European e-Delphi process to define expert consensus on electrochemotherapy treatment indications, procedural aspects, and quality indicators in melanoma.

BACKGROUND: Skin metastases are an important co-morbidity in melanoma. Despite broad adoption, electrochemotherapy implementation is hindered by a lack of treatment indications, uncertainty regarding procedural aspects, and the absence of quality indicators. An expert consensus may harmonize the approach among centres and facilitate comparison with other therapies. METHODS: An interdisciplinary panel was recruited for a three-round e-Delphi survey. A literature-based 113-item questionnaire was proposed to 160 professionals from 53 European centres. Participants rated each item for relevance and degree of agreement on a five-point Likert scale, and received anonymous controlled feedback to allow revision. The items that reached concordant agreement in two successive iterations were included in the final consensus list. In the third round, quality indicator benchmarks were defined using a real-time Delphi method. RESULTS: The initial working group included 122 respondents, of whom 100 (82 per cent) completed the first round, thus qualifying for inclusion in the expert panel (49 surgeons, 29 dermatologists, 15 medical oncologists, three radiotherapists, two nurse specialists, two clinician scientists). The completion rate was 97 per cent (97 of 100) and 93 per cent (90 of 97) in the second and third rounds respectively. The final consensus list included 54 statements with benchmarks (treatment indications, (37); procedural aspects, (1); quality indicators, (16)). CONCLUSION: An expert panel achieved consensus on the use of electrochemotherapy in melanoma, with a core set of statements providing general direction to electrochemotherapy users to refine indications, align clinical practices, and promote quality assurance programmes and local audits. The residual controversial topics set future research priorities to improve patient care.

Electrochemotherapy is an effective locoregional therapy for skin metastases from melanoma, a problem faced by almost half of patients with metastatic disease. The lack of comparative studies and the heterogeneity of its clinical application among centres make it challenging to support consistent, evidence-based recommendations. To address this unmet need, a three-round online survey was conducted to establish a consensus on treatment indications, standard operating procedures, and quality indicators. In the survey, a panel of 100 European melanoma experts agreed on 56 statements that can be used to improve patient selection, homogenize treatment application, and monitor outcomes.

Comparison of color-Doppler and qualitative and quantitative strain-elastography for differentiation of thyroid nodules in daily practice.

OBJECTIVE: Strain-elastography provides a new ultrasound-based method that can offer information about the stiffness of thyroid nodules as an indicator of malignancy. The aim of our study was to compare the utility of color-Doppler and strain-elastography in differentiating between benign and malignant nodules. DESIGN AND METHODS: 77 thyroid nodules (70 benign and 7 malignant) from 70 unselected patients (48 female/22 male, mean age 49.7±14.3 years) were evaluated with color-Doppler and elastography based on a five-scale elastogram score for qualitative elastography and strain ratio for quantitative elastography. As reference tissue we chose normal thyroid tissue [strain ratio a (SR a)] and cervical muscles [strain ratio b (SR b)]. The cytological or histological results were used as a reference standard. Diagnostic performances of qualitative and quantitative elastography were compared using ROC curves. RESULTS: Vascularization score 3 or 4 was associated with malignancy (p=0.024) as well as elastogram score 4 or 5 (p=0.070, n.s.s.). SR a was indicatively higher and SR b lower in the group of malignant nodules (p=0.065 and p=0.246, n.s.s.). The best cut-off points predicting malignancy were 3.32 for SR a (66.7% sensitivity, 83.3% specificity) and 0.10 for SR b (71.4% sensitivity, 67.1% specificity). CONCLUSION: In our study, the accuracy of elastography did not surpass other sonographic parameters in differentiating thyroid nodules. The technique can play a role as a supplementary parameter in assessment of malignancy to improve diagnostic efficacy. The best parameter is SR a, but SR b can serve as an alternative if SR a is not assessable.

TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors.

ASA404 (Vadimezan) belongs to a class of agents with disrupting properties against tumor vasculature, which is partly mediated by TNFα-signaling. Preclinical and early clinical studies have indicated promising results for ASA404, while extended clinical trials performed poorly. Our aim was to investigate the potential therapeutic applicability of ASA404 against endocrine tumors. Moreover, as the reason for the unpredictable clinical anti-tumor activity of ASA 404 remained uncertain in previous studies, we compared two tumor models of endocrine origin with different responses to ASA404 treatment. Specifically, we determined anti-tumoral effects in preclinical models of neuroendocrine tumors of the gastroenteropancreatic system (BON) and adrenocortical cancer (NCI-H295R) in vitro and in xenograft models in vivo. Upon treatment of tumor bearing mice significant anti-tumoral effects, an increase in TNFα as well as activation of TNFα-specific downstream signaling were evident in the BON tumor model while no comparable effects were detectable for NCI-H295R. We identified TNFAIP3/A20, a key molecule of an inhibitory feedback-loop downstream of TNF-receptor 1, CD40, Toll-like receptors, NOD-like receptors and the interleukin-1 receptor signaling cascades, as overexpressed in the adrenocortical carcinoma tumor model. Subsequent analyses of clinical patient samples confirmed a correlation between tumor TNFAIP3 expression levels and overall survival in patients with ACC. Taken together our findings provide evidence that modulation of TNFα-signaling could be of relevance both for the clinical course of ACC patients and as a marker of treatment response.

Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease.

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100 beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P<0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100 beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.

Liposomal polychemotherapy improves adrenocortical carcinoma treatment in a preclinical rodent model.

Owing to high relapse rates and early metastatic spread, prognosis in adrenocortical carcinoma (ACC) patients remains poor, highlighting the importance of developing new treatment alternatives for them. Recently, polychemotherapy regimens including etoposide, doxorubicin, and cisplatin together with mitotane (EDP-M) have been defined as the standard treatment for late-stage disease patients. Nevertheless, the administration of conventional cytostatic drugs is associated with severe and dose-limiting side effects. In an attempt to optimize existing clinical treatment regimens, in this study, we investigated the therapeutic efficacy of EDP-M in comparison with that of a paclitaxel-modified scheme (paclitaxel, doxorubicin, cisplatin plus mitotane (PDP-M)) in preclinical in vitro and in vivo models. In addition, based on an extraordinary uptake phenomenon of liposomes in ACC cells, we further evaluated liposomal variants of these protocols (etoposide, liposomal doxorubicin, liposomal cisplatin plus mitotane (LEDP-M) and nab-paclitaxel, liposomal doxorubicin, liposomal cisplatin plus mitotane (LPDP-M)). In vitro, PDP-M was more potent in the induction of apoptosis and inhibition of cell viability as well as cell proliferation than EDP-M. Following the administration of a single therapeutic cycle, we further demonstrated that LEDP-M and LPDP-M exerted significant antitumoral effects in vivo, which were not as evident upon EDP-M and PDP-M treatments. These results were confirmed in a long-term experiment, in which the highest and sustained antitumoral effects were observed for LEDP-M. In summary, liposomal cytostatic substances could represent a promising option that deserves testing in appropriate clinical protocols for the treatment of ACC patients.

Lack of influence of somatic mutations on steroid gradients during adrenal vein sampling in aldosterone-producing adenoma patients.

OBJECTIVE: Adrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somatic KCNJ5 K(+)-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1 and ATP2B3) might affect the final diagnosis and treatment of the affected patients. DESIGN: Fifty-nine patients with APAS who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio 2) and had undergone a mutation analysis of their tumor tissue were studied. the mutation status of the APAS was as follows: 19 KCNJ5 mutations, eight ATPase mutations (five ATP1A1 and three ATP2B3), and 32 patients with none of these mutations. METHODS: The lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for the KCNJ5-mutated, ATPase-mutated, and the KCNJ5/ATPase mutation-negative APA patients. RESULTS: The lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in the KCNJ5 mutation carriers and that of 20.5 in the KCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in the KCNJ5 mutation carriers and that of 0.2 in the KCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant. CONCLUSIONS: We did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS.

Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature.

CONTEXT: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. OBJECTIVE: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. MAIN OUTCOME MEASURES: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. RESULTS: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. CONCLUSIONS: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.

Evidence for two types of brown adipose tissue in humans.

The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.

Polypropylene meshes coated with a polysaccharide based bioadhesive for intra-abdominal mesh fixation in a rabbit model.

BACKGROUND: In this study, we evaluate a new bioadhesive for intra-abdominal onlay mesh fixation of a polypropylene-polyvinylchloride graft. METHODS: Three pieces of a commercially available polypropylene/polyvinylfluoride mesh, each 3 × 3 cm in size, and three pieces of the same mesh coated with a polysaccharide bioadhesive were fixated to the surface of the anterior abdominal wall of 30 New Zealand white rabbits. The fixation was performed either by using four transabdominal Prolene(®) 4/0 sutures, four spiral tacks (Protack 5 mm Tyco), or cyanoacrylate glue (Glubran(®) GEM, Viareggio, Italy). Each mesh position and the according kind of fixation were randomized before implantation. The animals were sacrificed 12 weeks postoperatively. After determining the extent of intra-abdominal adhesions, the meshes were excised en bloc with the anterior abdominal wall for tensile strength measurements and histological analysis. RESULTS: All meshes coated with the bioadhesive adhered to the intact peritoneum without extra fixation. Irrespective of the fixation technique coated meshes led to more and stronger adhesions. Mesh shrinkage by scarring was increased in coated meshes fixed with glue and low in uncoated meshes fixed with tacks. Testing the tensile strength, coated meshes fixed with transfascial sutures achieved the best results (16.14 ± 6.1 N), whereas coated meshes fixed with glue showed the lowest strength (10.39 ± 4.81 N). The foreign body reaction was considerably more distinctive using coated mesh. The mesh ingrowth was not influenced by this reaction. CONCLUSIONS: All meshes coated with the new bioadhesive were self-adhesive in that way; they stayed in position when attached to the peritoneum. Although this may facilitate intra-operative mesh fixation, the bioadhesive displayed several disadvantages, such as stronger adhesions and an increased shrinkage of the implant. The tensile strength was not influenced by the use of the bioadhesive. At present, we see no major advantage for polysaccharide bioadhesive applied in this study.

PAR-1 mediates the thrombin-induced mesothelial cell overproduction of VEGF and PAI-1.

PURPOSE: Thrombin mediates an excess in the production of neoangiogenetic (VEGF) and profibrotic (PAI-1) factors in human peritoneal mesothelial cells (HMC). The mechanisms leading to this overproduction have not been elucidated so far; in the context of peritoneal dialysis it can result in impaired peritoneal membrane function. OBJECTIVES: This study was performed to evaluate the presence of the thrombin receptor protease-activated receptor-1 (PAR-1) in HMC and to characterize its function in the thrombin-dependent effects mentioned above. METHODS: All experiments were performed using cultured primary HMC. Real-Time PCR and Western Blot were used to evaluate PAR-1; ELISA and Real-Time PCR were employed to examine PAR-1 effects on target mediators. RESULTS: We found that cultivated primary HMC show a basal presence of PAR-1. Stimulation with IL-1ß induced an increase of the mesothelial PAR-1 expression whereas stimulation with glycosilated human serum albumin or the ligand thrombin itself resulted in decreased PAR-1 expression. Stimulation with the specific PAR-1 ligand TFLLR-NH(2) caused increased VEGF and PAI-1 levels similar to stimulation with thrombin, whereas preincubation with PAR-1 blocking antibodies ATAP2 and WEDE15 attenuated the thrombin-induced overproduction of VEGF and PAI-1. CONCLUSIONS: HMC express PAR-1 and the receptor is involved in thrombin effects on these cells. These findings may be a basis for pharmacological prevention of neoangiogenesis and adhesions in the context of peritoneal dialysis and peritonitis.

Prolonged zona glomerulosa insufficiency causing hyperkalemia in primary aldosteronism after adrenalectomy.

CONTEXT: Unilateral adrenalectomy is the therapy of choice in aldosterone-producing adenoma (APA). Zona glomerulosa (ZG) insufficiency causing hyperkalemia after adrenalectomy has been described in case reports. OBJECTIVE: Our aim was to analyze the clinical relevance of ZG insufficiency causing hyperkalemia after adrenalectomy in a large series of patients with APA. DESIGN: This was a retrospective chart review. SETTING: The study was conducted at two tertiary university referral centers in Germany. PATIENTS: Data from 110 patients with confirmed APA adrenalectomized at the centers in Munich and Berlin between 2004 and 2012 were analyzed. MAIN OUTCOME MEASURES: The primary outcome was the incidence of ZG insufficiency causing hyperkalemia after adrenalectomy; the secondary outcome was the identification of risk factors predisposing for hyperkalemia. RESULTS: Eighteen of 110 patients (16%) developed postoperative hyperkalemia. The majority of these patients (n = 14) had undetectable plasma aldosterone levels after adrenalectomy; four had low aldosterone levels. In 12 of these patients, hyperkalemia was documented only once and resumed spontaneously. Prolonged hypoaldosteronism accompanied by hyperkalemia was observed in six patients (5% of total cohort). These patients needed continuous mineralocorticoid replacement therapy for 11-46 months. Mineralocorticoid antagonist treatment for 4 wk prior to surgery did not prevent hyperkalemia. In multivariate analysis, preoperatively decreased glomerular filtration rate and increased serum creatinine as well as increased postoperative creatinine and microalbuminuria remained significant predictors of hyperkalemia. CONCLUSION: Persistent postoperative hypoaldosteronism with hyperkalemia occurs in 5% of adrenalectomized PA patients through prolonged ZG insufficiency, requiring long-term fludrocortisone treatment. Potassium levels after adrenalectomy must be monitored to avoid life-threatening hyperkalemia.

Activation of peroxisome proliferator-activated receptor-gamma by glitazones reduces the expression and release of monocyte chemoattractant protein-1 in human mesothelial cells.

Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor-gamma- (PPARγ-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPARγ on MC was assayed in a Western Blot analysis. MC constitutively express PPARγ. Activation of this receptor via rosiglitazone (0,1-10 µmol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPARγ inhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNFα-induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNFα-stimulated mesothelial MCP-1 mRNA expression and release.

Long term outcome and quality of life after open incisional hernia repair--light versus heavy weight meshes.

BACKGROUND: Mesh repair of incisional hernia is superior to the conventional technique. From all available materials for open surgery polypropylene (PP) is the most widely used. Development resulted in meshes with larger pore size, decreased mesh surface and lower weight. The aim of this retrospective non randomized study was to compare the quality of life in the long term follow up (> 72 month) after incisional hernia repair with "light weight"(LW) and "heavy weight"(HW) PP meshes. METHODS: 12 patients who underwent midline open incisional hernia repair with a HW-PP mesh (Prolene® 109 g/m2 pore size 1.6 mm) between January 1996 and December 1997 were compared with 12 consecutive patients who underwent the same procedure with a LW-PP mesh (Vypro® 54 g/m2, pore size 4-5 mm) from January 1998. The standard technique was the sublay mesh-plasty with the retromuscular positioning of the mesh. The two groups were equal in BMI, age, gender and hernia size. Patients were routinely seen back in the clinic. RESULTS: In the long term run (mean follow up 112 ± 22 months) patients of the HW mesh group revealed no significant difference in the SF-36 Health Survey domains compared to the LW group (mean follow up 75 ± 16 months). CONCLUSIONS: In this study the health related quality of life based on the SF 36 survey after open incisional hernia repair with light or heavy weight meshes is not related to the mesh type in the long term follow up.

Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study.

BACKGROUND AND AIMS: Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma. METHODS: Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze-thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-α and PGE(2) and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC. RESULTS: Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more. CONCLUSION: DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment.

Cyanoacrylate glue for intra-abdominal mesh fixation of polypropylene-polyvinylidene fluoride meshes in a rabbit model.

BACKGROUND: Cyanoacrylate glues are tissue adhesive with high adherent and hemostatic properties. The aim of this study was to evaluate the efficacy of cyanoacrylates glue for polypropylene-polyvinylidene fluoride (PP-PVDF) intraperitoneal onlay mesh (IPOM) fixation in a rabbit model. MATERIALS AND METHODS: In 40 New Zealand white rabbits, three pieces (3×3cm) of a PP-PVDF mesh (n=120) were fixed in IPOM technique on both sides of a midline laparotomy. For mesh fixation we used spiral tacks, nonabsorbable sutures, or cyanoacrylate glue in a randomized manner. All animals were killed after 12 wk. The prosthetic materials were excised en bloc with the anterior abdominal wall for evaluation of the tensile strength and histologic analysis. Results are presented as mean and standard deviation. RESULTS: Meshes fixed with glue showed a significantly higher tenacity of adhesions (2.75±0.97) compared with those with tacks (2.44±0.97 sutures versus 1.91±0.92 tacks). The percentage of adhesions in the glue group was comparable to the suture group (36.50% ± 27.60% glue, 37.62% ± 27.36% suture). The tensile strength of stapled and sutured meshes was significantly higher than the tensile strength glued mesh (14.15±0.97N suture versus 14.84±0.74 stapler versus 9.64±0.78N glue). Mesh shrinkage was irrespective of the fixation technique. The inflammation reaction was more pronounced in the glue group. CONCLUSIONS: Although cyanoacrylate glue showed a considerable cellular ingrowth in this rabbit model, sutures and tacks proved to be superior for IPOM fixation of PP-PVDF meshes in terms of tensile strength.

Synthetic double-stranded RNA stimulates the expression of interferon-inducible protein 10 in human mesothelial cells.

Interferon-inducible protein 10 (IP-10) is a chemokine playing an important role in the restriction of viral spread. A time- and dose-dependent increase in IP-10 is found upon activation of viral receptors expressed on mesothelial cells, which provides novel evidence for a link between viral infections and inflammation of serous membranes.

Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients.

BACKGROUND: The role of laparoscopic adrenalectomy in the treatment of patients with adrenocortical carcinoma (ACC) is controversial. OBJECTIVE: Our aim was to compare oncologic outcome in patients with ACC who underwent either open adrenalectomy (OA) or laparoscopic adrenalectomy (LA) for localised disease. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of 152 patients with stage I-III ACC with a tumour < or =10 cm registered with the German ACC Registry. INTERVENTION: Patients were stratified into two groups according to the surgical procedure (LA or OA). For comparison, we used both a matched pairs approach by selecting for each patient from the LA group (n=35) one corresponding patient from the OA group (n=117) and multivariate analysis in all 152 patients. MEASUREMENTS: Disease-specific survival was chosen as the predefined primary end point. Secondary end points were recurrence-free survival, frequency of tumour capsule violation and postoperative peritoneal carcinomatosis, and incidence and reasons for conversion from LA to OA. RESULTS AND LIMITATIONS: LA and OA did not differ with regard to the primary end point using either the matched pairs approach (hazard ratio [HR] for death: 0.79; 95% confidence interval [CI], 0.36-1.72; p=0.55) or multivariate analysis (HR for death: 0.98; 95% CI, 0.51-1.92; p=0.92). Similarly, adjusted recurrence-free survival was not different between LA and OA (HR: 0.91; 95% CI, 0.56-1.47; p=0.69). Frequency of tumour capsule violation and peritoneal carcinomatosis were comparable between groups. In 12 of 35 patients of the LA group, surgery was converted to open surgery with no impact on the clinical outcome. CONCLUSIONS: For localised ACC with a diameter of < or =10 cm, LA by an experienced surgeon is not inferior to OA with regard to oncologic outcome.

Etoricoxib--preemptive and postoperative analgesia (EPPA) in patients with laparotomy or thoracotomy--design and protocols.

BACKGROUND AND OBJECTIVE: Our objective was to report on the design and essentials of the Etoricoxib protocol- Preemptive and Postoperative Analgesia (EPPA) Trial, investigating whether preemptive analgesia with cox-2 inhibitors is more efficacious than placebo in patients who receive either laparotomy or thoracotomy. DESIGN AND METHODS: The study is a 2 x 2 factorial armed, double blinded, bicentric, randomised placebo-controlled trial comparing (a) etoricoxib and (b) placebo in a pre- and postoperative setting. The total observation period is 6 months. According to a power analysis, 120 patients scheduled for abdominal or thoracic surgery will randomly be allocated to either the preemptive or the postoperative treatment group. These two groups are each divided into two arms. Preemptive group patients receive etoricoxib prior to surgery and either etoricoxib again or placebo postoperatively. Postoperative group patients receive placebo prior to surgery and either placebo again or etoricoxib after surgery (2 x 2 factorial study design). The Main Outcome Measure is the cumulative use of morphine within the first 48 hours after surgery (measured by patient controlled analgesia PCA). Secondary outcome parameters include a broad range of tests including sensoric perception and genetic polymorphisms. DISCUSSION: The results of this study will provide information on the analgesic effectiveness of etoricoxib in preemptive analgesia and will give hints on possible preventive effects of persistent pain. TRIAL REGISTRATION: NCT00716833.