High tumour mutational burden and EGFR/MAPK pathway activation are therapeutic targets in metastatic porocarcinoma.

BACKGROUND: Eccrine porocarcinoma (EPC) is a rare skin cancer arising from the eccrine sweat glands. Due to the lack of effective therapies, metastasis is associated with a high mortality rate. OBJECTIVES: To investigate the drivers of EPC progression. METHODS: We carried out genomic and transcriptomic profiling of metastatic EPC (mEPC), validation of the observed alterations in an EPC patient-derived cell line, confirmation of relevant observations in a large patient cohort of 30 tumour tissues, and successful treatment of a patient with mEPC under the identified treatment regimens. RESULTS: mEPC was characterized by a high tumour mutational burden (TMB) with an ultraviolet signature, widespread copy number alterations and gene expression changes that affected cancer-relevant cellular processes such as cell cycle regulation and proliferation, including a pathogenic TP53 (tumour protein 53) mutation, a copy number deletion in the CDKN2A (cyclin dependent kinase inhibitor 2A) region and a CTNND1/PAK1 [catenin delta 1/p21 (RAC1) activated kinase 1] gene fusion. The overexpression of EGFR (epidermal growth factor receptor), PAK1 and MAP2K1 (mitogen-activated protein kinase kinase 1; also known as MEK1) genes translated into strong protein expression and respective pathway activation in the tumour tissue. Furthermore, a patient-derived cell line was sensitive to EGFR and MEK inhibition, confirming the functional relevance of the pathway activation. Immunohistochemistry analyses in a large patient cohort showed the relevance of the observed changes to the pathogenesis of EPC. Our results indicate that mEPC should respond to immune or kinase inhibitor therapy. Indeed, the advanced disease of our index patient was controlled by EGFR-directed therapy and immune checkpoint inhibition for more than 2 years. CONCLUSIONS: Molecular profiling demonstrated high TMB and EGFR/MAPK pathway activation to be novel therapeutic targets in mEPC.

[Peripheral nerve blocks of the lower extremities. Clinical and practical aspects]. / Periphere Nervenblockaden an der unteren Extremität. Klinisch-praktische Aspekte.

Peripheral nerve blocks (PNBs) of the lower extremities are effective techniques for anesthesia and postoperative pain control. So far, these techniques have been used less frequently than PNBs of the upper limb. Nevertheless, growing awareness of complications of neuroaxial techniques, improved equipment and modern techniques for nerve localization have led to an increased use of PNBs of the lower limb. Anesthesiologists should be familiar with the anatomical basics and procedural details of these PNBs. They should also know the typical complications and side-effects and thoroughly inform patients about such potential problems. Continuous PNBs (perineural catheters) allow the benefits of PNBs to be prolonged into the postoperative period. Compared to continuous neuroaxial techniques continuous PNBs are equally effective for pain control but seem to be associated with fewer complications and side-effects.

Anterior sciatic nerve block--new landmarks and clinical experience.

BACKGROUND: Anterior sciatic nerve blocks can be complicated by several problems. Pain can be caused by bony contacts and, in obese patients, identification of the landmarks is frequently difficult. METHODS: In a first step, 100 normal anterior-posterior pelvic X-rays were analyzed. The landmarks of the classical anterior approach were drawn on these X-rays and assessed for their sufficiency. Then, in a prospective case study, 200 consecutive patients undergoing total knee replacement were investigated. These patients received femoral and sciatic nerve catheters for postoperative pain management. Using modified anatomical landmarks, sciatic nerve catheters were inserted 5 cm distal from the insertion site of the femoral nerve block perpendicularly in the midline of the lower extremity. This midline connected the insertion site of the femoral nerve catheter to the midpoint between the medial and lateral epicondyle. Correct catheter positioning was verified by magnetic resonance imaging (MRI) in six patients. RESULTS: Evaluation of pelvic X-rays showed that puncture following the classical landmarks pointed in 51% at the lesser trochanter, in 5% medial to the lesser trochanter and in 42% directly at the femur. In the latter patients, location of the sciatic nerve would have been difficult or even impossible. Using our modified anterior approach, the sciatic nerve could be blocked in 196 patients (98%). In nine patients (4.5%) blockade of the posterior femoral cutaneous nerve failed. Vascular puncture happened in 10 (5%) and bony contact in 35 patients (17.5%). Median puncturing depth was 9.5 (7.5-14) cm. Correct sciatic nerve catheter positioning was verified in all patients who underwent MRI. CONCLUSION: Our landmarks for locating the sciatic nerve help to avoid bony contacts and thereby reduce pain during puncture. Our method reliably enabled catheter placement.

[The effects of perioperative continuous administration of mivazerol on early postoperative hemodynamics and plasma catecholamines after major surgery]. / Die Auswirkungen der perioperativen Gabe des alpha 2-Adrenorezeptor-Agonisten Mivazerol auf frühpostoperative Hämodynamik und Plasmakatecholaminspiegel nach grossen chirurgischen Eingriffen.

OBJECTIVE: During and after surgical procedures a strong activation of the sympatho-adrenergic system is common with correlation to adverse cardiac outcome. Several drugs (alpha 2-adrenoceptor-agonists, beta blockers) are discussed to prevent this reaction. The new alpha 2-adrenoceptor-agonist mivazerol with marked specificity for alpha 2-adrenergic receptors may be suitable for this indication. The aim of the present study was to investigate the effects of perioperative continuous administration of mivazerol on plasma catecholamines, body temperature and calculated haemodynamic parameters in the early postoperative period in cardiac risk patients undergoing non-cardiac surgery. METHODS: 36 patients with known coronary heart disease or risk factors for coronary heart disease scheduled for elective abdominal or vascular surgery were included in the study. Patients received either mivazerol (n = 18) or placebo (n = 18) [initial dose 4 micrograms kg-1 for 10 minutes before induction of anaesthesia, followed by a continuous infusion of 1.5 micrograms kg-1 h-1 intraoperatively and for as long as 72 h after surgery] in a double-blinded, randomized manner. Blood pressure, heart rate and body temperature were measured every 10 minutes until 240 minutes after arrival at the ICU. During 240 minutes after arrival at the ICU measured parameters (CVP, PAP, PCWP, SaO2, SvO2, CO), calculated parameters (CI, SVR, PVR, VO2) and plasma catecholamines were measured at defined time intervalls. RESULTS: The plasma concentrations of epinephrine and norepinephrine and the heart rate were significantly lower in the mivazerol group in the study period. Regarding blood pressure and body temperature there were no differences between the groups. At some measuring points preload was higher in the mivazerol group, but there were no differences between the groups for measured (SaO2, SvO2, CO) and calculated (CI, SVR, PVR, VO2) cardiorespiratory parameters. The incidence of shivering, nausea and vomiting were similar in both groups. CONCLUSION: Continuous, perioperative administration of mivazerol decreased the heart rate and the plasma catecholamines in the early postoperative period, but did not affect blood pressure, body temperature and the incidence of shivering. There were also no effects of mivazerol on calculated haemodynamic parameters (CO, SVR, PVR, VO2). These findings show a selective decrease in heart rate by Mivazerol without markedly cardiorespiratory side effects.

[Remifentanil and alfentanil: Sympathetic-adrenergic effect in the first postoperative phase in patients at cardiovascular risk]. / Remifentanil und Alfentanil: Sympathiko-adrenerge Effekte in der frühen postoperativen Phase beim kardiovaskulären Risikopatienten.

UNLABELLED: Extubation and the immediate postoperative period are critical periods with strong sympatho-adrenergic stimulation. The aim of the present study was to investigate this period after balanced anaesthesia with remifentanil and alfentanil in cardiac risk patients. METHODS: 52 patients with coronary artery disease or with risk factors for coronary heart disease scheduled for elective extraperitoneal and extrathoracic operation were included in this study. Anaesthesia was induced by intravenous administration of etomidate, vecuronium and remifentanil (n = 27, 1 microgram/kg) or alfentanil (n = 25, 25 micrograms/kg). Anaesthesia was maintained with an Isoflurane/N2O/O2 mixture and by continuous intravenous infusion of remifentanil (0.25 microgram/kg/min) or alfentanil (45 micrograms/kg/h). During the first 60 minutes after extubation haemodynamic parameters were monitored and catecholamines were determined at defined time intervals. Parameters of recovery, the requirement of analgesics and cardiac medications were compared in both groups. Myocardial ischaemia was assessed by two-channel Holter electrocardiography. RESULTS: The beginning of spontaneous respiration and time of extubation were similar in both groups. The time interval until opening eyes and the time between the beginning of spontaneous respiration and extubation was shorter in the patients treated with remifentanil. In this group patients suffered earlier from pain and had a higher pain score. Although the plasma catecholamines were comparable in both groups, in the patients treated with remifentanil changes in haemodynamic parameters were more pronounced. The incidence of shivering and the requirements of analgesics and cardiac medications were higher in these patients. The incidence of ST-segment changes indicating myocardial ischaemia was similar. CONCLUSIONS: After balanced anaesthesia with remifentanil a more pronounced sympatho-adrenergic stimulation occurs because of the more rapid clearance of the analgesic effect in the recovery period compared to alfentanil requiring more analgesics and medications for the control of the haemodynamic parameters. Because of these specific pharmacological effects the use of remifentanil in cardiac risk patients has to be critically discussed.

[Postoperative vomiting after pars plana vitrectomy]. / Postoperatives Erbrechen nach Pars-plana-Vitrektomien.

In the present investigation we compared two different techniques of anaesthesia--total intravenous anaesthesia (TIVA) versus balanced anaesthesia--with and without antiemetic prophylaxis, with regard to postoperative nausea, strangling irritation and vomiting and their influence upon postoperative complications (intraocular bleedings) and postoperative intraocular pressure after pars plana vitrectomia. For this investigation four groups were formed. The anaesthesias were carried out as orotracheal intubational anaesthesia following two standard techniques, which only differ in the choice of the narcotics. Half the patients in each group were treated with an antiemetic prophylaxis of 2.5 mg DHBP. With regard to the occurrence of postoperative nausea and vomiting, the TIVA-groups proved to be better than those with balanced anaesthesia (16% to 43.5%; p < 0.05): DHBP in both methods led to a reduction of postoperative vomiting and nausea, but the differences showed not to be significant (p > 0.05). Best results were achieved with a combination of TIVA (propofol, alfentanil, atracurium, air/O2) and DHBP (4.7%). The total rate of postoperative complications in form of intraocular bleedings amounted to 8.6%. The appearance of complications increased when postoperative nausea and vomiting or increased intraocular pressure were observed (16.6% to 6.3%; 21.2% to 6.1%). Intraocular pressure, measured for four hours postoperatively, was significantly lower in the TIVA-groups than in the balanced anaesthesia-groups (15.5 +/- 7.7 mmHg to 18.3 +/- 8.2 mmHg). Therefore, we conclude that TIVA with propofol appears to be especially suitable for intraocular surgery.