EPAS1-mutated paragangliomas associated with haemoglobin disorders.

We report a large series of 40 patients presenting EPAS1-mutated paraganglioma (PGL) in whom we investigated a cause underlying chronic hypoxia. Four patients suffered from hypoxaemic heart disease. In patients with available haemoglobin electrophoresis results, 59% presented with a haemoglobin disorder, including six with sickle cell disease, five with sickle cell trait and two with heterozygous haemoglobin C disease. Histological and transcriptomic characterization of EPAS1 tumours revealed increased angiogenesis and high similarities with pseudohypoxic PGLs caused by VHL gene mutations. Sickle haemoglobinopathy carriers could thus be at increased risk for developing EPAS1-PGLs, which should be taken into account in their management and surveillance.

Performance of [18F]fluorocholine PET/CT in MEN1-related primary hyperparathyroidism before initial surgery or for persistent/recurrent disease.

PURPOSE: The aims of the study were to evaluate the performance and robustness of [18F]fluorocholine PET/CT in detecting hyperfunctioning parathyroid glands in MEN1-related primary hyperparathyroidism (pHPT) at different stages of their disease. METHODS: Retrospective French multicenter study including patients with MEN1 pHPT who underwent [18F]fluorocholine PET/CT at initial diagnosis or for evaluation of persistent/recurrent disease. PET/CT were independently reviewed by two readers in a blinded manner. The assessment of PET/CT on a per-patient basis was assessed using a comprehensive set of criteria that considered pathological findings or agreement with alternative diagnostic methods in non-operated patients. The secondary objectives included the analysis of the performance of PET/CT at a per-lesion level, with reference to a pathological Gold Standard, and examining its interobserver reproducibility. RESULTS: A total of 71 MEN1 patients were included (73 PET/CT) in the study. At the per-patient level (entire cohort), [18F]fluorocholine PET/CT sensitivity ranged from 98.5 to 100% among the different readers. An average of 1.77 glands per PET was described, with 2.35 glands at the initial diagnosis (n = 23) and 1.5 in previously operated cases (n = 50). PET/CT detected more lesions than conventional imaging work-up (neck ultrasound and/or scintigraphy). At the per-lesion level (41 operated patients), sensitivity ranged across different readers from 84.4 to 87%, and specificity ranged from 94.7 to 98.8%. At initial diagnosis, all patients that exhibited 3 or more abnormal glands on PET underwent subtotal parathyroidectomy while 7 out of 13 patients with 1 or 2 gland abnormalities on PET underwent less than subtotal parathyroidectomy. Finally, the degree of inter-observer agreement was high. CONCLUSION: [18F]fluorocholine PET/CT is a reliable and robust imaging modality for the evaluation of MEN1-related pHPT and could guide surgeons in achieving the optimal benefit-risk ratio. This study gives a great impetus for its adoption as a primary diagnostic tool in this context.

Health-related quality of life and radioiodine therapy in thyroid cancer patients: a before-and-after study.

OBJECTIVE: Thyroid cancers are on the rise, but the associated vital prognosis and long-term survival rates are very good. Therefore, treated patients' quality of life and psychological well-being are important considerations. The treatment usually involves surgery and radioactive iodine (radioiodine) ablation. This study aims to investigate potential effects of radioiodine ablation therapy on health-related quality of life, anxiety and depression symptoms, and nutritional status at 6 months post-therapy. METHODS: This study included 136 patients diagnosed with thyroid cancer. Absorbed doses to the salivary glands were estimated from dosimeters worn by patients. Patient health-related quality of life, psychological status and nutritional status were assessed before and 6 months after therapy using standardized questionnaires (including SF-36, Hospital Anxiety and Depression (HAD) scale). Statistical analyses included random-effects logistic and linear regressions adjusted for potential confounders. RESULTS: While no significant association was found between radioiodine exposure and anxiety or depression symptoms, or nutritional status, a significant increase in the SF-36 role physical sub- score was observed in relation with the salivary gland dose (ß= 6.54, 95%CI 2.71;10.36 for a 1-Gy increase). CONCLUSIONS: The findings suggest an improved physical health-related quality of life, namely reduced pain and functional impairment, 6 months after radioiodine therapy in thyroid cancer patients. No significant association was found between radioiodine exposure and mental health-related quality of life, anxiety or depression scores nor nutritional status. This study does not provide any evidence that radioiodine therapy has a potentially adverse effect on patient health-related quality of life.

Utility of a Second 99mTc-MIBI Scintigraphy Before Reoperation for Patients With Persistent Sporadic Primary Hyperparathyroidism: Results of a Retrospective Multicenter Study.

BACKGROUND: Persistent primary hyperparathyroidism (PHPT) occurs in 2.5% to 15% of cases after parathyroidectomy. Few studies have evaluated the best pre-reoperative imaging approaches for persistent sporadic PHPT. This retrospective multicenter study aimed to evaluate the benefit of a second pre-reoperative 99mTc-methoxy-isobutyl-isonitrile (MIBI) scintigraphy for patients with persistent PHPT who had a 99mTc-MIBI before their initial surgery. METHODS: The study enrolled 50 patients with persistent sporadic PHPT who had reoperation between 2006 and 2016 in three French University Hospitals (Angers, Nantes, and La Pitié Salpêtrière-Paris). Preoperative 99mTc-MIBI scan was performed before each operation. RESULTS: After the reoperation, 42 patients (84%) were cured. By the second 99mTc-MIBI, 31 patients (62%) had a removed gland identified. A new pathologic gland was identified by a second 99mTc-MIBI in 25 patients (50%), and this imaging permitted correction of an initial surgical error in six patients (12%). A second 99mTc-MIBI showed a sensitivity of 63%, a specificity of 89%, a positive predictive value (PPV) of 78%, and a negative predictive value (NPV) of 80%. A concordant second 99mTc-MIBI and ultrasonography (17 patients) showed a sensitivity of 70%, a specificity of 81%, a PPV of 70%, and an NPV of 81%. CONCLUSIONS: Performing a second 99mTc-MIBI scan permitted 62% of the persistent PHPT patients to be cured, allowing identification of new pathologic glands in 50% of the cases and correction of an initial surgical error in 12% of the cases, with high specificity and PPV. These results reinforce the fact that a second 99mTc-MIBI scan should be performed at first intention before reoperation of patients with persistent PHPT, regardless of the result from the initial 99mTc-MIBI scan.

Succinate detection using in vivo 1H-MR spectroscopy identifies germline and somatic SDHx mutations in paragangliomas.

PURPOSE: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients. METHODS: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor. RESULTS: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%. CONCLUSIONS: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs.

Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma.

BACKGROUND: Knowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS). METHODS: We developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours. RESULTS: In the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available. CONCLUSION: The analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.

Diffusion-weighted MRI is not superior to FDG-PET/CT for the detection of neck recurrence in well-differentiated thyroid carcinoma.

BACKGROUND: Management of patients with well-differentiated thyroid carcinoma (WDTC) and positive thyroglobulin (Tg)/negative iodine-131 whole body scintigraphy (WBS) remains challenging. Here, we investigate the specific role of diffusion-weighted magnetic resonance imaging of the neck (DW-MRI) as compared to rhTSH stimulated FDG-PET/CT in such patients. METHODS: Patients with WDTC, positive Tg/negative WBS were prospectively enrolled in the study. FDG-PET/CT and neck DW-MRI were performed on the same day after rhTSH stimulation. Neck-US was performed 24 hours after FDG-PET/CT and MRI to guide fine-needle aspiration (FNA). Patients with positive FNA underwent surgery. Patient with negative workup underwent new explorations at 6 and 18 months. RESULTS: A total of 86 FDG-PET/CT and 83 DW-MRI tests were performed in 40 patients (23 females; 17 males; 52±16 years). For detection of neck recurrences, sensitivity was equivalent for FDG-PET/CT and to DW-MRI at baseline (46% vs. 43%), at 6 months (30% vs. 20%) and at 18 months (11 vs. 10%). The comparison with a non-weighted Kappa test shows significant concordance between FDG-PET/CT and DW-MRI (K=0.741±0.062; P<0.0001). A relationship was observed between Tg and results of FDG-PET/CT, but not for DW-MRI. FDG-PET/CT permitted to detect iodine-refractory distant metastasis in 4 patients. CONCLUSIONS: In Tg-positive/WBS-negative DTC patients, low tumour burden, neck DW-MRI does not provide additional information compared to rhTSH-stimulated FDG-PET/CT. FDG-PET/CT has the best sensitivity, is acceptable for patients, allows whole body exploration and distant metastasis detections, and is correlated with Tg levels.

18F-Fluorocholine PET/CT and Parathyroid 4D Computed Tomography for Primary Hyperparathyroidism: The Challenge of Reoperative Patients.

BACKGROUND: To evaluate FCH-PET/CT and parathyroid 4D-CT so as to guide surgery in patients with primary hyperparathyroidism (pHPT) and prior neck surgery. METHODS: Medical records of all patients referred for a FCH-PET/CT in our institution were systematically reviewed. Only patients with pHPT, a history of neck surgery (for pHPT or another reason) and an indication of reoperation were included. All patients had parathyroid ultrasound (US) and Tc-99m-sestaMIBI scintigraphy, and furthermore, some patients had 4D-CT. Gold standard was defined by pathological findings and/or US-guided fine-needle aspiration with PTH level measurement in the washing liquid. RESULTS: Twenty-nine patients were included in this retrospective study. FCH-PET/CT identified 34 abnormal foci including 19 ectopic localizations. 4D-CT, performed in 20 patients, detected 11 abnormal glands at first reading and 6 more under FCH-PET/CT guidance. US and Tc-99m-sestaMIBI found concordant foci in 8/29 patients. Gold standard was obtained for 32 abnormal FCH-PET/CT foci in 27 patients. On a per-lesion analysis, sensitivity, specificity, positive and negative predictive values were, respectively, 96%, 13%, 77% and 50% for FCH-PET/CT, 75%, 40%, 80% and 33% for 4D-CT. On a per-patient analysis, sensitivity was 85% for FCH-PET/CT and 63% for 4D-CT. FCH-PET/CT results made it possible to successfully remove an abnormal gland in 21 patients, including 12 with a negative or discordant US/Tc-99m-sestaMIBI scintigraphy result, with a global cure rate of 73%. CONCLUSION: FCH-PET/CT is a promising tool in the challenging population of reoperative patients with pHPT. Parathyroid 4D-CT appears as a confirmatory imaging modality.

Rodent models of pheochromocytoma, parallels in rodent and human tumorigenesis.

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors characterized by a large spectrum of hereditary predisposition. Based on gene expression profiling classification, they can be classically assigned to either a hypoxic/angiogenic cluster (cluster 1 including tumors with mutations in SDHx, VHL and FH genes) or a kinase-signaling cluster (cluster 2 consisting in tumors related to RET, NF1, TMEM127 and MAX genes mutations, as well as most of the sporadic tumors). The past 15 years have seen the emergence of an increasing number of genetically engineered and grafted models to investigate tumorigenesis and develop new therapeutic strategies. Among them, only cluster 2-related predisposed models have been successful but grafted models are however available to study cluster 1-related tumors. In this review, we present an overview of existing rodent models targeting predisposition genes involved or not in human pheochromocytoma/paraganglioma susceptibility and their contribution to the improvement of pheochromocytoma experimental research.

Overview of recent guidelines and consensus statements on initial screening and management of phaeochromocytoma and paraganglioma in SDHx pathogenic variant carriers and patients.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a strong genetic predisposition, involving over 20 genes and with germline pathogenic variants identified in 40 % of cases. The succinate dehydrogenase (SDHx) genes are the most commonly implicated in hereditary PPGLs, accounting for 20 % of cases, and present unique diagnostic and treatment challenges due to their potential for multiple, recurrent, and aggressive manifestations, often necessitating lifelong follow-up. Over the past two decades, advances in biochemical and imaging assessments, management, and follow-up protocols have significantly improved care for both adult and paediatric patients. These advances include next-generation sequencing, new biochemical tests, cluster-specific functional imaging, and improved surgical and radiotherapy techniques, such as stereotactic surgery and peptide receptor radionuclide therapy (PRRT). International consensus guidelines have been developed to standardise the management of patients with SDHx pathogenic variants, emphasising multidisciplinary approaches and frequent tumour board discussions. These guidelines, summarised below, cover recommendations for initial genetic testing, tumour screening, follow-up care, and management of patients and asymptomatic carriers.

Feasibility of Liver Transplantation after 90 Y Radioembolization: Lessons from a Radiation Protection Incident.

ABSTRACT: Radioembolization using 90 Y is a growing procedure in nuclear medicine for treating hepatocellular carcinoma. Current guidelines suggest postponing liver transplantation or surgical resection for a period of 14 to 30 d after radioembolization to minimize surgeons' exposure to ionizing radiation. In light of a radiation protection incident, we reevaluated the minimum delay required between radioembolization and subsequent liver transplantation. A patient with a hepatocellular carcinoma underwent a liver transplantation 44 h after undergoing radioembolization using 90 Y (860 MBq SIR-Spheres). No specific radioprotection measures were followed during surgery and pathological analysis. We subsequently (1) evaluated the healthcare professionals' exposure to ionizing radiation by conducting dose rate measurements from removed liver tissue and (2) extrapolated the recommended interval to be observed between radioembolization and surgery/transplantation to ensure compliance with the radiation dose limits for worker safety. The surgeons involved in the transplantation procedure experienced the highest radiation exposure, with whole-body doses of 2.4 mSv and extremity doses of 24 mSv. The recommended delay between radioembolization and liver transplantation was 8 d when using SIR-Spheres and 15 d when injecting TheraSphere. This delay can be reduced further when considering the specific 90 Y activity administered during radioembolization. This dosimetric study suggests the feasibility of shortening the delay for liver transplantation/surgery after radioembolization from the 8th or 15th day after using SIR-Spheres or TheraSphere, respectively. This delay can be decreased further when adjusted to the administrated activity while upholding radiation protection standards for healthcare professionals.

Consideration of Early Dynamic Risk Stratification to Guide Discharge from Oncologic Follow-Up in Patients with Differentiated Thyroid Cancer.

Background: The current dogma is a life-long follow-up for patients treated for follicular-derived differentiated thyroid cancers (DTC). Our primary objective was to determine the time to recurrence in a series of DTC patients with an excellent response to therapy 6 months after total thyroidectomy and radioiodine therapy. The secondary objectives were to determine the time to suspicion of recurrence and to identify factors associated with recurrence. Methods: This retrospective cohort study included patients treated for DTC between 2008 and 2012 and in remission 6 months after total thyroidectomy and radioiodine treatment. The criteria for remission were negative imaging and suppressed thyroglobulin (Tg) <0.2 ng/mL or rh-TSH-(recombinant human TSH) stimulated Tg <1 ng/mL according to the 2015 ATA (American Thyroid Association) guidelines. Recurrence was defined by cytologically and/or histologically proven cervical lymph node metastasis or the administration of a second radioiodine treatment. Results: Among 721 patients treated for DTC, 158 were excluded because of persistent disease at 6 months, 71 because of missing follow-up data, and 492 were included. The mean and median follow-up time were 7.0 and 7.9 years (interquartile range IQR [2.1-11.3]). Recurrence occurred for 7 patients (1.4%), 1 initially classified as high recurrence risk, 3 as intermediate, and 3 as low risk according to the 2015 ATA guidelines. All relapses occurred within 10 years after initial management (4 within the first 5 years). For patients with recurrence, rise in Tg and/or suspicious lymph nodes were detected in six out of seven cases in the first 8 years and for the last case 10 years after initial surgery. Conclusion: Low and intermediate recurrence risk DTC patients with excellent response 6 months after total thyroidectomy and radioiodine and in remission 10 years later have an extremely low recurrence risk. Follow-up might be undertaken by primary care providers from this time point. These discharge recommendations should be confirmed by further prospective studies.

Enhanced therapeutic outcomes with atezolizumab-bevacizumab and SIRT combination compared to SIRT alone in unresectable HCC: A promising approach for improved survival.

BACKGROUND: Integrating immunotherapy with locoregional therapies marks a significant milestone in the realm of hepatocellular carcinoma (HCC) treatment . This study aimed to assess the impact of addition of Atezolizumab-Bevacizumab (AtezoBev) on the outcome patients treated with SIRT. METHODS: We conducted a study that included all Child-Pugh A HCC treated with SIRT since 2017. We examined the effects of the addition of 3 infusions of AtezoBev before the SIRT procedure and after SIRT on patients outcome (AtezoBev-SIRT group). Time-to-event data were analyzed using Kaplan-Meier with the log-rank test. RESULTS: Thirty five HCC patients treated with SIRT were included, of whom 23 % also received AtezoBev infusions. The two groups were similar in terms of liver function and HCC parameters. The median OS was not reached for patients who received AtezoBev in combination with SIRT and 14 months for patients only treated by SIRT. The median PFS was higher in the group treated by SIRT and AtezoBev vs SIRT alone (11.3 months vs 5.8 months). In the global cohort, 8 patients presented a downstaging (23 %), 4 underwent liver surgery (1 in the AtezoBev-SIRT group) and 4 liver transplantation (1 in the AtezoBev-SIRT group) CONCLUSIONS: The administration of AtezoBev, both before and after SIRT, is associated with enhanced OS and PFS outcomes compared to SIRT alone for unresectable HCC.

PRAP study-partial versus radical adrenalectomy in hereditary pheochromocytomas.

OBJECTIVE: Hereditary pheochromocytoma (hPCC) commonly develops bilaterally, causing adrenal insufficiency when standard treatment, radical adrenalectomy (RA), is performed. Partial adrenalectomy (PA) aims to preserve adrenal function, but with higher recurrence rates. This study compares outcomes of PA versus RA in hPCC. METHODS: Patients with hPCC due to pathogenic variants in RET, VHL, NF1, MAX, and TMEM127 from 12 European centers (1974-2023) were studied retrospectively. Stratified analysis based on surgery type and initial presentation was conducted. The main outcomes included recurrence, adrenal insufficiency, metastasis, and mortality. RESULTS: The study included 256 patients (223 RA, 33 PA). Ipsilateral recurrence rates were 9/223 (4%) after RA versus 5/33 (15%) after PA (P = 0.02). Metastasis and mortality did not differ between groups. Overall, 103 patients (40%) underwent bilateral adrenalectomy either synchronously or metachronously (75 RA, 28 PA). Of these, 46% developed adrenal insufficiency after PA.In total, 191 patients presented with initial unilateral disease, of whom 50 (26%) developed metachronous contralateral disease, most commonly in RET, VHL, and MAX. In patients with metachronous bilateral disease, adrenal insufficiency developed in 3/4 (75%) when PA was performed as the first operation followed by RA, compared to 1/7 (14%) when PA was performed as the second operation after prior RA (P = 0.09). CONCLUSION: In patients with hPCC undergoing PA, local recurrence rates are higher than after RA, but metastasis and disease-specific mortality are similar. Therefore, PA seems a safe method to preserve adrenal function in patients with hPCC, in cases of both synchronous and metachronous bilateral disease, when performed as a second operation.

International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

SDHx mutation and pituitary adenoma: can in vivo 1H-MR spectroscopy unravel the link?

Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the '3PAs' syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

Dysfunction of the Salivary and Lacrimal Glands After Radioiodine Therapy for Thyroid Cancer: Results of the START Study After 6-Months of Follow-Up.

Background: Understanding of changes in salivary and lacrimal gland functions after radioactive iodine therapy (131I-therapy) remains limited, and, to date, no studies have evaluated dose-response relationships between absorbed dose from 131I-therapy and dysfunctions of these glands. This study investigates salivary/lacrimal dysfunctions in differentiated thyroid cancer (DTC) patients six months after 131I-therapy, identifies 131I-therapy-related risk factors for salivary/lacrimal dysfunctions, and assesses the relationships between 131I-therapy radiation dose and these dysfunctions. Methods: A cohort study was conducted involving 136 DTC patients treated by 131I-therapy of whom 44 and 92 patients received 1.1 and 3.7 GBq, respectively. Absorbed dose to the salivary glands was estimated using a dosimetric reconstruction method based on thermoluminescent dosimeter measurements. Salivary and lacrimal functions were assessed at baseline (T0, i.e., immediately before 131I-therapy) and six months later (T6) using validated questionnaires and salivary samplings, with and without stimulation of the salivary glands. Statistical analyses included descriptive analyses and random-effects multivariate logistic and linear regressions. Results: There was no difference between T0 and T6 in the level of parotid gland pain, nor was there difference in the number of patients with hyposalivation, but there were significantly more patients with dry mouth sensation and dry eyes after therapy compared with baseline. Age, menopause, depression and anxiety symptoms, history of systemic disease, and not taking painkillers in the past three months were found to be significantly associated with salivary or lacrimal disorders. Significant associations were found between 131I-exposure and salivary disorders adjusted on the previous variables: for example, per 1-Gy increase in mean dose to the salivary glands, odds ratio = 1.43 [CI 1.02 to 2.04] for dry mouth sensation, ß = -0.08 [CI -0.12 to -0.02] mL/min for stimulated saliva flow, and ß = 1.07 [CI 0.42 to 1.71] mmol/L for salivary potassium concentration. Conclusions: This study brings new knowledge on the relationship between the absorbed dose to the salivary glands from 131I-therapy and salivary/lacrimal dysfunctions in DTC patients six months after 131I-therapy. Despite the findings of some dysfunctions, the results do not show any obvious clinical disorders after the 131I-therapy. Nevertheless, this study raises awareness of the risk factors for salivary disorders, and calls for longer follow-up. Clinical Trials Registration: Number NCT04876287 on the public website (ClinicalTrials.gov).

Long-Term Outcomes in Head and Neck Paragangliomas Managed with Intensity-Modulated Radiotherapy.

OBJECTIVES: Head & Neck Paragangliomas have been historically relying on surgery mostly, with worsened quality of life and major sequelae. Conventional external radiation therapy seems to offer an equivalent control rate with a low toxicity profile. The aim of this study was to assess the safety and efficiency of intensity-modulated radiation therapy in Head & Neck paragangliomas. METHODS: This is a retrospective monocentric study conducted in a referral center, including all patients treated with IMRT, whether as an exclusive or post-operative treatment for a tympanic and jugular, carotid, or vagal paraganglioma. Data collection was performed through the manuscript and computerized medical files, including consultation, operative, imaging, pathological analyses, delineation, and treatment planning reports. Success was defined as the complete or partial regression or stabilization without progression, or relapse in accordance with the RECIST criteria. Acute toxicities and long-term sequelae were assessed. RESULTS: Our cohort included 39 patients included between 2011 and 2021: 18 patients treated for a TJ PG (45.9%), 11 patients for a carotid PG (28.4%), and 9 for a vagal PG (23.1%). Twenty-nine patients had IMRT as an exclusive treatment (74.4%), whereas 10 patients had a post-operative complementary treatment (25.6%). Median follow-up in our cohort was 2318 days (average = 2200 days, 237-5690, sd = 1281.9). Among 39 patients, 37 were successfully controlled with IMRT (94.8%), and the toxicity profile was low without any major toxicity. CONCLUSION: IMRT seems an ideal treatment, whether exclusive or post-operative for Head & Neck paragangliomas. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:607-614, 2023.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.