[Surgery of pancreatic neuroendocrine neoplasms: state of the art]. / Chirurgie bei neuroendokrinen Neoplasien des Pankreas: State of the Art.

Pancreatic neuroendocrine neoplasms (pNEN) have a rising incidence and are increasingly diagnosed at early and thus potentially resectable stages. Due to the rarity of these neoplasms the recommendations of currently available guidelines are mainly based on retrospective data. Surgical and oncological treatment of these rare diseases should only be performed at specialized centers. In cases of resectability without indications of diffuse metastases, complete resection with curative intent should be the treatment of choice. For small nonfunctional pNENs < 2 cm watch and wait strategies are recommended as an alternative to surgical treatment. Recent data, however, also showed an increased survival even of small (1-2 cm) pNENs after resection. For benign insulinomas and small nonfunctional well-differentiated pNENs parenchyma-sparing procedures, such as enucleation and segmental resection are available. The question of the influence of lymph node metastases on long-term disease-free survival and overall survival and consequently the role of systematic lymphadenectomy is still a matter of debate. In pNENs > 2 cm formal resection with lymphadenectomy is considered the gold standard. Minimally invasive and robotic-assisted procedures are of increasing importance also for formal pancreatic resection.

[Surgery of adrenal diseases]. / Chirurgie der Nebennierenerkrankungen.

Incidentally discovered adrenal alterations should be separated into those without any clinical importance and adrenal diseases that have to be surgically or conservatively treated. Before operative treatment, in addition to the possible different functional activity of tumors, a differentiation must be made between sporadically arising singular or multiple adrenal tumors or nodular adrenal hyperplasia, adrenal tumors as part of a familial syndrome and metastases of other primary malignant tumors into the adrenal glands. Benign hormonally active adrenal tumors as well as questionable malignant tumors of the adrenal cortex are resected by minimally invasive techniques. For large malignant tumors infiltrating into surrounding tissues and tumors with proven lymph node metastases, the primarily open approach is indicated. Patients with adrenal diseases should always undergo an interdisciplinary assessment and in cases with clear indications for surgery, sometimes transferred to a center with experience in surgery and postoperative management of these patients.

Meta-analysis of α-blockade versus no blockade before adrenalectomy for phaeochromocytoma.

BACKGROUND: Preoperative α-blockade in phaeochromocytoma surgery is recommended by all guidelines to prevent intraoperative cardiocirculatory events. The aim of this meta-analysis was to assess the benefit of such preoperative treatment compared with no treatment before adrenalectomy for phaeochromocytoma. METHODS: A systematic literature search was undertaken in MEDLINE, Web of Science and CENTRAL without language restrictions. Randomized and non-randomized comparative studies investigating preoperative α-blockade in phaeochromocytoma surgery were included. Data on perioperative safety, effectiveness and outcomes were extracted. Pooled results were calculated as an odds ratio or mean difference with 95 per cent confidence interval. RESULTS: A total of four retrospective comparative studies were included investigating 603 patients undergoing phaeochromocytoma surgery. Mortality, cardiovascular complications, mean maximal intraoperative systolic and diastolic BP, and mean maximal intraoperative heart rate did not differ between patients with or without α-blockade. The certainty of the evidence was very low owing to the inferior quality of studies. CONCLUSION: This meta-analysis has shown a lack of evidence for preoperative α-blockade in surgery for phaeochromocytoma. RCTs are needed to evaluate whether preoperative α-blockade can be abandoned.

ANTECEDENTES: Todas las guías recomiendan el bloqueo alfa preoperatorio en la cirugía del feocromocitoma para prevenir eventos cardiocirculatorios intraoperatorios. El objetivo de este metaanálisis fue evaluar el beneficio de dicho tratamiento preoperatorio antes de la adrenalectomía por feocromocitoma en comparación con ningún tratamiento. MÉTODOS: Se realizó una búsqueda sistemática de la literatura en MEDLINE, Web of Science y CENTRAL sin restricciones de idioma. Se incluyeron estudios comparativos aleatorizados y no aleatorizados que investigaron el bloqueo alfa preoperatorio en la cirugía del feocromocitoma. Se extrajeron los datos en relación a la seguridad perioperatoria, la efectividad y los resultados. Los resultados agrupados se mostraron como razón de oportunidades (odds ratio, OR) o diferencia de medias (MD) con el correspondiente i.c. del 95%. RESULTADOS: Se incluyeron un total de cuatro estudios comparativos retrospectivos que analizaron a 603 pacientes sometidos a cirugía del feocromocitoma. La mortalidad, las complicaciones cardiovasculares, la media del valor máximo de la presión arterial sistólica y diastólica intraoperatoria y la media del valor máximo de la frecuencia cardíaca intraoperatoria no difirieron entre pacientes con o sin bloqueo. La certeza de la evidencia fue muy baja debido a la baja calidad de los estudios. CONCLUSIÓN: Este metaanálisis demuestra la falta de evidencia del bloqueo alfa preoperatorio en la cirugía del feocromocitoma. Se necesitan ensayos controlados aleatorizados para evaluar si se puede abandonar el bloqueo alfa preoperatorio.

[Resection strategies for adrenocortical carcinoma]. / Resektionsstrategie bei Nebennierenrindenkarzinomen.

Adrenocortical carcinomas (ACC) are rare and aggressive neoplasms. Due to their high rate of local recurrence and distant metastases (up to 85%) they are associated with a poor survival. The 5­year survival in ACC patients with lymph node metastasis or local infiltration is 50% and with distant metastasis less than 15%. An R0 resection with locoregional and para-aortic/paracaval lymphadenectomy is the only curative option and reasonable treatment possibility. The treatment of these patients should therefore be planned and carried out in centers. Local recurrences and distant metastases should also be treated with R0 resection when feasible, combined with neoadjuvant/adjuvant chemotherapy and/or radiation. In the case of an asymptomatic non-resectable ACC, debulking operations cannot be recommended. The primary operation can also be done in a minimally invasive procedure if principles of oncological surgery are followed (radical resection, no damage of the tumor capsule, lymphadenectomy), since survival after open and minimally invasive laparoscopic resection was comparable. Palliative resections are only indicated in symptomatic patients.

Outcome of surgery for pancreatic neuroendocrine neoplasms.

BACKGROUND: The incidence of pancreatic neuroendocrine neoplasms (pNEN) is increasing. This study aimed to evaluate predictors of overall survival and the indication for surgery. METHODS: Data collected between October 2001 and December 2012 were analysed. Histological grading and staging was based on the classifications of the World Health Organization, the International Union Against Cancer and the European Neuroendocrine Tumour Society. RESULTS: Some 310 patients (150 female, 48·4 per cent) underwent surgical resection. The final survival analysis included 291 patients. Five-year overall survival differed according to tumour grade (G): 91·0 per cent among 156 patients with pancreatic neuroendocrine tumours (pNET) G1, 70·8 per cent in 111 patients with pNET G2, and 20 per cent in 24 patients with pancreatic neuroendocrine carcinomas (pNEC) G3 (P < 0·001). Tumours graded G3 (hazard ratio (HR) 6·96, 95 per cent confidence interval 3·67 to 13·21), the presence of distant metastasis (HR 2·41, 1·32 to 4·42) and lymph node metastasis (HR 2·10, 1·07 to 4·16) were independent predictors of worse survival (P < 0·001, P = 0·004 and P = 0·032 respectively). Eight of 61 asymptomatic patients with pNEN smaller than 2 cm had tumours graded G2 or G3, and six of 51 patients had lymph node metastasis. Among patients with pNEC G3, the presence of distant metastasis had a significant impact on the 5-year overall survival rate: 0 per cent versus 43 per cent in those without distant metastasis (P = 0·036). CONCLUSION: Neuroendocrine tumours graded G3, lymph node and distant metastasis are independent predictors of worse overall survival in patients with pNEN.

EGFR/TGFα and TGFß/CTGF Signaling in Neuroendocrine Neoplasia: Theoretical Therapeutic Targets.

Neuroendocrine neoplasms (NENs) are a heterogeneous family of malignancies whose proliferation is partially dependent on growth factors secreted by the microenvironment and the tumor itself. Growth factors which were demonstrated to be important in experimental models of NENs include EGF (epidermal growth factor), TGF (transforming growth factor) α, TGFß and CTGF (connective tissue growth factor). EGF and TGFα bind to the EGF receptor to stimulate an intact RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Theoretically, TGFα stimulation can be inhibited at several points of the MAPK pathway, but success is limited to NEN models and is not evident in the clinical setting. TGFß1 stimulates TGFß receptors (TGFßRI and TGFßRII) resulting in inhibition of neuroendocrine cell growth through SMAD-mediated activation of the growth inhibitor P21(WAF1/CIP1). Although some NENs are inhibited by TGFß1, paradoxical growth is seen in experimental models of gastric and small intestinal (SI) NENs. Therapeutic targeting of TGFß1 in NENs is therefore complicated by uncertainty of the effect of TGFß1 secretion on the direction of proliferative regulation. CTGF expression is associated with more malignant clinical phenotypes in a variety of cancers, including NENs. CTGF promotes growth in gastric and SI-NEN models, and is implicated as a mediator of local and distant fibrosis caused by NENs of enterochromaffin cell origin. CTGF inhibitors are available, but their anti-proliferative effect has not been tested in NENs. In summary, growth factors are essential for NEN proliferation, and although interventions targeting these proteins are effective in experimental models, only limited clinical efficacy has been identified.

[Surgical therapy of abdominal and trunk soft tissue sarcomas]. / Chirurgische Therapie der Weichteilsarkome des Stammes und der Körperhöhlen.

Soft tissue sarcomas are rare tumours of mesenchymal cells which can arise in all parts of the body. Sarcomas of the trunk and abdominal cavity are a very heterogeneous group of tumours. This review focuses on retroperitoneal sarcomas, which tend to be asymptomatic for a long time, resulting in an advanced stage at presentation in most patients. Surgical resection is the basis for cure in these patients, possibly combined with radiation. In contrast to extremity sarcomas, the majority of patients with retroperitoneal sarcomas succumb to an isolated local recurrence of the disease. In case of local recurrence or distant metastases, surgical resection should again be contemplated.