MAML3-fusions modulate vascular and immune tumour microenvironment and confer high metastatic risk in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas are rare neuroendocrine tumours. Around 20-25 % of patients develop metastases, for which there is an urgent need of prognostic markers and therapeutic stratification strategies. The presence of a MAML3-fusion is associated with increased metastatic risk, but neither the processes underlying disease progression, nor targetable vulnerabilities have been addressed. We have compiled a cohort of 850 patients, which has shown a 3.65 % fusion prevalence and represents the largest MAML3-positive series reported to date. While MAML3-fusions mainly cause single pheochromocytomas, we also observed somatic post-zygotic events, resulting in multiple tumours in the same patient. MAML3-tumours show increased expression of neuroendocrine-to-mesenchymal transition markers, MYC-targets, and angiogenesis-related genes, leading to a distinct tumour microenvironment with unique vascular and immune profiles. Importantly, our findings have identified MAML3-tumours specific vulnerabilities beyond Wnt-pathway dysregulation, such as a rich vascular network, and overexpression of PD-L1 and CD40, suggesting potential therapeutic targets.

Surgical outcomes in the pheochromocytoma surgery. Results from the PHEO-RISK STUDY.

PURPOSE: To identify presurgical and surgical risk factors for postsurgical complications in the pheochromocytoma surgery. METHODS: A retrospective study of pheochromocytomas submitted to surgery in ten Spanish hospitals between 2011 and 2021. Postoperative complications were classified according to Clavien-Dindo scale. RESULTS: One hundred and sixty-two surgeries (159 patients) were included. Preoperative antihypertensive blockade was performed in 95.1% of the patients, being doxazosin in monotherapy (43.8%) the most frequent regimen. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more frequently (49.4% vs 25.0%, P = 0.003) than patients treated with phenoxybenzamine, but no differences in the rate of intraoperative and postsurgical complications were observed. However, patients treated with phenoxybenzamine had a longer hospital stay (12.2 ± 11.16 vs 6.2 ± 6.82, P < 0.001) than those treated with doxazosin. Hypertension resolution was observed in 78.7% and biochemical cure in 96.6% of the patients. Thirty-one patients (19.1%) had postsurgical complications. Prolonged hypotension was the most common, in 9.9% (n = 16), followed by hypoglycaemia in six patients and acute renal failure in four patients. 13.0% of complications had a score ≥3 in the Clavien-Dindo scale. Postsurgical complications were more common in patients with diabetes, cerebrovascular disease, higher plasma glucose levels, higher urinary free metanephrine and norepinephrine, and with pheochromocytomas larger than 5 cm. CONCLUSION: Preoperative medical treatment and postsurgical monitoring of pheochromocytoma should be especially careful in patients with diabetes, cerebrovascular disease, higher levels of plasma glucose and urine free metanephrine and norepinephrine, and with pheochromocytomas >5 cm, due to the higher risk of postsurgical complications.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Secondary thoracolumbar deformity and sagittal imbalance due to osteoporosis in a young man with Cushing's disease: A case report.

INTRODUCTION: To describe an unusual case of Cushing's disease with spontaneous axial pain due to multiple consecutive vertebral fractures which led to secondary deformity that required surgical treatment. PRESENTATION OF CASE: A 43-year-old man was referred to our service with back pain without previous trauma. He was diagnosed of refractory arterial hypertension and we observed centripetal obesity during exploration. With clinical findings and laboratory studies, ACTH-dependent Cushing's syndrome due to a pituitary microadenoma was diagnosed and the patient underwent an endoscopic-assisted endonasal transsphenoidal resection. Dual energy X-ray absorptiometry (DXA) revealed spine and hip osteoporosis. Moreover, X-ray, MR and CT showed multiple vertebral osteoporotic compression fractures in thoracic and thoracolumbar area. Secondary kyphosis thoracolumbar deformity and sagittal imbalance was treated by two-level Smith-Petersen osteotomies (SPO) and instrumented posterolateral arthrodesis T10-L3 using fenestrated pedicles screws with polymethyl methacrylate (PMMA). At six years of follow-up dual energy X-ray absorptiometry (DXA) recovered normal values (T-score lumbar spine L2-L4 1.4 and T-score hip -1.9) and X-ray study showed an adequate sagittal vertebral axis. DISCUSSION: Osteoporosis is a common feature of CD and fractures occur in 30-50% of cases. Treating the underlying cause reduces the risk of new fractures. Medical therapy is usually enough but consecutive multiple vertebral fractures related to glucocorticoid excess may lead to secondary painful deformity. CONCLUSION: Vertebral compression fractures result from secondary corticoid-induced osteoporosis in Cushing's disease. Early detection and treatment of primary disease decreases the risk of new fractures. However, unusual secondary spinal deformity or disability may require surgery.

Rhabdomyolysis due to primary hyperaldosteronism.

Rhabdomyolysis may be secondary to trauma, excessive muscle activity, hereditary muscle enzyme defects and other medical causes. Primary hyperaldosteronism is characterised by hypertension, hypokalemia, suppressed plasma renin activity, and increased aldosterone excretion. Rhabdomyolysis is not common in primary hyperaldosteronism. We report here a 42-year-old woman presenting with rhabdomyolysis as heralding symptom of primary hyperaldosteronism. We also carried out a search of the literature to identify all cases of rhabdomyolysis as the first-recognized expression of a primary hyperaldosteronism. Sixteen cases met the criteria for inclusion. When rhabdomyolysis occurs in a patient with hypokalemia and metabolic alkalosis, primary hyperaldosteronism has to be suspected: if confirmed, an aldosterone-producing adenoma is the most probable cause.