Purpose: Dihydrofolate reductase (DHFR) is the major target of methotrexate, a key component in childhood acute lymphoblastic leukemia (ALL) treatment. We recently reported an association of DHFR promoter polymorphisms with ALL outcome. Lower event-free survival correlated with haplotype *1, defined by A -317 and C -1610 alleles. Haplotype *1 was also associated higher DHFR expression. Experimental Design: Here, we analyzed adjacent 400-bp region participating in DHFR regulation as both a major promoter and a noncoding minor transcript. Results: Six polymorphisms were identified, of which five were single nucleotide polymorphisms and one was length polymorphism composed of variable number of 9-bp elements and 9-bp insertion/deletion. Haplotype analysis including all promoter polymorphisms revealed diversification of haplotype *1 into five subtypes (*1a-*1e). DNA variations of major promoter/noncoding transcript region and haplotype *1 subtypes were subsequently analyzed for the association with ALL outcome. Lower event-free survival was associated with an A allele of G 308 A polymorphism (P = 0.02) and with *1b haplotype (P = 0.01). This association was particularly striking in high-risk patients (P = 0.001) and was subsequently confirmed in independent patient cohort (P = 0.02). Haplotype *1b was the only haplotype *1 subtype associated with higher mRNA levels. Conclusions: The study provides a new insight into DHFR regulatory variations predisposing to an event in ALL patients. (Clin Cancer Res 2009;15(22):6931-8)

Study Design: This was a retrospective study. Objective: Evaluate the prognosis and surgical outcomes of patients with spinal metastasis from lung cancer undergoing surgical treatment. Summary of Background Data: The spine is the most common site of metastatic lesions in patients with lung cancer. There have been a few studies, all small cohorts studying prognosis and surgical outcomes and the results were discordant. Materials and Methods: A retrospective study on a prospectively collected database was conducted. Data collected were the following: age, tobacco use, tumor histology, American Spinal Injury Association score, revised Tokuhashi score, ambulatory status, perioperative complications, postoperative adjuvant treatment, and survival time. Univariate and multivariate analyses were performed to identify the prognostic factors of survival. Results: The authors studied 87 patients with a mean age of 61.3±1.9 years. Median survival was 4.1±0.8 months. Twenty-eight patients (32.2%) lived >6 months and 14 patients (16.1%) lived >12 months. The medical complication rate was 13.8% and the surgical complication rate was 5.7%. The 30-day mortality rate was 4.6%. Univariate analysis showed tobacco use, revised Tokuhashi score, preoperative and postoperative American Spinal Injury Association score, postoperative walking ability, postoperative radiotherapy, and postoperative chemotherapy were prognostic factors. There was no significant difference in survival between adenoma lung cancers, nonadenoma lung cancers, and small cell lung cancers (P=0.51). Multivariate analysis revealed tobacco use, revised Tokuhashi score, postoperative walking ability, postoperative radiotherapy, and postoperative chemotherapy affected the survival. Conclusions: This is the largest reported study of patients with spinal metastasis from lung cancer undergoing spinal surgery. It is the first study showing that tobacco use has a negative impact on survival. Spinal surgery improves the quality of life and offers nonambulatory patients a high chance of regaining walking ability with an acceptable risk of complications.

Bicruciate-retaining (BCR) total knee arthroplasty (TKA) has recently experienced a resurgence of popularity. It may be a good option among a younger, more active population because it restores knee kinematics better than other prosthetic designs. Results obtained in the first 100 BCR TKAs implanted with a simplified gap-balancing technique are reported, with special attention paid to knee flexion, through comparison with a cohort of 100 posterior-stabilized (PS) TKAs. We conducted a retrospective comparative cohort study of 100 BCR TKAs (90 patients) and 100 PS TKAs (88 patients). Knees with a BCR TKA lost significantly more flexion PS TKA in the early postoperative period when their preoperative flexion was less than 130 degrees (loss of 40 degrees vs. loss of 24 degrees). Postoperative range of motion was similar between BCR TKA and PS TKA when preoperative knee flexion was 130 degrees or more, and when there was no preoperative flexion contracture. Postoperative stiffening seems to be more frequent and of greater magnitude after BCR TKA, compared with PS TKA, in patients suffering from preoperative flexion stiffness. Further investigation on the causes of this phenomenon is warranted.

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