Lymphangiogenesis requires Ang2/Tie/PI3K signaling for VEGFR3 cell-surface expression

Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor 3 (VEGFR3), which is encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development, and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here, we used gene deletion, blocking Abs, transgene induction, and gene transfer to study how Ang2, its Tie2 receptor, and Tie1 regulate lymphatic vessels. We discovered that VEGF-C–induced Ang2 secretion from lymphatic endothelial cells (LECs) was involved in full Akt activation downstream of phosphoinositide 3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of an Ang2-blocking Ab decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of the PI3K catalytic p110α subunit or with small-molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C–induced lymphangiogenesis also in adult mice. Our results reveal an important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2/Tie/PI3K signaling.     

Diagnostic value of immunohistochemical IMP3 expression in core needle biopsies of pancreatic ductal adenocarcinoma

The oncofetal protein, insulin-like growth factor II messenger ribonucleic acid-binding protein 3 (IMP3), has been analyzed in many different tumors. Various studies have found that IMP3 is a marker for malignancy and is correlated with increased tumor aggressiveness and reduced overall survival. The diagnosis of pancreatic ductal adenocarcinoma (PDAC) in core needle biopsies can be challenging, and immunohistochemical markers are needed. We studied IMP3 expression in 177 core needle biopsies of the pancreas, including 112 PDACs, 55 cases with chronic sclerosing pancreatitis, and 10 biopsies with tumor-free pancreatic tissue without inflammation. An additional 18 biopsies of PDAC metastases (16 liver biopsies and 2 lymph node biopsies) were analyzed. To study IMP3 expression in large tissue sections, 45 pancreatic resection specimens (26 with PDAC and 19 with chronic sclerosing pancreatitis) were investigated. In contrast to normal or inflamed pancreatic tissue, which was negative in 47 of 65 (72.3%) cases and weakly positive in 15 of 65 (23.1%) cases, strong IMP3 expression was found in 99 of 112 (88.4%) PDACs. Therefore, sensitivity and specificity of IMP3 expression in the differential diagnosis of PDAC and chronic sclerosing pancreatitis using core needle biopsies were found to be 88.4% and 94.6%, respectively. These results were confirmed in the pancreas resection specimens. Furthermore, strong IMP3 expression was found in 17 of 18 (94.4%) of the PDAC metastases that were analyzed. Our study shows that IMP3 is an easy to use and potentially new immunohistochemical marker for the diagnosis of PDAC in core needle biopsies.     

Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy

OBJECTIVES: To evaluate CpG island hypermethylation in a set of candidate genes in prostate cancer (pCA) and its relationship to clinicopathologic parameters and a nomogram predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy. MATERIALS AND METHODS: Tissues of 78 prostate carcinomas, 32 benign prostate hyperplasias (BPHs), and prostate cell lines (LNCaP, DU145, PC3, BPH-1) were examined with MethyLight polymerase chain reaction at 13 gene loci (APC, CDC6, CTNNB1, E-Cadherin, EDNRB, FGFR2, GSTP1, NAB2, PKCmu, PTGS2, RAR-beta, RASL11A, WWOX). RESULTS: APC, RAR-beta, PTGS2, GSTP1, EDNRB, and CTNNB1 (83%, 71%, 65%, 33%, 14%, 9%, respectively) were methylated in pCA but rarely or not methylated in BPH. NAB2 and CDC6 were hypermethylated frequently in pCA (92%, 67%, respectively) and in BPH (91%, 59%, respectively). FGFR2, WWOX, E-Cadherin, PKCmu, and RASLL1A did not display noteworthy methylation in pCA (0-1%) or in BPH. CpG island hypermethylation at APC, retinoic acid receptor beta (RAR-beta), and PTGS2 discriminated with a sensitivity of 65-83% and a specificity of 97-100% between BPH and pCA. The combination of various genes increased the diagnostic expressiveness. PTGS2 hypermethylation correlated with seminal vesicle infiltration (p=0.047), capsular penetration (p=0.004), and pT stage (p=0.014). RAR-beta methylation was accompanied by a higher cumulative Gleason score (p=0.042). The probability of PSA-free-survival calculated with a Kattan nomogram correlated inversely with CpG island hypermethylation at EDNRB, RAR-beta, and PTGS2. All prostate cancer cell lines displayed a varying degree of demethylation after 5-aza-2'deoxycytidine treatment. CONCLUSIONS: CpG island hypermethylation at various gene loci is frequent in prostate cancer and can distinguish between neoplastic and noncancerous tissue. Furthermore, hypermethylation at PTGS2, RAR-beta, and EDNRB inversely correlated with PSA-free-survival according to a Kattan nomogram and has potential prognostic value.     

Adrenergic Receptor Genotype but Not Perioperative Bisoprolol Therapy May Determine Cardiovascular Outcome in At-risk Patients Undergoing Surgery with Spinal Block: The Swiss Beta Blocker in Spinal Anesthesia (BBSA) Study: A Double-blinded, Placebo-controlled, Multicenter Trial with 1-Year Follow-up

Background: Neuraxial blockade is used as primary anesthetic technique in one third of surgical procedures. The authors tested whether bisoprolol would protect patients at risk for cardiovascular complications undergoing surgery with spinal block.

Methods: The authors performed a double-blinded, placebo-controlled, multicenter trial to compare the effect of bisoprolol with that of placebo on 1-yr composite outcome including cardiovascular mortality, nonfatal myocardial infarction, unstable angina, congestive heart failure, and cerebrovascular insult. Bisoprolol was given orally before and after surgery for a maximum of 10 days. Adrenergic receptor polymorphisms and safety outcome measures of bisoprolol therapy were also determined.

Results: A total of 224 patients were enrolled. Spinal block could not be established in 5 patients. One hundred ten patients were assigned to the bisoprolol group, and 109 patients were assigned to the placebo group. The mean duration of treatment was 4.9 days in the bisoprolol group and 5.1 days in the placebo group. Bisoprolol therapy reduced mean heart rate by 10 beats/min. The primary outcome was identical between treatment groups and occurred in 25 patients (22.7%) in the bisoprolol group and 24 patients (22.0%) in the placebo group during the 1-yr follow-up (hazard ratio, 0.97; 95% confidence interval, 0.55-1.69; P = 0.90). However, carriers of at least one Gly allele of the [beta]1-adrenergic receptor polymorphism Arg389Gly showed a higher number of adverse events than Arg homozygous (32.4% vs. 18.7%; hazard ratio, 1.87; 95% confidence interval, 1.04-3.35; P = 0.04).     

Contralateral recurrence of a malignant solitary fibrous tumor of the pleura

We present an unusual case of a contralateral recurrence of malignant solitary fibrous tumor of the pleura (SFTP) nine years after a complete resection. Recurrence of malignant SFTP has already been described, but is usually localized. In our case the patient underwent surgical resection for a malignant SFTP of the left upper lobe in 2000. Nine years later computed tomography (CT)-scans showed lesions that were suspicious of tumor recurrence in the right lung. Thoracoscopy, wedge-resections and pathological findings revealed four nodules of a malignant SFTP of the right middle and lower lobe, histopathologically identical to the tumor, which had been resected nine years ago. A coincidental mucinous bronchioloalveolar carcinoma of the left lower lobe was resected by thoracotomy. To our knowledge this is the first report of contralateral recurrence of a malignant SFTP years after complete resection in the literature. The possibility of a new primary tumor on the right with local metastasis could not be excluded in the clinical and histopathological examinations. Therefore, contralateral recurrence of malignant SFTP should be considered in the postoperative follow-up even years after complete resection.     

Risk of graft fracture after dorso-ventral thoraco-lumbar spondylodesis: is there a correlation with graft size?

Study design

Retrospective clinical study in patients with dorso-ventral thoraco-lumbar spondylodesis.

Objective

To investigate whether the ratio between graft cross sectional area and the surface area of the adjacent endplates has any effect on the midterm stability of the spondylodesis.

Summary of background data

Dorso-ventral spondylodesis in the region of the thoraco-lumbar spine is one of the most frequent operations in orthopaedic surgery. Anterior stabilization with autologous iliac crest graft currently is a standard approach in many hospitals. Although numerous recommendations are given how to perform this technique, no clinical advice is available with regard to minimum graft size.

Methods

Sixty-four-slice CT-scans were obtained from 82 patients 4–12 months after posterior spondylodesis with anterior implantation of iliac crest graft and stabilization with an internal fixator. The scans were analyzed using image analysis software. First, the cross sectional area of the graft was calculated and then the surface area of the adjacent endplates. The ratio between graft cross sectional area and endplate surface area was then calculated from these two values. The grafts were then evaluated in sagittal reconstruction for signs of fracture.

Results

The probability for graft fracture in autologous tricortical grafts was >0.1% (p < 0.001) if the graft cross sectional area exceeded 23.9% of the surface area of the adjacent endplates. Patients with lower ratio values had a higher fracture risk and below a value of 10% all grafts fractured.

Conclusion

The relationship between graft cross sectional area and adjacent endplate area has an important effect on graft midterm stability in ventral spondylodesis of the thoraco-lumbar spine. In our opinion, the risk of graft fractures in dorso-ventral spondylodesis can be reduced by implantation of an appropriately sized graft without any additional procedures or instrumentation.     

Indirect versus direct laryngoscopy for routine nasotracheal intubation

Study Objective

To compare the effectiveness of the indirect laryngoscopes, Airtraq (A) and GlideScope (G), with the Macintosh (M) laryngoscope in routine nasotracheal intubation.

Design

Randomized, single-blinded study.

Setting

University-affiliated, tertiary-care hospital.

Patients

62 adult, ASA physical status 1 and 2 patients with normal airways requiring nasotracheal intubation for dental or maxillofacial surgery.

Intervention

Patients in Groups A and G underwent nasal intubation with the Airtraq and GlideScope, respectively, while laryngoscopy in Group M was performed with the Macintosh blade.

Measurements

Performance of the intubating tools was judged by the ease [Intubation Difficulty Scale (IDS) and numeric rating scale (NRS)] and time to intubation (laryngoscopy and endotracheal tube advancement). In addition, hemodynamic parameters, severity of postoperative sore throat, and posture of the intubator were recorded.

Main Results

IDS score was significantly lower with the Airtraq and GlideScope than with the Macintosh laryngoscope (mean ± SD: A 0.1 ± 0.3, G 0.3 ± 0.6, M 0.8 ± 1.0; P = 0.013). NRS reported by the intubators showed a similar preference for indirect over direct laryngoscopy (A 0.9 ± 0.7, G 1.1 ± 0.6, M 1.9 ± 1.1; P = 0.001). Duration of laryngoscopy and endotracheal tube insertion was similar in all groups. No significant intergroup differences in hemodynamic parameters were recorded. Postoperative sore throat was significantly reduced using the GlideScope compared with the other devices (P = 0.048).

Conclusion

The Airtraq and GlideScope facilitated nasotracheal intubation more so than the Macintosh laryngoscope in adults with apparently normal airways.     

Solitary navicular metastasis of a pulmonary adenocarcinoma

The authors present a case of a 62-year-old male with a symptomatic isolated midfoot metastasis as the first clinical presentation of a primary pulmonary tumor. In this case of a metastatic adenocarcinoma, the lesion leading to diagnosis was located in the foot. The poor outcome and the sparse relevant literature are presented in brief. Level of Evidence: Therapeutic, Level IV.