Similarity of Seroma Rate at the Medial Thigh following Free Flap Harvesting or Medial Thigh Lift: A Systematic Review and Meta-analysis.

Despite the growing use of autologous breast reconstruction with medial thigh-based free flaps, such as transverse upper gracilis (TMG) or profunda artery perforator (PAP) flaps, these procedures are infrequently performed on patients with obesity. This systematic review and meta-analysis aimed to compare the frequency of seroma occurrence, a common complication after medial thigh flap surgery. Comparison was performed between TMG and PAP flaps, as well as medial thigh lifts (MTL), a procedure with a similar operative technique but which is typically offered to patients with a higher body mass index (BMI). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, we analyzed EMBASE, PUBMED, and MEDLINE data (English/German). The primary outcomes assessed were occurrence of seroma, as well as hematoma and wound dehiscence. Subgroup analyses explored age, BMI, and various surgical factors. This meta-analysis incorporated 28 studies, totaling 1096 patients. MTL patients had significantly higher BMIs, whereas seroma rates were similar among TMG, PAP, and MTL patients. The incidence of hematoma and wound dehiscence was also similar across the groups. In the metaregression analysis, factors such as age and BMI showed no significant correlation with seroma occurrence in all groups. This systematic review and meta-analysis identified comparable rates of seroma formation after TMG flap, PAP flap, and MTL procedures. Considering that this phenomenon occurred despite the elevated BMI of the MTL group, we propose that patients with higher BMI need not be excluded as candidates for autologous medial thigh-based breast reconstruction. Hence, these procedures should not be limited to small- to medium-sized breasts. Large-scale prospective studies are imperative to validate these conclusions and reveal the underlying factors contributing to seroma formation.

Renal carcinoma CD105-/CD44- cells display stem-like properties in vitro and form aggressive tumors in vivo.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. Prognosis for ccRCC is generally poor since it is largely resistant to chemo- and radiotherapy. Many studies suggested that cancer stem cells/tumor initiating cells (CSCs/TICs) are responsible for development of tumor, disease progression, aggressiveness, metastasis and drug resistance. However, tumorigenic potential of CSCs/TICs isolated from established RCC cell lines - basic ccRCC research model - has never been investigated in vivo. CD105+, CD105-, CD44+ and CD44- as well as CD44-/CD105- CD44+/CD105+ and CD44-/CD105+ cells were isolated from Caki-1 RCC cell line, confirming coexistence of multiple subpopulations of stem-related phenotype in stable cell line. Sorted cells were injected subcutaneously into NOD SCID mice and tumor growth was monitored with MRI and PET/CT. Tumor growth was observed after implantation of CD105+, CD44+, CD44-, CD44-/CD105+ and CD44-/CD105- but not CD105- or CD44+/CD105+. Implantation of CD44-/CD105- cells induced tumors that were characterized by longer T1 and distinct metabolic pattern than other tumors. All the tumors were characterized by low uptake of [18F]FDG. CD105+ and CD44- tumors expresses Nanog and Oct-4, while CD44- tumors additionally expressed endothelial cell marker - CD31.

In Search of NPY Y4R Antagonists: Incorporation of Carbamoylated Arginine, Aza-Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists.

The cross-linked pentapeptides (2R,7R)-diaminooctanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2R,7R)-BVD-74D, (2R,7R)-1) and octanedioyl-bis(Tyr-Arg-Leu-Arg-Tyr-amide) (2) as well as the pentapeptide Ac-Tyr-Arg-Leu-Arg-Tyr-amide (3) were previously described as neuropeptide Y Y4 receptor (Y4R) partial agonists. Here, we report on a series of analogues of (2R,7R)-1 and 2 in which Arg2, Leu3, or Arg4 were replaced by the respective aza-amino acids. The replacement of Arg2 in 3 with a carbamoylated arginine building block and the extension of the N-terminus by an additional arginine led to the high-affinity hexapeptide Ac-Arg-Tyr-Nω-[(4-aminobutyl)aminocarbonyl]Arg-Leu-Arg-Tyr-amide (35), which was used as a precursor for a d-amino acid scan. The target compounds were investigated for Y4R functional activity in assays with complementary readouts: aequorin Ca2+ and ß-arrestin 1 or ß-arrestin 2 assays. In contrast to the parent compounds, which are Y4R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y4R antagonists.

High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling.

The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(ω)-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [(3)H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values.

Mimicking of Arginine by Functionalized N(ω)-Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High Affinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples.

Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8-13), an analogue of the C-terminal pentapeptide of neuropeptide Y, and a neuropeptide FF analogue) were subject of this proof-of-concept study. The N(ω)-carbamoylated arginines, bearing spacers with a terminal amino group, were incorporated into the peptides by standard Fmoc solid phase peptide synthesis. The synthesized chemically stable peptide derivatives showed high receptor affinities with Ki values in the low nanomolar range, even when bulky fluorophores had been attached. Two new tritiated tracers for angiotensin and neurotensin receptors are described.

Neuroendocrine Tumor of the Pancreas as a Manifestation of Cowden Syndrome: A Case Report.

CONTEXT: Germline mutations in the phosphatase and tensin homolog (PTEN) tumor suppressor gene are found in the majority of patients with Cowden syndrome (CS), who have an increased risk of breast, thyroid, and endometrial cancer. According to our current understanding of genetic changes in the PTEN gene and the resultant phenotypic features of CS, pancreatic neuroendocrine tumors (NETs) are not considered part of the clinical spectrum of CS. CASE DESCRIPTION: We report a unique case of an advanced NET of the pancreas in a patient with CS. The germline DNA sequencing confirmed the clinical diagnosis of CS and revealed a PTEN mutation c.697C→T (p.R233*) causing a premature stop codon in exon 7. The tumor DNA sequencing showed no loss of heterozygosity or any copy number changes and no other deleterious genetic alterations, including those commonly mutated in sporadic pancreatic NETs: MEN1, ATRX, DAXX, TP53, and genes involved in the mammalian target of rapamycin pathway. In addition, the high-throughput transcriptome analyzed by RNA-seq did not reveal any missed genetic alterations, aberrant splicing variants, gene fusions, or gene expression alterations. The immunohistochemical staining of the tumor for PTEN revealed an abnormal, uniformly strong cytoplasmic staining of tumor cells with virtually absent nuclear staining. CONCLUSION: The results from genetic testing and histopathological techniques used to confirm CS diagnosis and characterize this unusual tumor tempted us to believe that in this case, the pancreatic NET was not a sporadic malignancy that occurred by coincidence, but rather represented a new entity in the spectrum of malignancies associated with CS.

N(ω)-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y1 Receptor Antagonists and a Radiolabeled Selective High-Affinity Molecular Tool ([(3)H]UR-MK299) with Extended Residence Time.

Analogues of the argininamide-type NPY Y1 receptor (Y1R) antagonist BIBP3226, bearing carbamoyl moieties at the guanidine group, revealed subnanomolar Ki values and caused depression of the maximal response to NPY (calcium assay) by up to 90% in a concentration- and time-dependent manner, suggesting insurmountable antagonism. To gain insight into the mechanism of binding of the synthesized compounds, a tritiated antagonist, (R)-N(α)-diphenylacetyl-N(ω)-[2-([2,3-(3)H]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([(3)H]UR-MK299, [(3)H]38), was prepared. [(3)H]38 revealed a dissociation constant in the picomolar range (Kd 0.044 nM, SK-N-MC cells) and very high Y1R selectivity. Apart from superior affinity, a considerably lower target off-rate (t1/2 95 min) was characteristic of [(3)H]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t1/2 3 min, Kd 2.0 nM). Y1R binding of [(3)H]38 was fully reversible and fully displaceable by nonpeptide antagonists and the agonist pNPY. Therefore, the insurmountable antagonism observed in the functional assay has to be attributed to the extended target-residence time, a phenomenon of relevance in drug research beyond the NPY receptor field.

Prospective evaluation of follow-up in melanoma patients in Germany - results of a multicentre and longitudinal study.

BACKGROUND: Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially. METHODS: In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis. RESULTS: Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3-4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4year surveillance of 550 patients without tumour recurrence (stage I-IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3-4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these. CONCLUSIONS: We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival.

BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

[Recurrent fibrosarcomatous dermatofibrosarcoma protuberans. Ultrasound imaging]. / Rezidiv eines fibrosarkomatösen Dermatofibrosarcoma protuberans. Sonographische Darstellung.

Dermatofibrosarcoma protuberans (DFSP) is a rare dermal tumor of intermediate malignancy with a locally aggressive growth behavior with a high rate of recurrence. Wide local excision with histographic margin control as well as regular follow-ups including clinical as well as ultrasound examination are crucial to detect local recurrence or metastasis. Ultrasound imaging can not only identify recurrences but also asses their extent. We report on a patient with a relapse of fibrosarcomatous DFSP, which could be demonstrated by ultrasound imaging.

Microarray analysis of gene expression profiles in the rat kidney demonstrates a local inflammatory response induced by cardiopulmonary bypass.

CONTEXT: Cardiopulmonary bypass (CPB) is a commonly used technique in cardiac surgery but is associated with acute, transient, renal dysfunction that has a negative impact on long-term survival. OBJECTIVE: To unravel the molecular pathogenesis of renal injury following CPB. DESIGN: To obtain insight into the pathogenesis of renal dysfunction following CPB, we performed a microarray analysis of renal gene expression in the rat. SETTING: University Medical Centre Groningen. INTERVENTION: Rats underwent CPB or a sham procedure for 60 min and were sacrificed at 60 min, 1 and 5 days after the procedure. MAIN OUTCOME MEASURES: Renal gene expression profile as determined by microarray analysis. RESULTS: Expression of 420 genes was significantly altered in CPB compared to the sham procedure, and in 407 genes, this was evident in the acute phase (60 min) following CPB. Gene ontology analysis revealed 28 of these genes were involved in inflammatory responses, with high expression of genes downstream of mitogen-activated protein-kinase (MAP-kinase) signalling pathways. Potent inducers identified are from the interleukin-6 cytokine family that consists of interleukin-6 and oncostatin M (OSM), which signal through the gp130-cytokine receptor complex. The plasma concentration of interleukin-6 was hugely increased by CPB as measured by ELISA. Expression of genes downstream of these signalling pathways that lead to production of chemokines, adhesion molecules and molecules involved in coagulative pathways, was upregulated. CONCLUSION: CPB induces an acute and local inflammatory response in the kidney, which might contribute to renal injury. The signalling pathways involved identified by gene expression analysis may represent pharmacological targets to limit renal injury following CPB.

[Consumer safety, public heath, and environment : Scientific advice at the European level]. / Verbrauchersicherheit, öffentliche Gesundheit und Umwelt : Wissenschaftliche Beratung auf europäischer Ebene.

The European Commission aims at basing its policy decisions on sound scientific evidence. To ensure access to the best scientific expertise, it has created a committee-based advisory structure. The three scientific committees on Consumer Safety, on Health and Environmental Risks, and on Emerging and Newly Identified Health Risks develop opinions in the area of public health, environment, and consumer protection. This article provides an overview of the structure, areas of expertise, and working practices of the committees and gives examples for recently adopted opinions.

Mechanism of near-threshold production of the eta meson.

Measurements of the analyzing power for the pp-->pp eta reaction have been performed at excess energies of Q=10 and 36 MeV. The determined analyzing power is essentially consistent with zero, implying dominance of the s wave at both excess energies. The angular dependence of the analyzing power, combined with the isospin dependence of the total cross section for the eta meson production in nucleon-nucleon collisions, reveal that the excitation of the nucleon to the S11(1535) resonance is predominantly due to the exchange of the pi meson between the colliding nucleons.

Right bundle branch block and long-term mortality in patients with acute congestive heart failure.

OBJECTIVES: Risk stratification in acute congestive heart failure (ACHF) is poorly defined. The aim of the present study was to assess the impact of right bundle brunch block (RBBB) on long-term mortality in patients presenting with ACHF. METHODS AND RESULTS: The initial 12-lead electrocardiogram was analysed for RBBB in 192 consecutive patients presenting with ACHF to the emergency department. The primary endpoint was all-cause mortality during 720-day follow-up. This study included an elderly cohort (mean age 74 years) of ACHF patients. RBBB was present in 27 patients (14%). Age, sex, B-type natriuretic peptide levels and initial management were similar in patients with RBBB when compared with patients without RBBB. However, patients with RBBB more often had pulmonary comorbidity. A total of 84 patients died during follow-up. Kaplan-Meier analysis revealed that mortality at 720 days was significantly higher in patients with RBBB when compared with patients without RBBB (63% vs. 39%, P = 0.004). In Cox proportional hazard analysis, RBBB was associated with a two-fold increase in mortality (hazard ratio 2.18, 95% CI 1.26-3.66; P = 0.003). This association persisted after adjustment for age and comorbidity. CONCLUSIONS: RBBB is a powerful predictor of mortality in patients with ACHF. Early identification of this high-risk group may help to offer tailored treatment in order to improve outcome.

The use of B-type natriuretic peptide in the management of patients with diabetes and acute dyspnoea.

AIMS/HYPOTHESIS: The aim of this study was to determine the impact of measurement of B-type natriuretic peptide (BNP) levels on the management of patients with diabetes presenting with acute dyspnoea. METHODS: This study evaluated the subgroup of 103 patients with diabetes included in the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study (n=452). Patients were randomly assigned to a diagnostic strategy with (n=47, BNP group) or without (n=56, control group) the use of BNP levels assessed by a rapid bedside assay. Time to discharge and total cost of treatment were recorded as the primary endpoints. RESULTS: Although similar with regard to age and sex, patients with diabetes more often had pre-existing cardiovascular and renal disease and heart failure as the cause of acute dyspnoea compared with patients without diabetes. In addition, medical and economic outcomes were worse in patients with diabetes. The use of BNP levels significantly reduced time to discharge (median 9 days [interquartile range (IQR) 2-16] in the BNP group vs 13 days [IQR 8-22] in the control group; p=0.016). At 30 days, the diabetic patients in the BNP group had spent significantly fewer days in hospital compared with the diabetic patients in the control group (9 days [IQR 2-19] vs 16 days [IQR 8-24], respectively; p=0.008). Total treatment costs at 30 days were US$5,705 (IQR 2,285-9,137) in the BNP group and US$7,420 (IQR 4,194-11,966) in the control group (p=0.036). CONCLUSIONS/INTERPRETATION: The results of this study indicate that measurement of BNP levels improves the management of patients with diabetes presenting with acute dyspnoea.

Coronary artery disease and outcome in acute congestive heart failure.

OBJECTIVES: To quantify the prognostic impact of coronary artery disease (CAD) on patients with acute heart failure (HF). DESIGN: Prospective cohort study of 217 consecutive patients presenting with acute HF to the emergency department. Treatment, hospitalisation, the use of revascularisation procedures, and survival were observed during follow up of up to three years. RESULTS: CAD was present in 153 patients (71%). Patients with and without CAD were similar with respect to age and sex. Although adequate HF treatment was initiated more rapidly among patients with CAD, their initial outcomes including hospitalisation rate, time to discharge, and total treatment cost were significantly worse. Moreover, despite higher use of angiotensin converting enzyme inhibitors and beta blockers during follow up, patients with CAD had a significantly lower survival rate. Cumulative survival at 720 days was 48.7% of patients with CAD as compared with 76.4% of patients without CAD (p = 0.0004). In Cox regression analysis the presence of CAD increased the risk of death by more than 250% (hazard ratio 2.57, 95% confidence interval 1.50 to 4.39, p = 0.001). This strong association persisted after multivariate adjustments. The use of coronary angiography and coronary revascularisation procedures was low, both at initial presentation and during follow up. CONCLUSION: CAD is a strong and independent predictor of mortality among patients with acute HF. Whether, for example, less restrictive use of revascularisation procedures in this elderly HF population can improve the outcome for patients with CAD warrants further study.

The use of B-type natriuretic peptide in the management of elderly patients with acute dyspnoea.

OBJECTIVES: The aim of this study was to define the impact of B-type natriuretic peptide (BNP) levels on the management of elderly patients presenting with acute dyspnoea. DESIGN: We performed a prospective randomized controlled study in 269 elderly patients at least 70 years of age included in the B-type natriuretic peptide for Acute Shortness of breath Evaluation (BASEL) study. Patients were randomly assigned to a diagnostic strategy with (n = 136, BNP group) or without (n = 133, control group) the use of BNP levels provided by a rapid bedside assay. The time to discharge and the total cost of treatment were the primary end-points. RESULTS: Amongst elderly patients, baseline characteristics were well matched between both groups. The use of BNP levels significantly reduced the time to discharge (median 9.0 in the BNP group versus 11.0 days in the control group; P = 0.029). Total treatment cost was $5381 (95% CI, 4482-6280) in the BNP group when compared with $7411 (95% CI, 6180-8642; P = 0.009) in the control group. In addition, a significant reduction in 30-day mortality was observed (9% in the BNP group versus 17% in the control group; P = 0.039). CONCLUSIONS: Used in conjunction with other clinical information, rapid measurement of BNP in the emergency department improved the management of elderly patients presenting with acute dyspnoea and thereby reduced the time to discharge and the total treatment cost. In addition, BNP testing seemed to reduce 30-day mortality.