SDHB mutation

Robotic-assisted resection can be safe and effective for retroperitoneal malignant paragangliomas. However, management extends beyond surgery and requires cascade genetic testing to address familial risks. Because of the high probability of cancer associated with SDHB mutation, lifelong patient surveillance is imperative.

Patients with metastatic PPGL have a high rate of germline mutations, especially those with SDHB mutations. The metastatic PPGL is usually multisystem metastasis with the characteristics of mostly paraganglioma, large lesion diameter and high Ki-67 index.

P1, N=40, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jul 2025 --> Feb 2025 | Trial primary completion date: Jul 2025 --> Feb 2025

Although there are well-recognized classic clinical manifestations associated with pheochromocytoma, atypical presentation, such as vision changes in children, should be considered. In addition, malignant pheochromocytoma children with a high Pheochromocytoma of the Adrenal Gland Scaled Score and succinate dehydrogenase complex iron sulfur subunit B mutation require a long-term follow-up or even unplanned surgery because of the higher risk of recurrence.

Multifocality of HNPs correlates with the SDHD mutational subtype, and metastases correlate with the SDHB subtype. Knowledge of HNP phenotypes associated with SDH-related mutations has the potential to influence the management approach to such HNPs.

Our study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment.

This study provided a novel and useful tool for predicting SDHB mutations by integrating easily obtained clinical data. It may help clinicians select suitable genetic testing methods and make appropriate clinical decisions for these high-risk patients.

NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

The recurrence of PPGLs occurred more frequently in patients with SDHB mutations, with larger tumors and with higher urinary normetanephrine levels. Since PPGL recurrence may occur at any time after the initial PPGL diagnosis is performed, we recommend performing a strict follow-up in all patients with PPGLs, especially in those patients with a higher risk of recurrent disease.

Germline SDHB mutations can rarely cause PA in the absence of PPGL. They should be considered as a possible cause of aggressiveness and resistance to dopamine agonists in similar cases.

Among patients with RCC, unselected for a known familial predisposition, 13.4% had P/LP variants. Almost half of patients with P/LP variants had a potentially targetable mutation. Targeted gene panel testing is a feasible option for patients, particularly if syndromic features are present. Age and family history were not associated with P/LP variants. Future studies are needed to optimize current genetic evaluation criteria to expand the detection of patients with RCC who may have germline mutations.

P1, N=40, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting | N=180 --> 40

We demonstrate in a real-life clinical setting that all current therapies show reasonable efficacy in preventing disease progression, and this is equally true for patients with germline SDHB mutations.

The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis.

For the patients with SDHB mutation, it is recommended that people in SDHB mutation families undergo regular genetic testing or SDHB immunohistochemistry (IHC). The purpose of this paper is hopefully to provide some reference and help for follow-up researches on SDHB.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

The patient and a family member report increased emotional lability, and the patient reports multiple daily episodes of anxiousness. This case outlines the connection between paragangliomas and psychiatric symptoms, the impact they can have on patients' daily lives, and the importance of addressing the possibility of these symptoms and establishing a multispecialty healthcare team at the time of diagnosis.

This is the largest series of HN paragangliomas treated with SAbR, detailing a 10-year experience with a 5-fraction regimen that is well-tolerated and achieves excellent local control. Post-SAbR recurrences occurred outside of the radiation field but within the post-operative bed, suggesting that some post-operative patients may benefit from expanded radiation volumes or close surveillance for salvage therapy.

A non-highly avid PPGL on DOTATE scan should be considered as possibly having necrosis of tumors indicating a more aggressive tumor-biology. There might be a subgroup of patients in whom FDG-PET scan should be considered to gain additional information.

SDHB-deficiency was observed in 80% of paragangliomas with malignant behaviour, highlighting that SDHB IHC can be regarded as a biomarker of prognosis in paragangliomas. A higher GAPP score correlates with malignant behaviour and syndromic background, reinforcing that GAPP score is a useful tool for risk stratification in paragangliomas.

Furthermore, patients treated with sunitinib [HR 7.25, 95% CI 3.26-16.10, p< 0.001], regorafenib [HR 3.27, 95% CI 1.79-5.97, p< 0.001], or temozolomide [HR 3.58, 95% CI 1.40-9.16, p=0.008] had worsened OS. To our knowledge, this represents the largest SDH-def GIST analysis to date. Despite being believed to be mostly confined to the pediatric and adolescent population, and still often mislabeled as Pediatric GIST, SDH-def GIST occurs across the age spectrum, and a diagnosis later in life portends a worse prognosis. Moreover, male sex is a poor prognostic factor, raising questions as to the underlying biological differences to explain this finding.

No abstract available

Pheochromocytoma associated with SDHB mutation is a rare presentation. Genetic testing for suspecting cases is essential to help to establish the appropriate follow-up plan.

The extended timeframe between onset of cyanosis and development of PPGL supports long term regular monitoring of CCHD patients to detect PPGL. We suggest screening with plasma metaneprines and catecholamines at age 15 and every 3-5 years after.

No abstract available

The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.

The feasible duration for maintaining cultures must also be balanced against time required to reliably assess drug efficacy. Considerations potentially important for all in vitro studies include species differences, phenotype drift, changes that occur in transition from tissue to cell culture and the O2 concentration in which cultures are maintained.

For the prospective analysis, 18.8% (3/16) of participants in the SDHB (-) group had progressive tumors compared with 3.6% (7/197) in the SDHB (+) group (RR: 5.28, 95% CI: 1.51-18.47, P=0.009), statistical significance remained (RR: 3.35, 95% CI: 1.20-9.38, P=0.021) after adjusting for other clinicopathological factors. Our findings demonstrated patients with SDHB (-) tumors had a higher possibility of poor outcomes, and SDHB IHC can be regarded as an independent biomarker of prognosis in PCC/PGL.

Abdominal nonfunctional PGLs are associated with SDHB mutation, and SDHB staining should be performed as a screening.

SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.

To conclude, TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.

By developing methods to provide value to rare tumor patients, using a large catchment area and opportunity for remote participation, and collecting data in a tumor-agnostic way, we can learn about multiple rare tumors and share findings more quickly than if each rare tumor was studied alone. We describe the MyPART cohort and challenges to overcome for successful longitudinal rare tumor natural history studies.

We report an updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs, showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs as alternatives to I-131 MIBG and chemotherapy.

Transcriptional and methylation profiling and metabolite assessment showed an "intermediate signature" to suggest that both variants had a pathological role in tumour development. In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.

This panel accurately detected all CIMP-RCC tumors within the TCGA RCC cohort, identifying them as HLRCC -like, and could potentially be used to create a liquid biopsy-based screening tool. The CIMP signature in these aggressive tumors could provide both a useful biomarker for diagnosis and a target for novel therapies.

Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4κ monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy...PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.

OS rates correlated with the recently developed AJCC TNM staging and was not worse in hereditary disease. Stage IV disease exhibited a significantly shorter OS compared with stages I-III. Future staging systems could be adjusted to better separate stages I and II.

SDH germline mutation is the molecular biological mechanism of CSS while the most common type is SDHB mutation. The unique mechanism of tumorigenesis including hypoxia and hypermethylation caused by SDH deficiency renders target therapy with tyrosine kinase inhibitors ineffective, therefore complete surgical resection is the optimal treatment in the absence of tumor metastases.