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.     

二甲双胍对人肝癌Hep-G2细胞表皮生长因子及其受体表达的影响

目的 观察二甲双胍对人肝癌Hep-G2细胞表皮生长因子（EGF）及其受体（EGFR）的影响.方法 体外培养人肝癌Hep-G2细胞,用不同浓度二甲双胍进行干预,3-（4,5-二甲基噻唑-2）-2,5-二苯基四氨唑溴盐法检测二甲双胍对Hep-G2细胞生长的影响;Hoechst 33342染色荧光显微镜观察细胞的形态学变化,流式细胞术观察细胞凋亡;蛋白质印迹法（Western blot）检测EGF、EGFR的表达.结果 二甲双胍对肝癌细胞的活性具有明显的抑制作用,且呈剂量依赖性;以10 mmol/L作用终浓度抑制效果最明显,其48 h的细胞吸光度为（0.477 ±0.025）,与对照组（0.602±0.026）比较差异有统计学意义（P＜0.01）;逐渐增加二甲双胍的作用浓度,细胞凋亡率随之逐渐增加,药物组细胞凋亡率分别为（10.76±0.96）％、（20.77±1.16）％,与对照组（5.21±0.13）％相比差异均有统计学意义（P＜0.05）;Hoechst33342染色可见明显的细胞皱缩,核染色质浓缩,核碎裂等凋亡形态学变化;Western blot结果显示,EGF及其受体蛋白的表达随着二甲双胍作用浓度的增加而逐渐下调.结论 在体外,二甲双胍能够抑制人肝癌Hep-G2细胞增殖及诱导细胞凋亡,其抗肿瘤机制可能与细胞内EGF及EGFR表达下调有关.     

Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.     

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.     

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling. (Blood. 2005;105:410-419)      

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.