Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials.

Objective To offer a practical guide for the presurgical and anesthetic management of pheochromocytomas and sympathetic paragangliomas (PGLs). Methods This protocol was based on a comprehensive review of the literature and on our own multidisciplinary team's experience from managing pheochromocytoma and sympathetic PGLs at a referral center. Results Patients with pheochromocytomas and sympathetic paragangliomas (PGLs) may develop potentially life-threatening complications, especially during surgical procedures. A complete biochemical, radiological, genetic, and cardiological assessment is recommended in the preoperative stage as it provides an evaluation of the risk of surgical complications and malignancy, allowing individualization of the presurgical treatment. Treatment with α-blockade and proper volume expansion in the preoperative stage significantly reduces the perioperative morbidity. During surgery, the anesthesiologist should look for a deep anesthetic level that inhibits the cardiovascular effects of catecholamines to minimize the risk of intraoperative complications. Conclusions An optimal presurgical evaluation of pheochromocytomas/ sympathetic PGL requires a multidisciplinary approach, including a complete hormonal, radiological, cardiac, genetic, and functioning evaluation in most cases. A proper preoperative evaluation in combination with strict blood pressure and heart rate control, and blood volume status optimization, will significantly reduce the risk of intraoperative and perioperative complications. In those patients who unfortunately develop intraoperative complications, the role of the anesthesiologist is essential since the selection of the appropriate management has a direct impact on morbimortality reduction. Keywords Pheochromocytoma • Paragangliomas • Presurgical management • Anesthetic treatment • α-blockadeThis article was elaborated by the multidisciplinary adrenal/ paraganglioma team of the Hospital Ramón y Cajal. Madrid (Spain).

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We aimed to identify presurgical and surgical risk factors for intraoperative complications in patients with pheochromocytomas. A retrospective study of patients with pheochromocytomas who underwent surgery in ten Spanish hospitals between 2011 and 2021 was performed. One hundred and sixty-two surgeries performed in 159 patients were included. The mean age was 51.6±16.4 years-old and 52.8% were women. Median tumour size was 40 mm (range 10-110). Laparoscopic adrenalectomy was performed in 148 patients and open adrenalectomy in 14 patients. Presurgical alpha- and beta- blockade was performed in 95.1% and 51.9% of the surgeries, respectively. 33.3% of the patients (n=54) had one or more intraoperative complications. The most common complication was hypertensive crisis in 21.0%, followed by prolonged hypotension in 20.0% and hemodynamic instability in 10.5%. Patients pre-treated with doxazosin required intraoperative hypotensive treatment more commonly than patients pre-treated with other antihypertensive drugs (51.1% vs 26.5%, P=0.002). Intraoperative complications were more common in patients with higher levels of urine metanephrine (OR=1.01 for each 100 mcg/24h, P=0.026) and normetanephrine (OR=1.00 for each 100 mcg/24h, P=0.025), larger tumours (OR=1.4 for each 10mm, P<0.001), presurgical blood pressure >130/80mmHg (OR=2.25, P=0.027), pre-treated with doxazosin (OR= 2.20, P=0.023) and who had not received perioperative hydrocortisone (OR=3.95, P=0.008). In conclusion, intraoperative complications in pheochromocytoma surgery are common and can be potentially life-threatening. Higher metanephrine and normetanephrine levels, larger tumour size, insufficient blood pressure control before surgery, pre-treatment with doxazosin, and the lack of treatment with perioperative hydrocortisone are associated with higher risk of intraoperative complications.