF mutation from 1,564 patients were evaluated. Galectin-3 and HBME-1 demonstrated promising diagnostic accuracy, with diagnostic odds ratios (DORs) of 20.3 (95% CI: 9.7-42.5) and 15.0 (95% CI: 7.3-31.0), sensitivities of 0.74 (95% CI: 0.64-0.82) and 0.77 (95% CI: 0.67-0.84), and specificities of 0.88 (95% CI: 0.80-0.93) and 0.82 (95% CI: 0.73-0.89), respectively. Combined positivity yielded the highest DOR of 45.8 (95% CI: 17.7-118.6), sensitivity of 0.90 (95% CI: 0.81-0.95), and specificity of 0.84 (95% CI: 0.73-0.91). BRAF mutation had the lowest DOR of 6.6 (95% CI: 2.1-20.4) and sensitivity of 0.17 (95% CI: 0.09-0.29) but the highest specificity of 0.97 (95% CI: 0.93-0.99). Conclusion:Our meta-analysis indicates that Galectin-3 and HBME-1, particularly when combined, may improve differentiation between benign and malignant nodules. BRAF mutation is highly specific but lacks sensitivity. These biomarkers show potential, but none warrant stand-alone clinical use, emphasizing the need for large-scale validation and potentially a multi-marker approach to improve diagnostic accuracy.
SUMMARY:Corticotroph tumour progression (CTP) following bilateral adrenalectomy for Cushing's disease usually emerges within the first decade; substantially delayed presentations are uncommon and longer term surveillance recommendations remain imprecise. We report a patient presenting with CTP 37 years after adrenalectomy, representing one of the latest onset cases in the literature. Tumour profiling demonstrated an aggressive molecular phenotype including ATRX loss, MEN1 inactivation and CDK4 amplification, with a Ki-67 index of 10% and absent PD-L1 expression. Pembrolizumab, administered for a concurrent metastatic melanoma, was associated with a rapid and sustained biochemical and radiological response, making this the fifth reported case of CTP post-adrenalectomy responding to immune checkpoint inhibitor (ICI) therapy and notably the first without prior temozolomide exposure. This case illustrates three clinically relevant points: 1. lifelong post-adrenalectomy surveillance requires a structured long-term framework; 2. comprehensive molecular profiling of aggressive corticotroph tumours may inform prognosis and facilitate access to targeted therapies; and 3. ICI response in corticotrophinomas may occur despite PD-L1 negativity and without temozolomide-induced hypermutation, supporting the rationale for evaluating earlier immunotherapy in this biologically distinct subtype.
ContextSomatotrophinomas can occasionally occur in familial settings and may be associated with known germline mutations, such as MEN1, AIP, CDKN1B, PRKAR1A, SDHx, and MAX. Recently, the CHEK2 gene has emerged as a potential pituitary tumour predisposition gene. ObjectiveTo present a rare case of a patient with a pituitary somatotrophinoma and primary hyperparathyroidism (PHPT) associated with a likely pathogenic CHEK2 germline mutation, suggesting a novel MEN1-like phenotype. MethodsWe conducted a detailed clinical, biochemical, radiological, and genetic evaluation of a 38-year-old woman presenting with features of acromegaly and PHPT. Genetic testing for known MEN1 syndrome-associated genes and broader pituitary tumour predisposition genes was performed. ResultsThe patient presented with features of acromegaly of 3 years duration and a collagenoma. Laboratory evaluation revealed an elevated IGF-1. Biochemical and imaging studies also revealed PTH-dependent hypercalcaemia and bilateral inferior parathyroid adenomas. Genetic testing for a panel of genes causing hypercalcaemia – including MEN1 and CDKN1B – was negative; however, a pathogenic nonsense variant in CHEK2 (c.232C>T; p.(Gln78Ter); gnomAD frequency: 0.0006%) was detected with exome sequencing. The patient underwent transsphenoidal resection of the pituitary tumour followed by gamma-knife radiosurgery and received long-acting octreotide every four weeks. Parathyroidectomy was performed 1.5 years later. ConclusionThis is the first reported case of a CHEK2 germline mutation associated with somatotrophinoma, PHPT, and collagenoma, mimicking the clinical MEN1 syndrome. These findings expand the spectrum of possible CHEK2-associated neoplasia and highlight the need to consider CHEK2 as a possible candidate gene in patients with MEN1-like syndromes when common mutations have been excluded.
ObjectivePeptide receptor radionuclide therapy (PRRT) with lutetium-177 DOTATATE (177Lu-DOTATATE) is widely adopted as a later-line treatment (second-line or subsequent therapy) for patients with somatostatin receptor-positive neuroendocrine neoplasm. The registration NETTER-1 trial reported a late-onset adverse event of therapy-related myeloid neoplasms (tMNs), including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) in approximately 1% of patients. In this retrospective study, we sought to investigate the frequency of tMN in patients treated with 177Lu-DOTATATE at our institution over the last 8 years and determine the treatment characteristics of patients developing tMN. MethodsWe accessed the treatment files of patients with neuroendocrine neoplasms treated at our institution between January 2017 and January 2025 for pathology reports of myelodysplasia, leukemia, aplastic anemia and similar hematological disorders. ResultsA total of 173 patients received 177Lu-DOTATATE. A vast majority (77.5%) of them were treated with four therapy cycles. A total of 10/173 (5.8%) patients (4 males, 6 females) were diagnosed with tMN at a median of 23 months (5.63) after first cycle. One patient developed severe thrombocytopenia, stopped all treatments and was lost to follow-up. Two patients developed acute myelogenous leukemia (AML), six developed myelodysplastic syndrome (MDS), one developed aplastic anemia, and one developed multilineage dyspoiesis (the latter two also deemed to have MDS). Eight out of ten (80%) died after a median duration of 8 months (4.23) from tMN diagnosis. Two patients were diagnosed with AML after 2 and 4 years from the start of first cycle, while 40% of MDS cases were diagnosed by 1 year after cycle 1 of 177Lu-DOTATATE. Additionally, multilineage dyspoiesis was observed at around 5 years. ConclusionsThe prevalence of tMN was 5.8% in our patient population. We have noted a higher than previously reported percentage of myelodysplasia post-PRRT, especially with additional treatments and longer follow-ups.
Androgen deprivation therapy (ADT) is regularly used to treat locally advanced and metastatic prostate cancer (PCa) with toxicities, including metabolic syndrome (MS) and associated adverse hormonal changes. This study evaluated whether metformin mitigates changes in laboratory biomarkers associated with MS and type II diabetes mellitus (T2DM) in PCa patients receiving ADT. PRIME is a phase III double-blind, randomized controlled trial in which 166 normoglycemic patients with PCa receiving ADT were randomized to receive metformin or placebo. For this study, 47 patients from the metformin arm and 32 patients from the placebo arm underwent serum collection and analysis of the following analytes at baseline, 9, and 12 months: IGF-1, IGFBP1, IGFBP2, IGFBP3, IGFBP7, leptin, adiponectin, GDF15, insulin, C-peptide, GIP, GLP-1, and IL-6. Independent t-tests were used to determine whether significant changes in analytes were evident in patients receiving metformin vs placebo and to evaluate analyte changes from baseline for the metformin and placebo groups separately. Mean leptin values increased markedly in the placebo group and significantly less in the metformin group across all time points. Significant improvements were also observed in IGFBP1, IL-6, C-peptide, and GLP-1 with metformin compared with placebo. GDF15 and IGFBP3 significantly increased compared with baseline with ADT alone. This study demonstrates that metformin can mitigate biomarker changes induced by ADT associated with an increased risk of T2DM and MS. In addition, the attenuated increase in leptin signals a potential for improved PCa outcomes, as high leptin values have been correlated with aggressive disease and worse prognosis.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphomas (NHL) often sub-classified into major germinal centre (GC) and activated B-cell (ABC) cell-of-origin types. We have previously shown vitamin D receptor (VDR) expression in plasmablastic ABC-DLBCL cells and demonstrated inhibition of their growth by exogenous vitamin D (VitD3), however the vitamin D biology of GC-DLBCL cells remained unclear. Study of VDR and related molecule expression and vitamin D response across a panel of DLBCL and myeloma cell lines by Western blot, qPCR, flow cytometry and cell counting techniques. Analysis of gene expression and ChIP-seq in published cell line and/or primary DLBCL datasets. We show that some BCL6 hi GC-DLBCL cell lines express low levels of VDR, but appear resistant to VitD3, and associate VDR positivity in both GC- and ABC-DLBCL cell lines with the poor prognosis plasmacytic/activation marker CD38. ChIP-seq data suggest VDR may be a direct BCL6 target. Functionally, VitD3 and the EB-1089 analogue can reduce growth, inhibit MYC expression and increase CD38 expression by 50 to 400% on ABC-DLBCL and myeloma but not GC-DLBCL cells. CD38 is also activated by VitD3 treatment of human peripheral B cell lines, where VDR can bind to the CD38 locus, suggesting direct regulation. Combined VDR and cell-of-origin assessment may contribute to greater understanding of vitamin D’s role in mature B-cell lymphoma, and its interplay with BCL6 and MYC.
Objective:Mitotane is the standard therapy for advanced pediatric adrenocortical carcinoma (pACC). With improving survival, treatment-related long-term side effects and their impact on everyday functioning are becoming increasingly relevant. This multicenter pilot study provides first insights into this underexplored topic and lays the groundwork for future prospective investigations. Design and methods:Caregivers of children with pACC treated with mitotane completed an online questionnaire. Based on these retrospective caregiver-reported data, treatment-related side effects and growth parameters were assessed. Using two validated instruments - Child and Adolescent Scale of Participation (CASP) and Strengths and Difficulties Questionnaire (SDQ) - caregivers rated functional participation and behavioral outcomes. We classified patients according to ongoing versus completed mitotane therapy and compared them with a sibling control group. Results:The cohort included 24 children with pACC from eight countries, predominantly with advanced tumors (stage III-IV: 66.7%, median age: 7.4 years, 41.7% females). Half had completed mitotane therapy, and half were still receiving it. Most patients experienced relevant side effects, with adrenal insufficiency being the most frequent ongoing limitation. Patients on ongoing mitotane therapy showed reduced functional participation and more pronounced behavioral difficulties, whereas those who had completed therapy had outcomes comparable to their siblings. Conclusion:The findings of this pilot study suggest temporary impairments in functional participation and psychosocial behavior during mitotane treatment, with improvement after therapy completion. In contrast, endocrine sequelae, particularly adrenal insufficiency, may persist beyond treatment. These observations underscore the need for standardized long-term endocrine follow-up and support the feasibility of larger, prospective studies to evaluate long-term neuropsychological outcome, especially in younger children.
Poor outcomes in pancreatic neuroendocrine neoplasms (pNENs) partially result from the inability to identify early-stage disease in patients. Prevention strategies have focused on identifying high-risk patients through genetic susceptibility genes. This study aims to report the incidence of pathogenic germline variants (PGVs) in pNEN. 129 pNEN patients that underwent germline testing with Invitae between September 5, 2019, and February 15, 2022, were retrospectively analyzed. PGVs were found in 14.7% (19/129) of pNENs. PGVs in pancreatitis genes were detected in 7.7% (3/39) of the 39 pNEN patients with an available pancreatitis panel. CFTR alterations were the most common pancreatitis-associated gene identified (5.1%, 2/39). MUTYH alterations were the most frequently detected (3.9%, 5/129) PGV in pNENs. DNA or base repair PGVs were found in 7.8% (10/129). Our findings suggest that germline testing may play a role in the standard-of-care management of pNEN. MUTYH alterations merit further evaluation as a potential risk factor for pNEN.
Objective:Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare entity characterised by the proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH is a pre-neoplastic condition that can progress to localised or metastatic neuroendocrine tumours (NETs). The understanding of DIPNECH remains limited, and although the European Neuroendocrine Society has recommendations for its management, there are currently no established guidelines. Method:This study involves a case series of three patients with DIPNECH progressing to metastasis, as well as a narrative review of previous cases screened from Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica dataBASE (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL) and SCOPUS databases. Results:In 40 documented cases of DIPNECH progression to metastasis, metastatic spread was more frequently observed in the thoracic lymph nodes, with a disproportionately high incidence of atypical carcinoid features on histological examination. Conclusion:Patients with DIPNECH are a heterogeneous group, and based on current data, it is difficult to confidently predict which are more likely to experience metastases. We provide recommendations for surveillance for a range of possible outcomes, including if there is DIPNECH without metastases, if there are no metastases but particularly large lesions and when metastases are present. Patients with DIPNECH-associated atypical neuroendocrine tumours, TNM stage > IIA, R1 resection margins and/or involvement of the visceral pleura ought to be monitored most closely. There are currently insufficient data to make meaningful recommendations regarding treatment options to prevent metastases. Learning points:There are more published cases of metastases developing in the context of DIPNECH, suggesting that this is not an indolent condition in all cases.Thoracic lymph nodes tend to be the source of metastases, with a disproportionately high incidence of cases having atypical carcinoid features on histological examination.Patients with DIPNECH are a heterogeneous group, and based on current data, it is difficult to confidently predict which are more likely to experience metastases. Patients with DIPNECH and one or more of the following features: atypical neuroendocrine tumours, TNM stage > IIA, R1 resection margins and/or involvement of the visceral pleura, ought to be monitored as per ENETS and ESMO guidelines for atypical bronchial NETs. DIPNECH with typical bronchial NET should be followed as per ENETS and ESMO guidelines for typical bronchial NETs. Surveillance for nodules with no confirmed histology of DIPNECH should be followed as per the British Thoracic Society Guidelines.For patients with histologically proved DIPNECH but without visible lung neuroendocrine tumours, CT thorax surveillance scans for 1-2 years appear appropriate. If dominant lesions are >8 mm, due to increased chances of these sized lesions being malignant, it would be reasonable to undertake a baseline SSTR-PET (somatostatin receptor positron emission tomography) to confirm if any lesions are avid. If negative, the subsequent surveillance should be CT thorax, as long as there is no evidence of metastatic disease.If the baseline SSTR-PET scan demonstrates avidity and there is no discordant disease (i.e. all lesions identified on SSTR-PET are also visualised on CT), then CT surveillance alone is considered sufficient. However, small lesions <8 mm may be well below the spatial resolution of SSTR-PET and, therefore, should not be regarded as discordant disease. A repeat SSTR-PET scan is indicated only if there is evidence of lesion size progression or the emergence of new lesions on CT imaging.For patients with typical or atypical neuroendocrine tumours on a background of DIPNECH, as they appear to be more likely to metastasis, we advise following the recommendations made by the European Neuroendocrine Tumour Society for long-term follow-up post-excision.
The majority of thyroid cancers present as localized disease that is treated with surgery or radioactive iodine. Despite the effectiveness of radioactive iodine, 5-10% of thyroid cancers are radioiodine-resistant and are termed radioiodine-refractory (RAIR) thyroid cancers. RAIR tumors that spread distantly exhibit high mortality. Phase III trials, in the early 2010s, for tyrosine kinase inhibitors (TKIs) such as lenvatinib, sorafenib, and cabozantinib have shown promise in extending progression-free survival (PFS) in patients with RAIR, but it remains unclear whether these advances have improved disease-specific survival (DSS). We conducted a survival analysis of metastatic thyroid cancers using the Surveillance, Epidemiology, and End Results (SEER) national database to assess changes in DSS from 1992 to 2022. Patients were divided into three cohorts based on the year of diagnosis: 1992-2001, 2002-2011, and 2012-2022. Kaplan-Meier and Cox regression analyses were used to assess survival trends and effects of demographic and treatment variables. Our results suggest a modest but significant improvement in DSS for those diagnosed with distant metastasis of anaplastic, follicular, medullary, and oncocytic thyroid carcinoma in the most recent decade (2012-2022) compared to earlier periods. Limited information on detailed treatment data, imposed by the use of SEER, ought to be considered. Future studies with more detailed treatment data would be beneficial for confirming our findings and better characterizing RAIR thyroid cancer survival.
Multiple endocrine neoplasia (MEN) syndromes constitute a heterogeneous group of hereditary disorders predisposing to endocrine tumours of varying malignant potential. Recent advances in molecular genetics and tumour biology have significantly reshaped our understanding of underlying pathophysiology, enabling earlier diagnosis, genotype-specific surveillance and the emergence of targeted therapies. This review provides a contemporary overview of key recent advances and consensus guidelines across MEN syndromes, including MEN1, MEN2, MEN4, and MEN5 syndromes, SDHx syndrome, Carney complex, McCune–Albright syndrome, DICER1 syndrome and von Hippel–Lindau syndrome. These insights reflect a rapidly evolving field with genetic diagnosis at the centre of prognostic assessment, targeted surveillance and individualised management.
ObjectiveTo evaluate the impact of iodine-123 (I-123) diagnostic scintigraphy on management outcomes in patients undergoing follow-up for differentiated thyroid carcinoma (DTC), and to assess whether multidisciplinary team (MDT) discussion influences subsequent clinical pathways. MethodsA retrospective analysis was conducted of patients with DTC who underwent I-123 scintigraphy at an NHS trust. Demographic data, scan findings, and subsequent clinical actions were collected. Scans were categorised as MDT endorsed or requested by individual clinicians. Outcomes were assessed by distinguishing initial diagnostic actions prompted by I-123 imaging from definitive management outcomes following completion of downstream investigations. ResultsA total of 55 I-123 scans from 51 patients were included. New or abnormal findings were identified in 21 scans (38.2%). Initial diagnostic actions followed 23 scans (41.8%), most commonly further imaging. When management outcomes were reassessed after completion of downstream investigations, no definitive change in management occurred in 40 scans (72.7%), while 13 scans (23.6%) resulted in a definitive management change; in 2 scans (3.6%), outcomes were unclear. MDT-endorsed scans more frequently prompted initial diagnostic actions, although this difference was not statistically significant. Outcomes for MDT-requested scans and individually requested scans were near-identical (definitive change in management in 20% vs 20.7). ConclusionsI-123 scintigraphy can influence clinical decision-making during follow-up of patients with differentiated thyroid cancer, most commonly by prompting further diagnostic investigation. However, definitive changes in management occur in a minority of cases. These findings support a selective rather than routine role for I-123 imaging in follow-up.
SummaryMetastatic adrenocortical carcinoma in adults carries a very poor prognosis with rare complete response following local and systemic therapies. Combined therapy with etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) provided a better response rate than streptozotocin and mitotane (Sz-M). Here, we report three patients with metastatic adrenocortical carcinoma, two of which were participants in the FIRM-ACT study, who achieved and maintained long-term complete response following Sz-based therapy after disease progression or toxicity with first-line treatments. Learning pointsAlthough rare, complete long-term response of advanced metastatic ACC is possible.Sz-M (or even Sz alone) should be considered in patients with advanced ACC when EDP-M does not achieve disease control or cannot be continued due to toxicity limitations.
Paragangliomas (PGLs) are rare neuroendocrine neoplasms of neural-crest origin, with primary mesenteric localization representing an exceptionally uncommon entity that is rarely considered in the preoperative differential diagnosis of mesenteric masses. We report the case of a 51-year-old woman who was referred to our institute following the incidental detection of a 12 × 9 mm hypervascular nodule within the pelvic small bowel mesentery on contrast-enhanced computed tomography (CT). Subsequent 68Ga-DOTATOC positron emission tomography/CT showed intense somatostatin receptor uptake confined to the mesenteric nodule, with no other lesions. Dedicated pan-colonoscopy was unremarkable and 24-h urinary 5-hydroxyindoleacetic acid was within normal limits. Preoperative diagnosis of nodal metastasis from an occult ileal neuroendocrine tumor was made, and laparoscopic surgery was undertaken. Meticulous bimanual palpation of the small bowel with transillumination did not reveal any primary lesions, while a 1 cm mesenteric mass was identified and excised. Histology revealed a solid tumor with Zellballen architecture with tumor cells positive for chromogranin A and GATA3, and negative stains for cytokeratin, CDX2, and serotonin, establishing the diagnosis of paraganglioma. This case highlights the importance of recognizing paraganglioma as a potential diagnostic mimic in solitary somatostatin receptor-avid mesenteric nodules to prevent unnecessary investigations and guide appropriate surgical management. Learning pointsPrimary mesenteric paragangliomas should be considered in the differential diagnosis of solitary, hypervascularized mesenteric masses.A solitary SSTR-avid mesenteric nodule in an asymptomatic, biochemically silent patient does not necessarily imply nodal metastasis from an occult small intestinal neuroendocrine tumor.Considering alternative diagnoses may avoid unnecessary endoscopic, radiological, and surgical investigations for an intestinal primary lesion.Definitive diagnosis and risk stratification rely on histopathology and immunohistochemistry, including epithelial markers, GATA3, and SDHB.Awareness of mesenteric paraganglioma as a diagnostic mimic can prevent overtreatment and guide appropriate surgical management.
ObjectiveDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphomas (NHLs) often sub-classified into major germinal centre (GC) and activated B-cell (ABC) cell-of-origin types. We have previously shown vitamin D receptor (VDR) expression in plasmablastic ABC-DLBCL cells and demonstrated inhibition of their growth by exogenous vitamin D (VitD3); however, the vitamin D biology of GC-DLBCL cells remained unclear. Design/methodsStudy of VDR and related molecule expression and vitamin D response across a panel of DLBCL and myeloma cell lines by western blot, qPCR, flow cytometry and cell counting techniques. Analysis of gene expression and ChIP-seq in published cell line and/or primary DLBCL datasets. ResultsWe show that some BCL6hi GC-DLBCL cell lines express low levels of VDR, but appear resistant to VitD3, and associate VDR positivity in both GC- and ABC-DLBCL cell lines with the poor prognosis plasmacytic/activation marker CD38. ChIP-seq data suggest that VDR may be a direct BCL6 target. Functionally, VitD3 and the EB-1089 analogue can reduce growth, inhibit MYC expression and increase CD38 expression by 50–400% on ABC-DLBCL and myeloma but not GC-DLBCL cells. CD38 is also activated by VitD3 treatment of human peripheral B cell lines, where VDR can bind to the CD38 locus, suggesting direct regulation. ConclusionsCombined VDR and cell-of-origin assessment may contribute to a greater understanding of vitamin D’s role in mature B-cell lymphoma and its interplay with BCL6 and MYC.
Background: This study aimed to evaluate whether early renal and bone marrow effects – previously identified through laboratory tests – can be detected using MRI and 18F-FLT PET-MR in neuroendocrine tumor patients treated with 177Lu-DOTATATE. Despite known early changes, precise clinical tools to monitor these effects remain limited. Methods: Ten patients with metastatic NETs, scheduled to initiate at least four treatment cycles of 177Lu-DOTATATE, were included. MRI was performed at all designated treatment time points, whereas F-FLT PET was acquired only at baseline and on day 2 following treatment initiation. Bone marrow (BM) fat conversion, proliferative activity, and renal effects were studied with MRI and 18F-FLT PET-MR. Laboratory tests for hematology and kidney and liver function were taken. Results: Six patients completed the full imaging protocol with MRI, of whom 18F-FLT PET-MR examinations were performed in two patients. All subjects demonstrated increased BM fat content during the study interval, with a mean of +12.8%. The magnitude of the increase varied substantially, from +3.8% to +23.5%. There was a strong correlation between increased BM fat content and reduced peripheral blood cell counts. Decreased FLT uptake was found on day 2 after treatment. An increase in renal arterial flow and parenchymal volume was detected during the first week after treatment. No sustained renal effects were observed. Conclusions: The hematological effects observed with laboratory tests after 177Lu-DOTATATE treatment in neuroendocrine tumor patients can be detected by MRI as an increase in bone marrow fat content. This finding was supported by decreased FLT uptake on 18F-FLT PET-MR, indicating decreased bone marrow cell proliferation. MRI can also identify renal effects associated with this therapy.
Introduction: Physical activity interventions could play a critical role in tolerance and outcome during anti-neoplastic therapy. Aim: This study aims to evaluate the role of physical activity and its maintenance on treatment safety and efficacy in patients with advanced thyroid cancer. Methods: We enrolled 28 patients with advanced thyroid cancer, treated with kinase inhibitor therapy for a median follow-up of 26 months. Three modified long-form International Physical Activity Questionnaires were administered before treatment, at an intermediate follow-up point and at the last follow-up point. Metabolic equivalents were calculated at each time point. Tumour response was evaluated according to RECIST, version 1.1. Results: Patients inactive at baseline experienced more treatment interruptions during both the first (85 vs 30%, P = 0.01) and second half of the follow-up period (85 vs 47%, P = 0.08) and had more frequently a progressive disease (42 vs 14%, P = 0.15), compared to those who were mildly or highly active. Patients who declined their physical activity during treatment had more treatment interruptions (100 vs 31%, P = 0.006), more adverse events considering both the number (>5) and the grade (≥3) (100 vs 31%, P = 0.006 and 100 vs 38%, P = 0.01), more hospitalization due to toxicities (66 vs 8%, P = 0.008) and a more progressive disease (40 vs 8%, P = 0.09). The number of toxicities was inversely correlated with metabolic equivalents lost (r = −0.15, P = 0.04). Conclusion: This is the first study showing that maintaining adequate physical activity levels is associated with better treatment tolerance and outcomes in advanced thyroid cancer patients on kinase inhibitor therapy, supporting the need for prospective prehabilitation trials.
Summary Parathyroid hormone-related peptide (PTHrP)-secreting pancreatic neuroendocrine tumours (Pan-NETs) are a rare cause of humoural hypercalcaemia of malignancy (HCM). We report two contrasting cases of metastatic well-differentiated PTHrP-secreting Pan-NETs (WHO grade 2; Ki-67: 7 and 8%, respectively), highlighting the variability in disease progression, response to multiple treatment modalities, and long-term outcomes. The first patient, a 55-year-old woman with mild hypercalcaemia who was largely asymptomatic except for a persistent dry cough at presentation, achieved stable disease control following eight years of treatment with somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT), and chemotherapy. During a prolonged period of uncontrolled hypercalcaemia prior to chemotherapy, she developed rapid bilateral hip osteoarthrosis and tumour calcification, a rare complication from long-standing calcium elevation. The second patient, a 34-year-old woman, had a more aggressive disease course, requiring multiple hospital admissions for refractory moderate-to-severe hypercalcaemia and variceal bleeding. Despite initial tumour stabilisation following PRRT, she developed refractory hypercalcaemia, demonstrating only partial response to zoledronate, high-dose denosumab, and maximal somatostatin analogue therapy, and ultimately succumbed to progressive disease and metabolic deterioration. These cases underscore the heterogeneity of PTHrP-secreting Pan-NETs and the challenges in optimising treatment strategies, given the lack of data on the optimal sequencing of therapies. Notably, calcium can serve as a reliable tumour marker for disease control, with persistent severe hypercalcaemia being a potential prognostic factor of poor outcome in patients with PTHrP-related hypercalcaemia. International collaboration and knowledge exchange are needed to ascertain the most effective management of this rare functional syndrome. Learning points Consider PTHrP secretion in the context of hypercalcaemia in Pan-NETs.Calcium level can serve as a tumour marker in patients with PTHrP-related hypercalcaemia for assessing treatment response, disease progression, and tumour aggressiveness, with persistent hypercalcaemia being a prognostic factor for poor outcome.Hypercalcaemia may be resistant to standard treatments, and higher doses of denosumab may be necessary to achieve adequate control.An individualised multimodal treatment approach, including SSAs, PRRT, targeted therapy, chemotherapy, or a combination thereof, should be utilised to control PTHrP-secreting Pan-NETs.Although the optimal sequencing of these therapies remains unclear, multidisciplinary team discussions and shared decision-making are essential in managing such complex cases.
Objective: The prognostic value of primary tumor size in duodenal neuroendocrine neoplasms (dNENs) ≤20 mm remains uncertain. Although size is used to guide management, its independent effect on survival is unclear. Design and methods: We performed a population-based study using the US SEER database (1975–2021), including adults with histologically confirmed dNENs ≤20 mm. Disease-specific survival (DSS) was the primary endpoint. Associations between tumor size, stage, lymph-node involvement, and DSS were evaluated using chi-squared tests, logistic regression, Kaplan–Meier curves, and Cox models. Receiver operating characteristic (ROC) analysis identified the optimal size cutoff. Mediation analysis assessed whether stage or grade mediated the size–DSS relationship. Results: Among 3,515 eligible cases, median age was 65 years, 51% were male, and 89% had well-differentiated NETs. Most tumors were localized (85.2%) and ≤10 mm (74.4%). Median follow-up was 56 months, with 160 disease-specific deaths (4.6%). In univariable analysis, size >10 mm was associated with worse DSS, but the association disappeared after adjustment for grade, stage, and surgery. Grade G3 and advanced stage independently predicted poorer survival, while radical surgery was protective. Larger tumors were more frequently high grade and advanced stage (P < 0.001), and each 1 mm increase raised the odds of nodal metastasis by 12% (OR 1.12). ROC analysis identified a size threshold of 10.5 mm (AUC = 0.74). Stage mediated only ∼2% of the size–DSS association. Conclusions: In duodenal NENs ≤ 20 mm, tumor size >10 mm correlates with disease extent but does not independently affect DSS, supporting its role as a stratification marker rather than a prognostic factor.
Summary:Pathogenic germline variants in the genes encoding the various subunits of the succinate dehydrogenase (SDH) enzyme complex are strongly associated with hereditary phaeochromocytomas and paragangliomas (PPGLs). Germline pathogenic variants (PGVs) in the SDHA gene are also found in individuals with wild-type gastrointestinal stromal tumours (GISTs) and paragangliomas. However, the penetrance of SDHA variants is relatively low. Only a minority of carriers will develop tumours as a result of the genetic condition. As a result, careful clinical interpretation is therefore required to avoid unnecessary over-investigation or undue concern. Current national guidelines recommend that SDHA variants should only be considered actionable (that is, to lead to surveillance in the proband and family screening) if they are identified in individuals with a personal or family history of an SDHA-related tumour. Nevertheless, SDHA variants are increasingly detected as a result of whole genome sequencing or multigene panel testing. This emphasises the importance of clinical context when deciding on surveillance or family testing. We describe three carriers of germline SDHA variants. The first case is a 72-year-old male with a history of prostate cancer and GIST, where genetic testing revealed germline variants in BRCA2 and SDHA. Tumour-derived DNA from his GIST demonstrated a somatic PDGFRA driver mutation, and SDH staining was preserved, indicating a sporadic PDGFRA-driven GIST rather than a classical SDHA-deficient tumour. While truncating SDHA variants such as this one have been reported in SDH-deficient GIST, the current UK practice considers them low penetrance and typically not actionable in the absence of SDH-deficient pathology. Accordingly, cascade testing of the SDHA variant was not recommended in his family, and no surveillance for SDH-associated tumours was initiated, although we recognise that some international guidelines may take a more precautionary approach. The second case features a 59-year-old female with wild-type GIST and a family history of brain tumours and breast cancer. Testing of tumour-derived DNA identified an SDHA variant, later confirmed of germline origin. Surveillance for other SDH-associated tumours for the proband and cascade testing for her relatives were recommended. The third case involves a man in his sixties with prostate cancer, found to carry an incidental SDHA variant after undergoing broad cancer predisposition panel testing. He had no personal/family history of SDH-associated tumours, and his prostate cancer showed strong SDHA expression, indicating that the variant was non-actionable, and no surveillance for SDH-associated tumours or familial cascade testing was recommended. These cases underscore the importance of interpreting SDHA variants carefully, as the identification of germline SDHA variants does not always indicate the need for aggressive surveillance or intervention. Learning points:Germline SDHA variants increase the risk of PPGLs and wild-type GISTs.The penetrance of germline SDHA variants in carriers without an SDHA-related tumour is low.Careful clinical assessment is essential to determine if a patient with an SDHA germline mutation has an SDHA-related tumour.This is particularly complex in GISTs, as only wild-type GISTs (those without somatic variants in c-Kit or PDGFRA) are likely to be SDHA-related.Immunohistochemistry for expression of SDH subunits can help clarify whether a tumour is related to SDHA variants.
