Toll-like receptor interactions: tolerance of MyD88-dependent cytokines but enhancement of MyD88-independent interferon-beta production

Toll-like receptors (TLRs) signal through two main pathways: a myeloid differentiation factor (MyD)88-dependent pathway that acts via nuclear factor kappaB (NF-kappaB) to induce proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and a MyD88-independent pathway that acts via type I interferons to increase the expression of interferon-inducible genes. Repeated signalling through TLR4 and a number of other TLRs has been reported to result in a reduction in the subsequent proinflammatory cytokine response, a phenomenon known as TLR tolerance. In this study we have shown that, whilst NF-kappaB activation and production of TNF-alpha and interleukin-12 by murine RAW264.7 and J774.2 cells in response to stimulation by TLR4, -5, -7 or -9, was reduced by prior stimulation with TLR4, -5, -7 or -9 ligands, the primary stimulation of TLR3, which does not use the MyD88 pathway, did not reduce the TNF-alpha or interleukin-12 responses to subsequent TLR stimulation. The response to TLR3 stimulation was not diminished by prior TLR ligand exposure. Furthermore, the production of interferon-beta (IFN-beta) following stimulation of TLR3 or -4, which is MyD88-independent, was increased by prior activation of TLR4, -5, -7 or -9. In contrast, TLR9 ligand-induced IFN-beta production, which is MyD88-dependent, was tolerized by prior TLR stimulation. These results are consistent with differential regulation of MyD88-dependent and MyD88-independent cytokine production following serial activation of TLRs.     

Surgical training for anatomical endoscopic enucleation of the prostate

Anatomical endoscopic enucleation of the prostate has been proposed as a potentially superior benign prostatic hyperplasia surgery than conventional transurethral resection of prostate. However, the learning curve of the procedure is steep, hence limiting its generalisability worldwide. In order to overcome the learning curve, a proper surgical training is extremely important. This review article discussed about various aspects of surgical training in anatomical endoscopic enucleation of the prostate. In summary, no matter what surgical technique or energy modality you use, the principle of anatomical enucleation should be followed. When one starts to perform prostate enucleation, a 50 to 80 g prostate appears to be the ‘best case’ to begin with. Mentorship is extremely important to shorten the learning curve and to prevent drastic complications from the procedure. A proficiency-based progression training programme with the use of simulation and training models should be the best way to teach and learn about prostate enucleation. Enucleation ratio efficacy is the preferred measure for assessing skill level and learning curve of prostate enucleation. Morcellation efficiency is commonly used to assess morcellation performance, but the importance of safety rather than efficiency must be emphasised.     

Development of appropriateness criteria for the surgical treatment of symptomatic lumbar degenerative spondylolisthesis (LDS)

Purpose

Spine surgery rates are increasing worldwide. Treatment failures are often attributed to poor patient selection and inappropriate treatment, but for many spinal disorders there is little consensus on the precise indications for surgery. With an aging population, more patients with lumbar degenerative spondylolisthesis (LDS) will present for surgery. The aim of this study was to develop criteria for the appropriateness of surgery in symptomatic LDS.

Methods

A systematic review was carried out to summarize the current level of evidence for the treatment of LDS. Clinical scenarios were generated comprising combinations of signs and symptoms in LDS and other relevant variables. Based on the systematic review and their own clinical experience, twelve multidisciplinary international experts rated each scenario on a 9-point scale (1 highly inappropriate, 9 highly appropriate) with respect to performing decompression only, fusion, and instrumented fusion. Surgery for each theoretical scenario was classified as appropriate, inappropriate, or uncertain based on the median ratings and disagreement in the ratings.

Results

744 hypothetical scenarios were generated; overall, surgery (of some type) was rated appropriate in 27 %, uncertain in 41 % and inappropriate in 31 %. Frank panel disagreement was low (7 % scenarios). Face validity was shown by the logical relationship between each variable’s subcategories and the appropriateness ratings, e.g., no/mild disability had a mean appropriateness rating of 2.3 ± 1.5, whereas the rating for moderate disability was 5.0 ± 1.6 and for severe disability, 6.6 ± 1.6. Similarly, the average rating for no/minimal neurological abnormality was 2.3 ± 1.5, increasing to 4.3 ± 2.4 for moderate and 5.9 ± 1.7 for severe abnormality. The three variables most likely (p < 0.0001) to be components of scenarios rated “appropriate” were: severe disability, no yellow flags, and severe neurological deficit.

Conclusion

This is the first study to report criteria for determining candidacy for surgery in LDS developed by a multidisciplinary international panel using a validated method (RAM). The panel ratings followed logical clinical rationale, indicating good face validity. The work refines clinical classification and the phenotype of degenerative spondylolisthesis. The predictive validity of the criteria should be evaluated prospectively to examine whether patients treated “appropriately” have better clinical outcomes.     

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.     

Haematopoietic stem cell transplantation (HSCT) in Europe 2002. Changes in indication and impact of team density. A report of the EBMT activity survey

This 2002 European Group for Blood and Marrow Transplantation (EBMT) activity survey concentrates on current status, increase and decrease in haematopoietic stem cell transplantation (HSCT) activity in Europe and investigates the association of transplant rates with team density. In 2002, there were 20 207 HSCT, 6915 allogeneic (34%), 13 292 autologous (66%) and 3947 additional re- or multiple transplants collected from 586 centres in 39 European countries. Main indications were leukaemias (6523 (32%; 76% allogeneic)); lymphomas (10 760 (53%; 92% autologous)); solid tumours (1913 (9%; 92% autologous)) and nonmalignant disorders (874 (4%; 92% allogeneic)). Compared to 2001, there were increases (>10%) for AML, ALL 1st CR, CML not 1st cP, MDS, SAA and CLL in allogeneic HSCT and for MDS, Ewing's sarcoma, soft-tissue sarcoma and ovarian cancer in autologous HSCT. Decreases (>10%) were observed in autologous HSCT for acute leukaemias beyond 1st CR, CML cP, glioma, breast cancer and lung cancer. Correlation of transplant rates (number of transplants per 10 million inhabitants) with team density (number of transplant teams per 10 million inhabitants) suggests different diffusion patterns for autologous compared to allogeneic HSCT. These data describe current practice for blood and marrow transplantation in Europe and give some hints about mechanisms involved in HSCT rates.     

Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation

Donor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.     

Influences of Gender on Complication Rate and Outcome after Roux-en-Y Gastric Bypass: Data Analysis of More Than 10,000 Operations from the German Bariatric Surgery Registry

Background

Since 1 January 2005, bariatric surgery has been monitored in Germany. All related data are registered prospectively in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University Magdeburg.

Methods

Data collection regarding obesity and metabolic surgery was started in an online database in 2005. Follow-up data are collected once a year. Participation in the quality assurance study is voluntary.

Results

Since 2005, 10,330 Roux-en-Y gastric bypass (RYGB) procedures have been performed in Germany. In total, 8,013 patients were female and 2,317 were male. Male patients suffered significantly more comorbidities than female patients. The men also had higher body mass indexes (BMIs) and ages than the women at the time of operation. Data on the gender-specific aspects of RYGB from the Nationwide Survey of Bariatric Surgery in Germany (GBSR) showed a significant difference in anastomotic insufficiency at the gastro-entero-anastomosis. The leakage rate was 2.37 % (55/2,317) in men and 1.68 % (135/8,013) in women. Additionally, specific complication and mortality rates were significantly higher in male than in female patients.

Conclusions

Metabolic and obesity surgery is becoming increasingly popular in Germany. Data from the GBSR show significant differences in preoperative comorbidities and postoperative complication and mortality rates between male and female patients. There is a need for further evaluation of gender-specific aspects to optimize patient selection and reduce specific postoperative complications.     

French Spine Surgery Society guidelines for management of spinal surgeries during COVID-19 pandemic

Since the outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in China, various measures have been adopted in order to attenuate the impact of the virus on the population. With regard to spine surgery, French physicians are devoted to take place in the national plan against COVID-19, the French Spine Surgery Society therefore decided to elaborate specific guidelines for management of spinal disorders during COVID-19 pandemic in order to prioritize management of patients. A three levels stratification was elaborated with Level I: Urgent surgical indications, Level II: Surgical indications associated to a potential loss of chance for the patient and Level III: Non-urgent surgical indications. We also report French experience in a COVID-19 cluster region illustrated by two clinical cases. We hope that the guidelines formulated by the French Spine Surgery Society and the experience of spine surgeons from a cluster region will be helpful in order optimizing the management of patients with urgent spinal conditions during the pandemic.