Thoracoscopy vs. thoracotomy for the repair of esophageal atresia and tracheoesophageal fistula: a systematic review and meta-analysis.

Esophageal atresia (EA) and tracheoesophageal fistula (TEF) require emergency surgery in the neonatal period to prevent aspiration and respiratory compromise. Surgery was once exclusively performed via thoracotomy; however, there has been a push to correct this anomaly thoracoscopically. In this study, we compare intra- and post-operative outcomes of both techniques. A systematic review and meta-analyses was performed. A search strategy was developed in consultation with a librarian which was executed in CENTRAL, MEDLINE, and EMBASE from inception until January 2017. Two independent researchers screened eligible articles at title and abstract level. Full texts of potentially relevant articles were then screened again. Relevant data were extracted and analyzed. 48 articles were included. A meta-analysis found no statistically significant difference between thoracoscopy and thoracotomy in our primary outcome of total complication rate (OR 0.98, [0.29, 3.24], p = 0.97). Likewise, there were no statistically significant differences in anastomotic leak rates (OR 1.55, [0.72, 3.34], p = 0.26), formation of esophageal strictures following anastomoses that required one or more dilations (OR 1.92, [0.93, 3.98], p = 0.08), need for fundoplication following EA repair (OR 1.22, [0.39, 3.75], p = 0.73)-with the exception of operative time (MD 30.68, [4.35, 57.01], p = 0.02). Considering results from thoracoscopy alone, overall mortality in patients was low at 3.2% and in most cases was due to an associated anomaly rather than EA repair. Repair of EA/TEF is safe, with no statistically significant differences in morbidity when compared with an open approach.Level of evidence 3a systematic review of case-control studies.

siRNA knockdown of mitochondrial thymidine kinase 2 (TK2) sensitizes human tumor cells to gemcitabine.

Nucleoside metabolism enzymes are determinants of chemotherapeutic drug activity. The nucleoside salvage enzyme deoxycytidine kinase (dCK) activates gemcitabine (2', 2'-difluoro-2'-deoxycytidine) and is negatively regulated by deoxycytidine triphosphate (dCTP). Reduction of dCTP in tumor cells could, therefore, enhance gemcitabine activity. Mitochondrial thymidine kinase 2 (TK2) phosphorylates deoxycytidine to generate dCTP. We hypothesized that: (1) TK2 modulates human tumor cell sensitivity to gemcitabine, and (2) antisense knockdown of TK2 would decrease dCTP and increase dCK activity and gemcitabine activation. siRNA downregulation of TK2 sensitized MCF7 and HeLa cells (high and moderate TK2) but not A549 cells (low TK2) to gemcitabine. Combined treatment with TK2 siRNA and gemcitabine increased dCK. We also hypothesized that TK2 siRNA-induced drug sensitization results in mitochondrial damage that enhances gemcitabine effectiveness. TK2 siRNA and gemcitabine decreased mitochondrial redox status, DNA content, and activity. This is the first demonstration of a direct role for TK2 in gemcitabine resistance, or any independent role in cancer drug resistance, and further distinguishes TK2 function from that of other dTMP-producing enzymes [cytosolic TK1 and thymidylate synthase (TS)]. siRNA knockdown of TK1 and/or TS did not sensitize cancer cells to gemcitabine indicating that, among the 3 enzymes, only TK2 is a candidate therapeutic target for combination with gemcitabine.

Targeted siRNA silencing of indoleamine 2, 3-dioxygenase in antigen-presenting cells using mannose-conjugated liposomes: a novel strategy for treatment of melanoma.

Indoleamine 2, 3-dioxygenase (IDO) expression in dendritic cells (DCs) leads to the inhibition of T-cell activation, induction of T-cell apoptosis, and promotion of T-cell differentiation into regulatory T cells. All of these could promote tumor escapement of the host's immune surveillance system. We hypothesized that DC-targeted gene silencing of IDO would enhance antitumor immunity and thus restrain tumor growth. Mannose receptors are highly expressed in antigen-presenting cells (APCs) including DCs. In this study, we developed a novel APC-targeted small interfering RNA delivery system using mannosed liposomes (Man-lipo) with encapsulated IDO small interfering RNA (Man-lipo-siIDO), which preferentially knocked down IDO expression in draining lymph node and spleen of melanoma-bearing mice. Mice treated with Man-lipo-siIDO displayed a delayed time of onset of implanted murine melanomas, increased survival time, reduced tumor size, and increased reactivity of T cells from spleen and lymph nodes against melanoma antigens. The enhanced antitumor immunity may be linked to inhibition of apoptosis in CD8 and CD4 T cells as well as Treg cells in spleen and lymph nodes. This study is the first to demonstrate that Man-lipo-siIDO can preferentially targets APCs and efficiently silence IDO expression in vitro and in vivo; events expected to enhance antitumor immune reactions against melanoma xenografts. This study supports the hypothesis that Man-lipo-siIDO may possess the potential for development as an immune-targeting therapeutic anticancer agent.

Just because we can, should we? A discussion of treatment withdrawal.

Children's nurses are vocationally committed to promoting the health of children, relieving their suffering, enhancing their development, helping them to achieve a sense of worth and a confidence in their future. Supporting parents and medical colleagues while the decision is made to withdraw or withhold life-sustaining treatment is one of the most difficult aspects of children's nursing practice. Current guidelines support the withholding or withdrawing of life-sustaining treatment from children in brain death, permanent vegetative state, and no chance, no purpose or unbearable situations. Societal and professional attitudes to euthanasia and assisted suicide may be changing and this could lead to changes in legislation and guidelines. However, nurses must be clear about the differences: currently any measure, practice or treatment administered with the primary intention to cause death is not allowed. This is not the same as any measure, practice or treatment administered with the intent to relieve suffering and promote comfort, that can cause or hasten death.