Protocol for presurgical and anesthetic management of pheochromocytomas and sympathetic paragangliomas: a multidisciplinary approach.

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.

Surgical and postsurgical management of abdominal paragangliomas and pheochromocytomas.

PURPOSE: To describe our current protocol for surgical and postsurgical management of abdominal paragangliomas (PGLs) and pheochromocytomas, with a special focus on multidisciplinary management in centres with experience. METHODS: The physicians involved in the management of patients with abdominal PGLs and pheochromocytomas of our hospital reviewed systematically current knowledge on the surgical management of abdominal PGLs and pheochromocytomas. RESULTS: Currently, surgery is considered the treatment of choice for abdominal PGLs and pheochromocytomas. The choice of surgical approach is determined based on the location of the lesion, size, patient́s body habitus and the likelihood of malignancy. Laparoscopic surgery is usually considered the gold standard approach for pheochromocytomas, but open access should be considered in invasive and/or potentially malignant tumours >8-10 cm and for abdominal PGLs. Postsurgical management of pheochromocytomas and PGLs includes close hemodynamic monitoring and treatment of postsurgical complications, the pathological study of the surgical specimen, reassessment of hormonal and/or radiological status and planning of follow-up based on the risk of recurrence and malignancy. CONCLUSION: Surgery represents the treatment of choice of most abdominal PGLs and pheochromocytomas. Optimal postsurgical evaluation, including hemodynamic, pathological, hormonal, and radiological evaluation, should be performed by a multidisciplinary team specializing in PGL/pheochromocytoma management.

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy.

BACKGROUND: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. PATIENTS AND METHODS: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. RESULTS: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. CONCLUSION: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers.

Bruton's tyrosine kinase (BTK) as a promising target in solid tumors.

Bruton's tyrosine kinase (BTK) is a non-receptor intracellular kinase that belongs to the TEC-family tyrosine kinases together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase (RLK), and IL-2 inducible T-Cell kinase (ITK). All these proteins play a key role in the intracellular signaling of both B and T lymphocytes. Recently, some preclinical data have demonstrated that BTK is present in certain tumor subtypes and in other relevant cells that are contributing to the tumor microenvironment such as dendritic cells, macrophages, myeloid derived suppressor cells and endothelial cells. Ibrutinib (PCI-32765) is an orally available small molecule that acts as an inhibitor of the BTK and is approved for the treatment of patients with some hematological malignancies. It has been suggested that ibrutinib may also have a potential antitumor activity in solid neoplasms. In this sense, ibrutinib has the ability to revert polarization of TCD4+ to Th1 lymphocytes to increase the cytotoxic ability of T CD8+ and to regulate tumor-induced immune tolerance by acting over tumor infiltrating cells activity and immunosuppressive cytokines release. Furthermore, based on its molecular activity and safety, ibrutinib has been considered as a partner for treatment combination with PI3K/AKT/mTOR inhibitors or with immune-checkpoint inhibitors, inhibiting immunosuppressive signals from the tumor microenvironment, and overcoming the immune resistance to current anti-PD1/PDL1 immunotherapeutic drugs by the CXCR4/CXCL2 pathway regulation. Currently, a broad range of different studies are evaluating the activity of ibrutinib either as single agent or in combination in patients with solid tumors.

Manejo quirúrgico y posquirúrgico de paragangliomas abdominales y feocromocitomas / Surgical and postsurgical management of abdominal paragangliomas and pheochromocytomas

Objetivo Describir nuestro protocolo actual para el manejo quirúrgico y posquirúrgico de los paragangliomas abdominales (PGL) y los feocromocitomas, con especial atención en el manejo multidisciplinar en centros con experiencia. Métodos Los facultativos implicados en el tratamiento de pacientes con PGL abdominales y feocromocitomas de nuestro hospital revisaron sistemáticamente la evidencia científica actualmente disponible sobre el tratamiento quirúrgico de los PGL abdominales y feocromocitomas. Resultados La cirugía se considera el tratamiento de primera elección para los PGL abdominales y feocromocitomas. La decisión sobre el tipo de abordaje quirúrgico se basa en la localización y el tamaño de la lesión, la constitución corporal del paciente y la probabilidad estimada de malignidad. La cirugía laparoscópica suele considerarse el abordaje de referencia para los feocromocitomas, pero en los tumores invasivos y/o potencialmente malignos de más de 8-10 cm y en los PGL abdominales debe considerarse el abordaje abierto. El tratamiento posquirúrgico de los feocromocitomas y los PGL incluye una monitorización hemodinámica estrecha, el tratamiento de las complicaciones posoperatorias, el estudio patológico de la muestra quirúrgica, la reevaluación del estado hormonal y/o radiológico y la planificación del seguimiento en función del riesgo de recurrencia y malignidad. Conclusión La cirugía representa el tratamiento de elección de la mayoría de los PGL abdominales y feocromocitomas. La evaluación posoperatoria óptima, que incluye la evaluación hemodinámica, patológica, hormonal y radiológica, debe ser realizada por un equipo multidisciplinar especializado en el tratamiento de PGL/feocromocitomas (AU)

Purpose To describe our current protocol for surgical and postsurgical management of abdominal paragangliomas (PGLs) and pheochromocytomas, with a special focus on multidisciplinary management in centres with experience. Methods The physicians involved in the management of patients with abdominal PGLs and pheochromocytomas of our hospital reviewed systematically current knowledge on the surgical management of abdominal PGLs and pheochromocytomas. Results Currently, surgery is considered the treatment of choice for abdominal PGLs and pheochromocytomas. The choice of surgical approach is determined based on the location of the lesion, size, patient́s body habitus and the likelihood of malignancy. Laparoscopic surgery is usually considered the gold standard approach for pheochromocytomas, but open access should be considered in invasive and/or potentially malignant tumours > 8-10 cm and for abdominal PGLs. Postsurgical management of pheochromocytomas and PGLs includes close hemodynamic monitoring and treatment of postsurgical complications, the pathological study of the surgical specimen, reassessment of hormonal and/or radiological status and planning of follow-up based on the risk of recurrence and malignancy. Conclusion Surgery represents the treatment of choice of most abdominal PGLs and pheochromocytomas. Optimal postsurgical evaluation, including hemodynamic, pathological, hormonal, and radiological evaluation, should be performed by a multidisciplinary team specializing in PGL/pheochromocytoma management (AU)

Prognostic and predictive role of the PI3K-AKT-mTOR pathway in neuroendocrine neoplasms

Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs. However, there are not any established prognostic or predictive biomarkers to select the best therapy option to individualize treatment. Although a relation between alterations in the PI3K-AKT-mTOR pathway and clinical outcomes has not been found, these anomalies are considered attractive biomarkers. Additional molecular analysis should be integrated in future clinical trials' design to identify potential predictive or prognostic biomarkers

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