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Magneto-rheological (MR) materials can respond reversibly and quickly under the effect of an external magnetic field. MR materials contain micron-sized iron particles. These iron particles are typically dispersed in an elastomer or a liquid. These materials due to their properties constitute a kind of smart material in terms of engineering material. Such materials are used as isolators in various engineering applications, structures, and sound control subsystems. This study aimed to determine the mechanical properties for shear behavior of MR materials for under harmonic loading. Parameters such as matrix materials with different hardness values, powder types, magnetic field, frequency, and deformation were studied. The parameters related to the MR material itself were analyzed with the obtained data. The present study reveals that considering the sensitivity to magnetic field parameter, composite materials having the most suitable properties were produced with Shore 2 hardness value and SQ magnetic powder. It had been observed on increase about 200% at the rate of Shore A10 and A2 as a result of comparing the hardness scale. Also according to the powder rate while there was an increase on worth effect of relative MR, it is seen that the biggest increase had been in SQ powder with 199% worth. When looked some studies in literature, about comparing different hardness values such as matrix materials powder types etc. there aren’t any studies. The state of magnetic field thinks that features such as MR effect, Storage, and Loss modulus haven’t been examined yet.

Background Axial spondyloarthritis (AxSpA) is a chronic inflammatory disease of the axial skeleton which manifests as inflammatory back pain and progressive stiffness of the spine. Patients with axial disease and other features of SpA but no unequivocal sacroiliitis in conventional X-ray now termed as non-radiographic axial spondyloarthritis (nr-AxSpA). Those patients can be diagnosed on the basis of the presence of active inflammation in magnetic resonance imaging (MRI) or human leukocyte antigen B27 (HLA-B27).Systemic lupus erythematosus (SLE) is a chronic inflammatory disease of unknown etiology that may affect the skin, joints, kidneys, lungs, nervous system, sereous membranes, and/or other organs of the body. Sjogrens syndrome (SS) is the second most common autoimmune rheumatic condition characterized by lymphocytic infiltrate of the exocrine glands, resulting in dysfunction and destruction of them. Antiphospholipid syndrome (APS) is the association of thrombosis and/or pregnancy morbidity with antiphospholipid antibodies (aPL) (lupus anticoagulant [LA], anticardiolipin antibodies (aCL), and/or anti-2 -glycoprotein-I antibodies (a2 GPI). Methods Case Presentation We report a 55-year-old female patient having the association of nr-AxSpA, SLE, secondary APS, and SjS. Diagnosis of nr-AxSpA was made based upon the presence inflammatory low-back pain, human leukocyte antigen B27 positivity, and presence of sacroiliitis only in MRI. SLE was diagnosed with butterfly-shaped rash on her cheeks, inflammatory arthritis, photosensitivity, erythema involving dorsal inter-joint area of hand fingers, alopecia together with antinuclear antibody (ANA) and anti-dsDNA positivity, low serum complement levels, leucopenia and thrombocytopenia. Additional presence of sicca symptoms, low Schirmer I test, anti SSA/Ro and anti-SSB/La positivity, supported by positive labial salivary gland biopsy led to the diagnosis of SjS. Results Furthermore, this patient also had miscarriage at 16th week and cerebral vascular disease at 33 years. Besides, IgG and IgM anticardiolipin antibodies were found to be positive twice. Therefore, she was also diagnosed as secondary APS. She fulfilled the relevant criteria for AxSpA, SLE, SjS and APS. Conclusions To our knowledge, this is the first case report showing the association of these four diseases, with different genetic, etiopathogenetic and clinical systemic inflammatory diseases. Funding Source(s): No

Secretory meningiomas constitute a relatively rare subtype of meningiomas and present often with massive peritumoural oedema. From our previous report, a high number of mast cells were demonstrable in this subtype of meningiomas. The present study aimed to obtain more information about mast cell derived progangiogenic factors and mediators as well as VEGF receptors in secretory meningioma. Additionally, the correlation of histological factors such as the presence of mast cells and the radiological evidence of surrounding tumour oedema was analysed.Sixteen cases of secretory meningioma were examined. Relevant clinical information was obtained from the patient files. The peritumoural oedema was determined either by CT or MRI scans and graded as mild, moderate and severe. Immunohistochemical studies of histamine, substance P, serotonin, VEGF and VEGF receptors were performed. A double-blind quantitative evaluation of mast cells staining positively for VEGF in a comparison with total mast cells in secretory meningiomas was made by two histopathologists.There was no immunoreactivity against histamine or substance P within the tumour tissue or in mast cells. Fine granules of serotonin were demonstrated within the mast cells and a coarse granular expression of VEGF was found within the mast cells. Our preliminary data demonstrated that tumours with moderate to severe degree of peritumoural oedema usually contained more than 50% of VEGF-staining positive mast cells.Secretory meningiomas are characterized by a significantly increased number of mast cells. VEGF and serotonin might be involved in the pathophysiological process of this vasogenic brain oedema. The preliminary data demonstrated the potential relation between the radiological evidence of increasing oedema and the high numbers of mast cell staining positively for VEGF.

Introduction: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high lev- els of epidermal growth factor receptor (EGFR) (immunohistochem- istry score of ≥200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. Methods: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy end- points according to tumor EGFR mutation status. Results: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 dele- tions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of ≥200), a survival benefit for the addition of cetuximab to chemotherapy was demon- strated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. Conclusions: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

The addition of cetuximab to first-line chemotherapy substantially prolonged survival in patients with advanced non-small cell lung cancer whose tumors expressed high levels of epidermal growth factor receptor (EGFR; immunohistochemistry score of ≥200 on a scale of 0-300).To evaluate the interobserver reproducibility of this EGFR immunohistochemistry scoring system, based on both the tumor cell membrane staining intensity (graded 0-3+) and the percentage of cells staining at each intensity.In parts 1 (initial feasibility study) and 2 of this 2-part round robin test, sections of different non-small cell lung cancer tissue microarrays were stained in a central reference laboratory. Following reference evaluation, EGFR expression in 30 selected tumor cores was characterized in serial sections by lung cancer pathology specialists. The reproducibility of scoring by different raters was assessed. Analysis of between-rater agreement was based on the allocation of EGFR immunohistochemistry scores into low- (200) and high- (≥200) EGFR expression groups.After discussion with raters of the issues impacting reproducibility identified in part 1 and following adjustment of processes, part 2 of the round robin test showed a high interobserver agreement in EGFR immunohistochemistry scoring, with an overall concordance rate of 90.9% and a mean κ coefficient of 0.812. Specimens with a reference EGFR immunohistochemistry score of lower than 200 and of 200 or higher showed mean concordance rates of 94.7% and 85.6%, respectively.After appropriate training, assessing EGFR expression by this immunohistochemistry-based method allowed a highly reproducible allocation of non-small cell lung cancers into clinically relevant high- or low-EGFR expression groups.

Contains fulltext : 118506.pdf (Publisher’s version ) (Closed access) Molecular pathology is an integral part of daily diagnostic pathology and used for classification of tumors, for prediction of prognosis and response to therapy, and to support treatment decisions. For these reasons, analyses in molecular pathology must be highly reliable and hence external quality assessment (EQA) programs are called for. Several EQA programs exist to which laboratories can subscribe, but they vary in scope, number of subscribers, and execution. The guideline presented in this paper has been developed with the purpose to harmonize EQA in molecular pathology. It presents recommendations on how an EQA program should be organized, provides criteria for a reference laboratory, proposes requirements for EQA test samples, and defines the number of samples needed for an EQA program. Furthermore, a system for scoring of the results is proposed as well as measures to be taken for poorly performing laboratories. Proposals are made regarding the content requirements of an EQA report and how its results should be communicated. Finally, the need for an EQA database and a participant manual are elaborated. It is the intention of this guideline to improve EQA for molecular pathology in order to provide more reliable molecular analyses as well as optimal information regarding patient selection for treatment.

Fibroepithelial polyp of vagina (FEPV) is a mucosal polypoid lesion with a fibro vascular stalk and oedematous or hypocellular stroma covered by squamous epithelial surface. FEPV is extremely rare before menarche and after menopause. This article describes a two year old girl with a vaginal polyp and the histological analysis of which revealed to be a FEPV. Surgical excision of the mass was performed, and in 1 year of follow-up no recurrence was detected. A review of the literature showed that there were four cases of FEPV in neonatal girls. While these reported cases were neonatal, our case is the first case of FEPV in a two year old girl.

Purpose We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D–mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. Methods Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. Results Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D–mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. Conclusion The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D–mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.

The CRYSTAL and OPUS randomised clinical trials demonstrated that adding cetuximab to first-line chemotherapy in patients with KRAS wild-type metastatic colorectal cancer (mCRC) significantly improved treatment outcome compared with chemotherapy alone. The objective of this pooled analysis was to further investigate these findings in patients with KRAS wild-type tumours using extended survival data and following an enhancement in the ascertainment rate of KRAS and BRAF tumour mutation status from these studies.Pooled individual patient data from each study were analysed for overall survival (OS), progression-free survival (PFS) and best overall response rate (ORR) in patients evaluable for KRAS and BRAF mutation status. Treatment arms were compared according to mutation status using log-rank and Cochran-Mantel-Haenszel tests.In 845 patients with KRAS wild-type tumours adding cetuximab to chemotherapy led to a significant improvement in OS (hazard ratio [HR] 0.81; p=0.0062), PFS (HR 0.66; p0.001) and ORR (odds ratio 2.16; p0.0001). BRAF mutations were detected in 70/800 evaluable tumours. No significant differences were found in outcome between the treatment groups in these patients. Prognosis was worse in each treatment arm for patients with BRAF tumour mutations compared with those with BRAF wild-type tumours.Analysis of pooled data from the CRYSTAL and OPUS studies confirms the consistency of the benefit obtained across all efficacy end-points from adding cetuximab to first-line chemotherapy in patients with KRAS wild-type mCRC. BRAF mutation does not appear to be a predictive biomarker in this setting, but is a marker of poor prognosis.

Findings from the phase 3 FLEX study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival, compared with cisplatin and vinorelbine alone, in the first-line treatment of EGFR-expressing, advanced non-small-cell lung cancer (NSCLC). We investigated whether candidate biomarkers were predictive for the efficacy of chemotherapy plus cetuximab in this setting.Genomic DNA extracted from formalin-fixed paraffin-embedded (FFPE) tumour tissue of patients enrolled in the FLEX study was screened for KRAS codon 12 and 13 and EGFR kinase domain mutations with PCR-based assays. In FFPE tissue sections, EGFR copy number was assessed by dual-colour fluorescence in-situ hybridisation and PTEN expression by immunohistochemistry. Treatment outcome was investigated according to biomarker status in all available samples from patients in the intention-to-treat population. The primary endpoint in the FLEX study was overall survival. The FLEX study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT00148798.KRAS mutations were detected in 75 of 395 (19%) tumours and activating EGFR mutations in 64 of 436 (15%). EGFR copy number was scored as increased in 102 of 279 (37%) tumours and PTEN expression as negative in 107 of 303 (35%). Comparisons of treatment outcome between the two groups (chemotherapy plus cetuximab vs chemotherapy alone) according to biomarker status provided no indication that these biomarkers were of predictive value. Activating EGFR mutations were identified as indicators of good prognosis, with patients in both treatment groups whose tumours carried such mutations having improved survival compared with those whose tumours did not (chemotherapy plus cetuximab: median 17·5 months [95% CI 11·7-23·4] vs 8·5 months [7·1-10·8], hazard ratio [HR] 0·52 [0·32-0·84], p=0·0063; chemotherapy alone: 23·8 months [15·2-not reached] vs 10·0 months [8·7-11·0], HR 0·35 [0·21-0·59], p0·0001). Expression of PTEN seemed to be a potential indicator of good prognosis, with patients whose tumours expressed PTEN having improved survival compared with those whose tumours did not, although this finding was not significant (chemotherapy plus cetuximab: median 11·4 months [8·6-13·6] vs 6·8 months [5·9-12·7], HR 0·80 [0·55-1·16], p=0·24; chemotherapy alone: 11·0 months [9·2-12·6] vs 9·3 months [7·6-11·9], HR 0·77 [0·54-1·10], p=0·16).The efficacy of chemotherapy plus cetuximab in the first-line treatment of advanced NSCLC seems to be independent of each of the biomarkers assessed.Merck KGaA.

Background: The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC). Patients and methods: The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented. Results: Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed. Conclusions: These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Background We aimed to improve the postoperative outcome of high-risk patients (American Society of Anesthesiologists class 3 and 4) recovering from colorectal cancer surgery by using recombinant human G-CSF (filgrastim) as perioperative prophylaxis. Methods In a double-blinded, placebo-controlled trial, 80 patients undergoing left-sided colorectal resection were randomized to filgrastim or placebo. Filgrastim (5 μg/kg) or placebo was administered in the afternoon on day –1, 0, and +1 relative to the operation. Primary endpoints were in a hierarchic order: quality of life (QoL) over time (determined at discharge, 2 and 6 months after operation with the European Organization for Research and Treatment of Cancer questionnaire) and the McPeek recovery score, which measures death and duration of stays in the intensive care unit and hospital. Predefined secondary endpoints were global QoL, subdomains of QoL, postoperative recovery, duration of stay, 6-month overall survival, complication rates, and cellular and immunologic parameters. Results There were no significant differences in both primary endpoints between the treatment groups. A significant improvement (P < .05) was obtained by filgrastim prophylaxis in the QoL subdomain family life /- social functioning,; thus, more patients recovered to their preoperative state (14 vs 4 with placebo) as determined by structured interviews. Duration of hospital stay (14 vs 12 days) and noninfectious complications were decreased from 8% to 3%. Conclusions High-risk patients undergoing major operation for colorectal cancer profited from filgrastim prophylaxis with regard to duration of hospital stay, noninfectious complications, social QoL, and subjective recovery from operation. These endpoints, however, were secondary, and the primary endpoints (overall QoL and the McPeek index) did not show comparable benefits. A new confirmatory trial with the successful endpoints of this trial, as well as a cost analysis, will be needed to confirm the results before a general recommendation for the prophylactic use of G-CSF in high-risk cancer patients can be given.

Nevus sebaceous (NS), also known as organoid nevus, is a congenital skin hamartoma involving pilosebaceous follicle, epidermis and adnexal structures, which usually occurs in the head and neck region. During the first stage, which is seen in infancy and childhood, the lesion remains static, but can subsequently grow during puberty to become more evident and verrucous or nodular. Depending on the location and extent, nevus sebaceous causes only a cosmetic problem during childhood; however, the development of benign and malignant neoplasms on the lesion is the most severe complication during adulthood. The association between nevus sebaceous and various benign and malignant cutaneous neoplasms is well documented. Basal cell carcinoma (BCC) is the most common malignant lesion, and syringocystadenoma papilliferum (SP) is the most common benign tumor associated with nevus sebaceous. Development of squamous cell carcinoma within NS is very rare. The literature contains only a few reports of simultaneous multiple malignant tumors developing on nevus sebaceous. We present a review of the literature and report the case of a 42-year-old female patient with two squamous-cell carcinomas (SCC) simultaneously within a single NS.

To evaluate the outcome of reoperations in patients with duodenopancreatic neuroendocrine tumors (PETs) in a tertiary referral center.The management of reoperations in PETs is still controversial.A total of 125 patients with PETs that underwent surgery between 1987 and 2004 at our institution were retrospectively evaluated. The diagnosis of PETs was based on clinical symptoms, biochemical tests, and histopathology. Patients with at least one reoperation were analyzed regarding clinical characteristics, pathology, operations, and long-term follow-up.A total of 33 patients with a median age of 42 years were identified for this study: 13 patients had gastrinomas, 12 patients had nonfunctional islet cell tumors, 6 patients had insulinomas, and 2 patients had vipomas; 24 patients had sporadic NETs, 9 patients had a MEN-1-syndrome; 27 patients had histologically verified malignant tumors; 33 initial operations and 50 reoperations were performed. The initial procedures comprised 27 resections of the primary tumor and 6 explorative laparotomies; 28 of all reoperations were resections of distant metastases, including 15 liver resections; 19 resections of the pancreas or duodenum were performed during reoperations. The overall morbidity and mortality was 45% and 4.8%, respectively. After a median follow-up of 124 months (range, 16-384 months), 27 of 33 patients are still alive, 12 without evidence of disease. All 6 patients with benign tumors are still alive. The 5-, 10-, and actuarial 25-year survival rate for patients with malignant tumors were 81%, 72%, and 36%, respectively. The survival rate was significantly related to the patients age at time of initial operation and better in patients younger than 50 years compared with patients older than 50 years (P = 0.0007), and the presence or development of metastases (none or lymph node metastases versus distant metastases: P = 0.01).We show that an aggressive surgical approach leads to long-term survival in patients with malignant PETs. Although long-term cure can only be achieved in a proportion of patients with malignant PETs, significant long-term palliation can be achieved.

Background. Argon plasma coagulation (APC) is based on the principle of ionised argon creating conductive plasma between an activating electrode and tissue surface and is used as an effective alternative coagulation technique in various surgical disciplines. This trial aims to compare thermal injury in rat brain caused by APC and conventional bipolar coagulation technique. Methods. A controlled study design with constant power setting and application time was established. Twenty rats were randomised into the APC and bipolar groups. Each group of ten rats had 20 treated lesions. Early and late histopathological changes, as well as maximum extent of the lesion after 48 hours (h) and 12 days were studied in overall 20 lesions. Findings. Although the maximum depth of the lesions was different in APC (2.2 mm) and bipolar (1.8 mm) groups after 48 h, this did not achieve statistical significance (p = 0.151). The superficially coagulated area was significantly larger after APC compared with the bipolar technique at the 48 h time point (p = 0.032). After twelve days there were no differences in penetration depth (p = 0.310) or coagulated area (p = 0.222). Conclusion. Tissue defects after APC application on rat brains were comparable to conventional bipolar technique in this trial. The results suggest that argon plasma coagulation (APC) is an effective coagulation technique.

Postoperative outcome of patients is determined by recovery characteristics and self-reported quality of life. The first can be assessed with the McPeek score which values three aspects of recovery: mortality, postoperative critical care and duration of hospitalization. We calculated the McPeek score of 669 patients in three trials: (1) colorectal cancer surgery, (2) antihistamine/volume loading in various operations, and (3) cholecystectomy. Beforehand, the average of intensive care unit treatment and duration of hospitalization were determined for the different operations to define McPeek score points. The score was tested on reliability, validity, and sensitivity. In addition, clinical applicability was assessed in a survey. The score was reliable with similarly distributed score points in the three trials at different institutions. Inter-rater reliability was high (97% overlap). Validity was proven by moderate high correlation to convergent criteria such as complications (trial I to III r=0.43, r=0.38, r=0.60), preoperative American Society of Anesthesiologists class (ASA) (r=0.24, r=0.28, r=0.57), and age (r=0.23, r=0.32, r=0.31). The score was different between patients with and without neoplasms (P

Inactivating mutations of wild-type p53 (WTp53) tumor suppressor gene are common in anaplastic thyroid cancer (ATC) and are associated with poor prognosis. Mutated p53 (MTp53) has been implicated with angiogenesis. Therefore, the potential of MTp53 knockout by oligodeo xyribonucleotide phosphorothioates (ODNs) to affect VEGF production of undifferentiated thryoid cancer cells with a recessive MTp53 mutation was evaluated. Transient transfection with 20 bp ODNs complementary to portions of exon 10 of p53 and a negative contr of ODN (HIV-RT) were carried out in FTC-133 cells. In vitro secretion of VEGF protein was quantified by EIA and correlated to cell numbers, which was evaluated by in vitro MTT assay. Transfection of undiffarentifiated thyroid cancer cells with ODN reduced VEGF secretion of FTC-133 cells following transfection by 34% as compared to the negative control (cell transfected with ODN-HIV; p=0.03). These results suggest that transient MTp53 knockout with ODNs complementary to p53 nucleotide sequences impair secretion of VEGF in the undifferentiated thyroid cancer cell line FTC-133.

To evaluate the outcome of an aggressive surgical approach for duodenopancreatic neuroendocrine tumors (PETs) associated with multiple endocrine neoplasia type 1 (MEN1).The management of PETs is still controversial in the setting of the autosomal dominant inherited MEN1 syndrome.MEN1 patients that had either biochemical evidence of functioning PETs or visualized nonfunctioning PETs larger than 1 cm in size on imaging were operated. Since 1997, patients were followed annually by biochemical testing and imaging studies.Twenty-six genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 17) or nonfunctioning (n = 9) PETs. Ten (38%) patients had malignant PETs as characterized by the presence of lymph node (10 patients) and/or distant metastases (2 patients). The surgical approach was selected based on the type, location, and size of PETs. Four Zollinger-Ellison syndrome (ZES) patients required pylorus preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure, 20 patients underwent other duodenopancreatic resections, and 2 patients had simple enucleations of PETs. After median 83 months (range, 5-241 months), 24 patients were alive and 2 patients died of an unrelated cause. All patients with insulinoma or vipoma and 7 of 11 patients with ZES were biochemically cured, including the ZES patients who underwent PPPD. However, 19 of 26 (73%) patients developed new small PETs (1 cm) in the pancreatic remnant, but no patient had yet detectable metastases on imaging.Early and aggressive surgery of PETs in MEN1 patients prevents the development of liver metastases, which are the most life-threatening determinant. PPPD might be the procedure of choice for MEN1-ZES, which has to be proven in large scale studies.

The angiogenesis inhibitor TNP-470 (AGM-1470) has shown encouraging results in animal models of established tumors. However, results of recent clinical trials using TNP-470 have been disappointing. Since little is known about the effects of TNP-470 at the minimal disease stage, we analyzed the effects of TNP-470 on the early stages of tumor establishment. Twenty thousand green fluorescent protein (GFP)-transfected murine CT-26 (colonic carcinoma) or Panc-02-H0 (pancreatic adenocarcinoma) cells were inoculated in dorsal skin-fold chambers in BALB/c or C57BL6 mice. Tumor area and microvessel density (MVD) were quantified by intravital microscopy (IVM). Body weight was also monitored. Effects were compared with those in a conventional model involving subcutaneous (s.c.) inoculation of 106 tumor cells, followed by measurement of tumor volume, endogenous plasma VEGF/endostatin (ELISA) and proliferation/apoptosis/microvessel density (Ki-67/TUNEL/CD-34). TNP-470 was injected s.c. over the 10-day experimental period (30 mg/kg every 2 days [n=6] to 100 mg/kg/day [n=5 dorsal skin-fold chamber model, n=4 s.c. tumor model]). At 30 mg/kg/every second day neither CT-26 nor PANC-02-H0 tumors were inhibited in neither of the two models. TNP-470 dosage was escalated in CT-26-bearing animals until an antiangiogenic effect could be observed. In the IVM model, only TNP-470 100 mg/kg/day reduced MVD (P=0.006), but failed to block the onset of angiogenesis and tumor area increase. Body weight decreased by 25% (P

The solid-pseudopapillary tumor (SPT) is a very rare pancreatic neoplasm that predominantly affects young females. About 450 cases have been described in the world literature and approximately 20% of the reported patients were children. The occurrence of SPT with distant metastases in children is extremely rare with only two previously reported cases. We now report a 16-year-old Asian girl with a large SPT and synchronous multiple liver metastases who was successfully treated in a 2-step strategy, including initial pylorus-preserving partial duodenopancreatectomy, right hemicolectomy, resection and allografting of the portal vein and secondary resection of 12 liver metastases. The patient is disease free after a follow-up of 18 months after resection of the primary tumor, suggesting that an aggressive surgical treatment might also be justified for metastasized SPT.

INTRODUCTION The efficacy of 5-HT(3)-receptor antagonists suggests a role of serotonin in the pathogenesis of postoperative nausea and vomiting (PONV). However, studies investigating the relationship between the turnover of serotonin and PONV were contradictory. Therefore we carried out a pilot study in order to find out whether results can be obtained that would justify further studies on a larger scale. METHODS A total of 22 patients scheduled for elective gynaecological laparoscopy were enrolled. A balanced anaesthesia using sufentanil, etomidate, cisatracurium, isoflurane and nitrous oxide was administered and 5-hydroxyindoleaceticacid (5-HIAA) concentrations in the urine were measured within the 24 h after surgery. RESULTS Only the patients that vomited postoperatively had a significant change in the concentrations of 5-HIAA over the time course investigated. However, comparison of urinary 5-HIAA concentrations of the group comprising patients that vomited with those that had no PONV did not reveal a significant difference. CONCLUSIONS Results of this study support further investigation of the relationship between serotonin and PONV and suggest that there may in fact be an association between PONV and increased serotonin turnover.

Background The appropriate treatment for a sporadic endocrine tumour may be different from those that present as part of the multiple endocrine neoplasia type 1 (MEN1) syndrome. As primary hyperparathyroidism (pHPT) and pancreaticoduodenal endocrine tumours (PETs) are the most common organ manifestations of MEN1, the prevalence of germline mutations in the MEN1 gene was determined in young patients with apparently sporadic pHPT or PETs. Methods Eighteen of 705 patients with pHPT and 11 of 93 patients with PETs operated on between 1987 and 2001 had no family history of MEN1, only one organ manifestation and were aged 40 years or less at the time of diagnosis. Fifteen patients with pHPT and eight with PETs agreed to MEN1 gene mutation analysis, which was performed by single-strand conformational variant analysis and direct DNA sequencing. Results Two of 15 patients (13·3 (95 per cent confidence interval (c.i.) 1·6 to 40·4) per cent) with apparently sporadic pHPT had a MEN1 germline mutation. Both mutations were found in patients with pHPT due to multiglandular disease, whereas the remaining 13 patients had a solitary adenoma. None of the eight patients with PETs carried a MEN1 germline mutation. Conclusion Sporadic pHPT due to multiglandular disease in patients younger than 40 years may represent the first organ manifestation of MEN1 despite a negative family history.

Tumor growth is dependent on the balance of positive and negative regulators of angiogenesis. Antiangiogenic compounds inhibit endothelial cell biology in vitro and angiogenesis in vivo. Therefore antiangiogenic therapy presumes to be an effective treatment for pancreatic cancer. We wanted to determine the effect of antiangiogenic therapy on the growth of human pancreatic cancer in a mouse model. The angiogenesis inhibitors TNP-470 and antiangiogenic antithrombin III (aaATIII) were tested in vitro for their ability to inhibit endothelial cell proliferation. These inhibitors, along with the known antiangiogenic molecule endostatin, were then employed to treat two different primary human pancreatic cancers implanted subcutaneously into the dorsa of immunodeficient (SCID) mice. Treated tumors were examined histologically for microvessel density, apoptosis, and proliferation. All three inhibitors suppressed the growth of pancreatic tumors in vivo. Immunohistochemical analysis revealed increased degrees of apoptosis and reduced microvessel density in treated tumors compared to untreated tumors, although tumor cell proliferation was the same in both groups. None of the inhibitors tested significantly inhibited proliferation of human pancreatic cancer cells, although both TNP-470 and aaATIII were able to inhibit the proliferation of endothelial cells. The observed tumor suppression may be due to increased tumor cell apoptosis as a result of capillary dropout. These studies show that after the angiogenic switch in a human tumor, there is residual production of angiogenesis inhibitors.

Molecular mechanisms contributing to the tumorigenesis of pancreatic endocrine tumors (PETs) are still not well understood. Allelic deletions at chromosome 22q12.3 were detected in about 30-60% of PETs, suggesting that inactivation of one or more tumor suppressor genes on this chromosomal arm is important for their pathogenesis. Because the putative tumor suppressor gene tissue inhibitor of metalloproteinase-3 (TIMP-3) has been located at 22q12.3, we undertook a genetic analysis of TIMP-3 to determine its role in the tumorigenesis of PETs. Single-strand conformational polymorphism analysis, methylation-specific PCR, RNA expression analysis, and immunohistochemistry of TIMP-3 were performed in 21 sporadic PETs. Thirteen of 21 PETs (62%) revealed TIMP-3 alterations, including promoter hypermethylation and homozygous deletion. The predominant TIMP-3 alteration was promoter hypermethylation, identified in 8 of 18 (44%) PETs. It was tumor-specific and corresponded to loss or strong reduction of TIMP-3 protein expression. Notably, 11 of 14 (79%) PETs with metastases had TIMP-3 alterations, compared with only 1 of 7 (14%) PETs without metastases (P < 0.02). These data suggest a possibly important role of TIMP-3 in the tumorigenesis of human PETs, especially in the development of metastases, which has to be further evaluated in large-scale studies.

BackgroundThe value of peritoneal lavage for intra-abdominal contamination and infection has never been proven scientifically. In contrast, the stimulation of host defence mechanisms with cytokines such as granulocyte colony-stimulating factor (G-CSF) has appeared promising in recent clinical trials.MethodsClinic modelling randomized trials (CMRTs), which model the complexity of the clinical reality, were used in rats in which peritoneal contamination and infection (PCI) was produced with human stool bacteria. The following groups were compared: trial 1, intraoperative peritoneal lavage with saline versus taurolin (18 rats per group); trial 2, no lavage versus saline lavage versus saline lavage plus subcutaneous administration of G-CSF (18 rats per group); trial 3, lavage with saline versus no lavage (30 rats per group). The primary endpoint was mortality at 120 h. Secondary endpoints were the phagocytic activity of granulocytes, and systemic and peritoneal cytokine levels.ResultsIn trial 1 lavage with taurolin was not superior to that with saline (five of 18 versus eight of 18 animals survived; P = 0·32). In trial 2, six of 18 animals having no lavage and three of 18 receiving saline lavage survived. The combination of lavage and G-CSF increased the number of animals surviving to 11 of 18 (P < 0·05). Lavage combined with G-CSF stimulated granulocyte phagocytic activity (P < 0·01) and reduced the levels of interleukin (IL) 6 (P < 0·01) and tumour necrosis factor α (P < 0·05) in peritoneal fluid, as well as plasma levels of IL-6 (P < 0·05) and IL-10 (P < 0·01). In trial 3, survival was not significantly different in animals having lavage (14 of 30) and no lavage (19 of 30) (P = 0·14).ConclusionIn these CMRTs of intra-abdominal contamination and infection, peritoneal lavage was not beneficial, but when lavage was combined with subcutaneous administration of G-CSF mortality was reduced and the local and systemic cytokine response was downgraded. Results from these CMRTs were used directly to define the trial conditions of a randomized clinical trial with G-CSF. Peritoneal lavage is not recommended.

Objective and design: Mesenteric traction syndrome is described as sudden tachycardia, hypotension and flush. Among other etiological factors eventeration or mesenteric traction of the small intestine may cause histamine release from mesenteric mast cells. We hypothesized that mesenteric traction syndrome may be positively influenced by prophylactic antihistamine administration.¶Methods: Male patients (n = 17, ASA groups III-IV, 48–78 years old) were investigated in a randomised double blind study during elective abdominal aortic aneurysm (AAA) repair. Eight patients had pre-anaesthetic prophylaxis with dimetindene (H1-receptor antagonist) plus cimetidine (H2-receptor antagonist), 9 patients received placebo. Anaesthesia and invasive haemodynamic monitoring were standardised in all patients. Haemodynamic parameters, plasma histamine concentrations and clinical symptoms were determined 1 min after skin incision, as well as 5 and 20 min after mesenteric traction. Statistical analyses were performed using the Student's t-test, Chi2-test for incidences and Mann-Whitney-U-test for continuous data.¶Results: The incidence of histamine release was 55.5 % (5/9) in the placebo group vs. 37.5 % (3/8) in the antihistamine group (p > 0.05, Chi2-test). Plasma histamine levels (mean ± SD) were higher in the placebo group than in the antihistamine group at 5 and 20 min after mesenteric traction but the difference did not reach statistical significance. Arrhythmias were significantly more frequent in the placebo group (6 times) than in the antihistamine group (none) (p = 0.005 Chi2-test). Systolic blood pressure was not statistically different between groups (e.g. 5 min after mesenteric traction, mean ± SD; placebo 111 ± 20 mm Hg vs. antihistamines 119 ± 35 mm Hg). However, in the placebo group the haemodynamics only stabilised 5 min after mesenteric traction when anaesthetic gas concentration was repeatedly reduced and vasopressor/volume administration was increased (placebo-group = 20 times/ antihistamine-group = 8 times, p = 0.001, t-test).¶Conclusion: Prophylactic administration of antihistamines reduced the incidence of histamine release as well as the incidence of arrhythmias and the amount of stabilising measures during mesenteric traction. Prophylaxis with H1 and H2 antihistamines may be of perioperative benefit and should therefore be considered in AAA-surgery.

To investigate the incidence of occult posterior injuries of the pelvic ring in patients with isolated fractures of the pubic rami, additional computed tomography (CT) was performed. Data from 70 patients were collected within a prolective study. Solitary fractures of the anterior pelvic ring based on conventional radiographic diagnosis were included. Spiral CT, slice thickness 5 mm, was carried out in all patients. In only 47% of cases was the diagnosis of isolated fractures of the pubic rami confirmed. A further 35 fractures of the sacrum and two partial disruptions of the sacroiliac joint were diagnosed using CT. All sacral fractures were incomplete, most were found at the anterior part of the bone. Furthermore, CT revealed three acetabular fractures. Dorsal injuries were significantly more frequent after high energy accidents. Clinical examination did not assist in the prediction of posterior injuries of the pelvic ring. There was no correlation between the extent of the anterior injuries in conventional x-ray and incidence of the posterior injuries in CT. None of the patients with dorsal injuries underwent operative treatment. In conclusion, CT is not required for the routine diagnosis of supposed isolated fractures of the pubic rami.

In a retrospective study diagnostic procedures and outcome of treatment were evaluated in 33 patients with traumatic spondylolisthesis of the axis (Hangman's fracture) who were treated in our department between 1986 and 1999. There were 18 men and 15 women with an average age of 41 (17-88) years. The cause of the injury was in 23 cases an accident as a driver of a car, in 2 cases an accident with a bike, 2 patients had an accident as a pedestrian. 5 patients fell on their head and 1 patient was hit by a beam. In 15 cases there were relevant accompanying injuries. To assess the stability of the injury, a subtle radiological examination was performed including functional X-rays. After introduction of the MRI and increasing experience with the method as a standard procedure in clinical practice it was used instead of functional X-rays to get a direct image of the involvement of the discoligamental structures.17 patients with stable lesions were treated conservatively, 15 with a Minerva-cast, 2 with a halo-jacket. One polytraumatized patient had temporary immobilization with a stiff-neck. 16 patients with discoligamental instability C2/3 were treated operatively by Robinson-spondylodesis with additional anterior plating. In one case an additional posterior fusion was necessary. After 6-8 weeks all of the conservative treated patients achieved solid bony consolidation. The patients operated on did so as well within 6 to 8 weeks. Two polytraumatized patients died. 18 of the 31 surviving patients were free of pain. 12 patients complained of pain or tension of the cervical muscles during physical stress. 1 patient suffered of paresthesia of the ulnar left hand. Average duration of hospital stay was 12,9 days (1-47). All working people returned to their job. Differences in the outcome of the conservative and the operative treatment group could not be seen. We derive from these results that Hangman's fractures, mostly caused by a hyperextension trauma, achieve solid bony fusion by conservative treatment in most of the cases. The Minerva-cast has proved its capability. In cases of instable luxation fractures including tearment of the anterior longitudinal ligament and affection of the intervertebral disc C2/3 we suggest operative stabilization. We prefer the modified Robinson-spondylodesis with additional anterior plating which proved its value as a method achieving solid bony fusion combined with low rate of complications.

Sepsis is still a major problem in human medicine with a high mortality rate. Nearly all attempts to improve the outcome of septic patients with immune modulators failed. In most of these trials only mechanistic endpoints such as mortality rate, complication rate, cytokine levels and physiological parameters were assessed. Only in a very few trials quality of life had been chosen as primary endpoint. In basic research and especially in animal experiments in the field of sepsis and oncology, only molecular investigations which explain drug and treatment interactions were in the focus of the scientific community. Animal models simulating clinical complexity and investigating outcomes like quality of life were very rare. The aim of this study was to demonstrate alterations in sickness behaviour – the animal equivalent to quality of life in man – in rats as a response to sepsis after prophylaxis with G-CSF and antibiotics. Sickness behaviour was assessed by measurement of core body temperature, food and water intake, locomotor activity and circadian rhythm of these parameters. Complex animal experiments in rats were performed including anaesthesia, antibiotic and cytokine (G-CSF) prophylaxis, volume substitution, laparotomy, contamination and infection with human faecal suspension and postoperative analgesia. In group A (sham) and D (antibiotic + G-CSF) the mortality rate was 0% , but in group B (no prophylaxis) 33% (3/9) and in group C (antibiotic prophylaxis) 11% (1/9) of the animals died. Before infection all rats showed clear circadian patterns of locomotor activity and body temperature with physiologically higher values during the night-time. Immediately after operation and infection temperature increased, water and food intake, locomotor activity decreased and circadian rhythms were lost. Body temperature and water consumption were already normalised at day 2 after infection in all groups. Normal food intake was re-established in group C and D at day 3 while one more day was needed for recovery in Group C. Restoration of locomotor activity occurred in group D at day 5, in group C at day 7. In group B locomotor activity remained suppressed during the whole observation period of 8 days postoperatively. In conclusion, in septic rats sickness behaviour, an equivalent to quality of life in humans, is improved rapidly by a prophylaxis with G-CSF in combination with antibiotics and can be used as a new outcome in preclinical surgical research.

Adding cetuximab to chemotherapy improved survival in patients with recurrent/metastatic squamous cell carcinoma of the head and neck. Although HPV and p16 statuses have prognostic value, the observed survival benefit conferred by cetuximab is independent of both. This pattern remained in a combined analysis of both p16 and HPV and in patients with oropharyngeal cancer separately.Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status. Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays. Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients. The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.

To investigate the occurrence of carpal ligamentous injuries in patients with fractures of the distal radius, the results of 122 wrist arthroscopies were analysed within a retrospective study. Indications for arthroscopy included suspected carpal instability according to radiographic findings and/or the necessity for internal fixation of the radius fracture. Arthroscopy revealed acute scapholunate ligament tears in 84 patients. Scapholunate separation was found to be of prognostic value for ligament tears. There was no association between ligamentous lesions and carpal angles or fracture dislocation. Scapholunate ligament tears were most frequent in sagittal articular fractures. In these cases, wrist arthroscopy should be performed during operative treatment of the radius fracture to allow direct visualization and subsequent repair of ligamentous tears.

The longitudinal muscle (LM) represents a strong muscular structure of the anal canal situated between the internal (IAS) and the external anal sphincter (EAS). Terminal fibres of this muscle insert at the submucosa of the anal canal, representing the m. canalis ani. Others cross the subcutaneous part of the EAS to become the m. corrugator ani. Thus, the LM connects the visceral and somatic parts of the anal sphincter complex. Histologically ganglionic cells and as Vater-Pacinian corpuscles can be identified inside the LM. Morphology, topography and histology of the LM suggest that this muscle participates in maintaining anorectal continence. It is mandatory that the exact functions of this muscular structure be to elaborated upon, if we are to understand the mechanism of anorectal continence.

Background: The phase III EXTREME and CRYSTAL studies demonstrated that the addition of cetuximab to chemotherapy significantly improved survival in the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) and KRAS wild-type metastatic colorectal cancer (mCRC). In advanced non-small-cell lung cancer (NSCLC), high EGFR expression was identified as a tumour biomarker that can predict survival benefit associated with the addition of cetuximab to first-line chemotherapy. We investigated whether tumour EGFR expression level was predictive of cetuximab benefit in EXTREME and CRYSTAL study patients. Methods: Prospectively collected tumour immunohistochemistry data were used to generate an EGFR immunohistochemistry score (scale 1-300) for patients in the EXTREME and CRYSTAL studies. For each study, the association between tumour immunohistochemistry score and cetuximab benefit was investigated. The EXTREME and CRYSTAL studies are registered with Clinical Trials.gov, numbers NCT00122460 and NCT00154102, respectively. Findings: Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the ITT population of the CRYSTAL study with EGFR-expressing, KRAS wild-type disease. The distribution of immunohistochemistry scores was similar between the treatment arms of each study, but differed between studies. A clinically relevant benefit for progression-free and overall survival associated with the addition of cetuximab to chemotherapy was seen across the full score range in EXTREME study patients. Similarly, CRYSTAL study patients derived a clinical benefit across the full score range, with no meaningful association between EGFR expression level and benefit. Interpretation: The addition of cetuximab to chemotherapy improved survival in the first-line treatment of recurrent/metastatic SCCHN and KRAS wild-type mCRC regardless of tumour EGFR expression level, indicating that in contrast to findings in NSCLC, EGFR expression level is not a clinically useful predictive biomarker in these settings. (C) 2012 Elsevier Ltd. All rights reserved.