Esophagectomy without mortality: What can surgeons do?

Introduction: Surgical resection remains the mainstay treatment for patients with localized esophageal cancer. It is, however, a complex procedure. Mortality rate used to be high, but in recent years, death rate has been reduced to below 5% in specialized centers. Methods: Outcome of esophagectomy can be improved by paying attention to (1) appropriate patient section, (2) choice of surgical techniques and their execution, and (3) optimizing perioperative care. A volume-outcome relationship is also evident. Surgeons can perform esophagectomy without mortality, but a multi-disciplinary team management is essential to achieve this goal. © 2009 The Society for Surgery of the Alimentary Tract.postprin

Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: Final report of a randomized, controlled trial of preoperative chemotherapy versus surgery Alone

BACKGROUND. Surgery is the standard treatment for patients with resectable esophageal carcinoma, but the long term prognosis of these patients is unsatisfactory. Some randomized trials of preoperative chemotherapy suggest that the prognosis of patients who respond may be improved. METHODS. This randomized, controlled trial compared patients with clinically resectable esophageal epidermoid carcinoma who underwent surgery alone (Arm A) with those who received preoperative chemotherapy (Arm B). Overall survival and the prognostic impact of major response to chemotherapy were analyzed. Forty-eight patients were enrolled in each arm. Chemotherapy consisted of two or three cycles of cisplatin (100 mg/m2 on Day 1) and 5-fluorouracil (1000 mg/m2 per day continuous infusion on Days 1-5). In both study arms, transthoracic esophagectomy plus two-field lymphadenectomy was performed. The two groups were comparable in terms of patient characteristics. RESULTS. Forty-seven patients were evaluable in each arm. The curative resection rate was 74.4% (35 of 47 patients) in Arm A and 78.7% (37 of 47 patients) in Arm B. Treatment-related mortality was 4.2% in both arms. The response rate to preoperative chemotherapy was 40% (19 of 47 patients), including 6 patients (12.8%) who achieved a pathologic complete responses. Overall survival was not improved significantly. The 19 patients in Arm B who responded to chemotherapy and underwent curative resection had significantly better 3-year and 5-year survival rates (74% and 60%, respectively) compared with both nonresponders (24% and 12%, respectively; P = 0.0002) and patients in Arm A who underwent complete resection (46% and 26%, respectively; P = 0.01): Patients who achieved a pathologic complete response (P = 0.01), but not those who achieved a partial response (P = 0.2), had significantly improved survival. CONCLUSIONS. Patients with resectable esophageal carcinoma who underwent preoperative chemotherapy and obtained a pathologic complete response had a significantly improved long term survival. Major efforts should be undertaken to identify patients before neoadjuvant treatments who are likely to respond

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG2000cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems

Jejunum free flap in hypopharynx reconstruction: Case series

BACKGROUND: Surgical treatment of hypopharyngeal cancers with extension to the retrocricoid region generally requires a circumferential pharyngolaryngectomy followed by a reconstruction of the removed segment of the upper digestive tract. Historically, many techniques have been used in order to achieve a safe and functional reconstruction. Jejunum interposition is generally considered the best reconstructive technique. METHODS: This study examines the details of the surgical technique, the complications, the oncological and the functional results in a series of 29 consecutive patients submitted to circumferential pharyngoesophageal resection for advanced hypopharyngeal cancer followed by reconstruction with a free flap of jejunum. RESULTS: Three of the transplants failed because of venous thrombosis. The overall success rate was 90%. There were no general complications. A good swallowing has been preserved in all our patients. All our patients where a phonatory prosthesis was positioned (20/29) were able to achieve speech following speech therapy and all were satisfied with their own capacity to communicate. CONCLUSIONS: The prognosis of hypopharyngeal tumours (18–40% at 5 years) remains poor, but jejunum autografts are being shown to be an excellent choice for the reconstruction of the cervical hypopharyngo-oesophagus offering the patient fast rehabilitation and a reasonable quality of survival. Our experience confirm that this kind of reconstruction is safe with a good results in improving oncologic controls and restoring a good quality of life

Phosphodiesterase type 4 expression and anti-proliferative effects in human pulmonary artery smooth muscle cells

BACKGROUND: Pulmonary arterial hypertension is a proliferative vascular disease, characterized by aberrant regulation of smooth muscle cell proliferation and apoptosis in distal pulmonary arteries. Prostacyclin (PGI(2)) analogues have anti-proliferative effects on distal human pulmonary artery smooth muscle cells (PASMCs), which are dependent on intracellular cAMP stimulation. We therefore sought to investigate the involvement of the main cAMP-specific enzymes, phosphodiesterase type 4 (PDE4), responsible for cAMP hydrolysis. METHODS: Distal human PASMCs were derived from pulmonary arteries by explant culture (n = 14, passage 3–12). Responses to platelet-derived growth factor-BB (5–10 ng/ml), serum, PGI(2 )analogues (cicaprost, iloprost) and PDE4 inhibitors (roflumilast, rolipram, cilomilast) were determined by measuring cAMP phosphodiesterase activity, intracellular cAMP levels, DNA synthesis, apoptosis (as measured by DNA fragmentation and nuclear condensation) and matrix metalloproteinase-2 and -9 (MMP-2, MMP-9) production. RESULTS: Expression of all four PDE4A-D genes was detected in PASMC isolates. PDE4 contributed to the main proportion (35.9 ± 2.3%, n = 5) of cAMP-specific hydrolytic activity demonstrated in PASMCs, compared to PDE3 (21.5 ± 2.5%), PDE2 (15.8 ± 3.4%) or PDE1 activity (14.5 ± 4.2%). Intracellular cAMP levels were increased by PGI(2 )analogues and further elevated in cells co-treated with roflumilast, rolipram and cilomilast. DNA synthesis was attenuated by 1 μM roflumilast (49 ± 6% inhibition), rolipram (37 ± 6%) and cilomilast (30 ± 4%) and, in the presence of 5 nM cicaprost, these compounds exhibited EC(50 )values of 4.4 (2.6–6.1) nM (Mean and 95% confidence interval), 59 (36–83) nM and 97 (66–130) nM respectively. Roflumilast attenuated cell proliferation and gelatinase (MMP-2 and MMP-9) production and promoted the anti-proliferative effects of PGI(2 )analogues. The cAMP activators iloprost and forskolin also induced apoptosis, whereas roflumilast had no significant effect. CONCLUSION: PDE4 enzymes are expressed in distal human PASMCs and the effects of cAMP-stimulating agents on DNA synthesis, proliferation and MMP production is dependent, at least in part, on PDE4 activity. PDE4 inhibition may provide greater control of cAMP-mediated anti-proliferative effects in human PASMCs and therefore could prove useful as an additional therapy for pulmonary arterial hypertension

Role of Plant-Specific N-Terminal Domain of Maize CK2β1 Subunit in CK2β Functions and Holoenzyme Regulation

Protein kinase CK2 is a highly pleiotropic Ser/Thr kinase ubiquituous in eukaryotic organisms. CK2 is organized as a heterotetrameric enzyme composed of two types of subunits: the catalytic (CK2α) and the regulatory (CK2β). The CK2β subunits enhance the stability, activity and specificity of the holoenzyme, but they can also perform functions independently of the CK2 tetramer. CK2β regulatory subunits in plants differ from their animal or yeast counterparts, since they present an additional specific N-terminal extension of about 90 aminoacids that shares no homology with any previously characterized functional domain. Sequence analysis of the N-terminal domain of land plant CK2β subunit sequences reveals its arrangement through short, conserved motifs, some of them including CK2 autophosphorylation sites. By using maize CK2β1 and a deleted version (ΔNCK2β1) lacking the N-terminal domain, we have demonstrated that CK2β1 is autophosphorylated within the N-terminal domain. Moreover, the holoenzyme composed with CK2α1/ΔNCK2β1 is able to phosphorylate different substrates more efficiently than CK2α1/CK2β1 or CK2α alone. Transient overexpression of CK2β1 and ΔNCK2β1 fused to GFP in different plant systems show that the presence of N-terminal domain enhances aggregation in nuclear speckles and stabilizes the protein against proteasome degradation. Finally, bimolecular fluorescence complementation (BiFC) assays show the nuclear and cytoplasmic location of the plant CK2 holoenzyme, in contrast to the individual CK2α/β subunits mainly observed in the nucleus. All together, our results support the hypothesis that the plant-specific N-terminal domain of CK2β subunits is involved in the down-regulation of the CK2 holoenzyme activity and in the stabilization of CK2β1 protein. In summary, the whole amount of data shown in this work suggests that this domain was acquired by plants for regulatory purposes

Connexin channels and phospholipids: association and modulation

<p>Abstract</p> <p>Background</p> <p>For membrane proteins, lipids provide a structural framework and means to modulate function. Paired connexin hemichannels form the intercellular channels that compose gap junction plaques while unpaired hemichannels have regulated functions in non-junctional plasma membrane. The importance of interactions between connexin channels and phospholipids is poorly understood.</p> <p>Results</p> <p>Endogenous phospholipids most tightly associated with purified connexin26 or connexin32 hemichannels or with junctional plaques in cell membranes, those likely to have structural and/or modulatory effects, were identified by tandem electrospray ionization-mass spectrometry using class-specific interpretative methods. Phospholipids were characterized by headgroup class, charge, glycerol-alkyl chain linkage and by acyl chain length and saturation. The results indicate that specific endogenous phospholipids are uniquely associated with either connexin26 or connexin32 channels, and some phospholipids are associated with both. Functional effects of the major phospholipid classes on connexin channel activity were assessed by molecular permeability of hemichannels reconstituted into liposomes. Changes to phospholipid composition(s) of the liposome membrane altered the activity of connexin channels in a manner reflecting changes to the surface charge/potential of the membrane and, secondarily, to cholesterol content. Together, the data show that connexin26 and connexin32 channels have a preference for tight association with unique anionic phospholipids, and that these, independent of headgroup, have a positive effect on the activity of both connexin26 and connexin32 channels. Additionally, the data suggest that the likely in vivo phospholipid modulators of connexin channel structure-function that are connexin isoform-specific are found in the cytoplasmic leaflet. A modulatory role for phospholipids that promote negative curvature is also inferred.</p> <p>Conclusion</p> <p>This study is the first to identify (endogenous) phospholipids that tightly associate with connexin channels. The finding that specific phospholipids are associated with different connexin isoforms suggests connexin-specific regulatory and/or structural interactions with lipid membranes. The results are interpreted in light of connexin channel function and cell biology, as informed by current knowledge of lipid-protein interactions and membrane biophysics. The intimate involvement of distinct phospholipids with different connexins contributes to channel structure and/or function, as well as plaque integrity, and to modulation of connexin channels by lipophilic agents.</p