Intrafocal injection of tranexamic acid decreases early return to hospital after high tibial osteotomy.

INTRODUCTION: High tibial osteotomy (HTO) is a surgery performed to treat the symptoms and prevent the progression of medial osteoarthritis. Post-operative bleeding has led to early returns to hospital following surgery. Intrafocal injection of tranexamic acid (TXA) could reduce this bleeding complication. The objective of the study was to evaluate the effect of TXA during HTO on the incidence of post-operative complications and early returns to hospital. MATERIALS AND METHODS: This retrospective study included 251 cases of HTO performed between May 2012 and October 2021, with the use of TXA introduced in May 2017. The experimental (n = 102) and control (n = 149) groups were compared as to the rate of post-operative early returns. The influence of confounding factors was evaluated, including age, sex, body mass index (BMI), tobacco use, grade of medial femorotibial osteoarthritis (MFTO), magnitude of angular correction (MAC), and surgery duration. RESULTS: No statistically significant difference was found between the groups with regards to all variables except age. The experimental group was significantly older (54.4 years; σ = 7.5) than the control group (50.4 years; σ = 7.9; p < 0.001). We observed a decrease in emergency department (ED) visits in the experimental group (15.7%) compared to the control (30.2%; p = 0.008) and a decrease in early returns in the experimental group (28.4%) compared to the control (40.5%; p = 0.049). No statistically significant difference in demographic data, MFTO, or MAC was found among patients with and without an early return, in both the experimental and control groups. CONCLUSION: The intrafocal injection of TXA during HTO decreases early returns to hospital.

Complications of Bicruciate-Retaining Total Knee Arthroplasty: The Importance of Alignment and Balance.

Bicruciate-retaining total knee arthroplasty (BCR TKA) results in kinematics closer to the native knee and in greater patient satisfaction but information concerning its outcome and complications is lacking.The goal of this study is to report the clinical and radiological outcomes of BCR prosthesis implanted using a spacer-based gap balancing technique and to assess if some preoperative factors are associated with a worse prognosis.A cohort of 207 knees in 194 patients who underwent BCR TKA, with a minimum 1-year follow-up, was retrospectively analyzed.Patients were followed at 6 weeks, 6 months, 1 year, and then every following year postoperatively, and filled questionnaires (Knee Society and Knee injury and Osteoarthritis Outcome Score) at every visit. Clinical and radiological assessments included range of motion, knee alignment, pain, and complications as defined by the Knee Society's Standardized list and definition of Complication of Total Knee Arthroplasty.Forty-three knees (20.8%) suffered major complications. Twenty-one knees (10.1%) underwent revision at an average of 32.1 months after the index procedure. Revision-free survival at 100 months was 85.7%. Revision was performed for aseptic tibial loosening in eight knees (3.9%) and stiffness in five knees (2.4%). There were 29 reoperations other than revision (14.0%), the most frequent procedure being manipulation under anesthesia in 14 knees (6.8%). Minor complications included tendonitis (20.8%), persistent synovitis (6.8%), and superficial wound infections (6.3%).All outcomes scores were greatly improved at the 1-year follow-up compared with preoperatively (p < 0.001). However, maximum flexion at the last follow-up was significantly reduced compared with preoperatively (mean maximum flexion ± standard deviation: 119.9 ± 15.6 vs. 129.9 ± 14.4, p < 0.001). Aseptic tibial loosening was associated with a hypercorrection in varus of preoperative valgus knees (p = 0.012).BCR TKA can give functional results similar to other types of prostheses but involves a substantial risk of complications. Important factors that can explain failed BCR TKA and guide its use were identified, more particularly knee alignment and its role in aseptic tibial loosening.

Can Pelvic Incidence Change After Lumbo-Pelvic Fixation for Adult Spine Deformity, and Would the Change be Affected by the Type of Pelvic Fixation?

STUDY DESIGN: Retrospective review. OBJECTIVE: To assess the change in pelvic incidence (PI) after lumbo-pelvic fixation and the differential impact of the type of pelvic fixation: S2-alar-iliac screws (S2AI) versus Iliac screws (IS) on postoperative PI. SUMMARY OF BACKGROUND DATA: Recent studies suggest that changes occur to the previously assumed fixed PI after spino-pelvic fixation. METHODS: Adult spine deformity (ASD) patients who underwent spino-pelvic fixation with≥4 levels of fusion were included. Preoperative and postoperative PI, lumbar lordosis (LL), thoracic kyphosis, pelvic tilt, sacral slope, PI-LL mismatch, and the Sagittal Vertical Axis (SVA) were analyzed on EOS imaging. A significant PI change was established at≥6°. Patients were categorized based on the type of pelvic fixation (S2AI vs. IS). RESULTS: One-hundred-forty-nine patients were included. Of these, 77(52%) had a>6° change in their PI postoperatively. In patients with high preoperative PI (>60°), 62% had a significant PI change compared with 33% of patients with normal PI (40°-60°) and 53% in patients with low PI (<40°; P =0.01). PI was likely to decrease in patients with high baseline PI (>60°) and to increase in patients with low baseline PI (<40°). Patients with a significant PI change had a higher PI-LL. Patients in the S2AI group (n=99) and those in the IS group (n=50) were comparable at baseline. In the S2AI group, 50 (51%) patients had>6° change in their PI compared with 27(54%) patients in the IS group( P =0.65). In both groups, patients with high preoperative PI were more prone to significant postoperative changes ( P =0.02 in IS, P =0.01 in S2AI). CONCLUSION: PI changed significantly in 50% of patients postoperatively, especially in those with high/low preoperative PI and those with severe baseline sagittal imbalance. This occurs similarly in patients with S2AI and those with IS screws. Surgeons should keep in mind these anticipated changes while planning ideal LL, as this impacts postoperative PI-LL mismatch. LEVEL OF EVIDENCE: 4.

How Does Spino-Pelvic Fixation Affect Post-Operative Compensatory Mechanisms in Adult Spinal Deformity?

STUDY DESIGN: Retrospective single-center multi-surgeon cohort study. OBJECTIVES: Compare the post-operative changes in the compensatory mechanisms of the sagittal balance according to the type of pelvic fixation: S2-Alar-iliac screws (S2AI) vs iliac screws (IS) in patients with Adult spine deformity (ASD). METHODS: ASD patients who underwent spino-pelvic fixation and remained with a PI-LL >10° mismatch post-operatively were included. Pre-operative and 1-year-follow-up PI, Lumbar lordosis (LL), pelvic tilt (PT), sacral slope (SS), thoracic kyphosis (TK), femur obliquity angle (FOA), knee flexion angle (KFA) and ankle flexion angle (AFA) were analyzed on EOS imaging. Patients were categorized based on their pelvic fixation type (S2AI vs IS), and the pre-operative to 1-year-post-operative changes (ΔX°) in the compensatory mechanisms were compared between groups. RESULTS: Patients with S2AI (n = 53) and those with IS (n = 26) screws were comparable at baseline. ΔSS averaged 9.87° in the S2AI compared to 13.2° in the IS (P = .001), whereas the ΔKFA reached 6.01° in the S2AI as opposed to 3.06° in the IS (P = .02). The ΔPT was comparable between both groups (6.35°[S2AI group] vs 5.21°[ISgroup], P = .42). ΔTK, ΔLL, ΔFOA and ΔAFA were comparable between both groups. CONCLUSION: The type of pelvic fixation impacts significantly the post-operative compensatory mechanisms in patients with ASD. Patients with S2AI screws are more likely to compensate their remaining post-operative PI-LL mismatch through their knees and less likely through their pelvis compared to patients with IS, despite similar changes in PT. This could be explained by an increased SI joint laxity in ASD patient and the lower resistance of the iliac connectors to the junctional mechanical stresses, allowing for sacro-iliac joint motion in patients with IS.

Assessing the Performance of Prognostic Scores in Patients with Spinal Metastases from Lung Cancer Undergoing Non-surgical Treatment.

STUDY DESIGN: Retrospective study. PURPOSE: The purpose of this study was to see how well the Tomita score, revised Tokuhashi score, modified Bauer score, Van der Linden score, classic Skeletal Oncology Research Group (SORG) algorithm, SORG nomogram, and New England Spinal Metastasis Score (NESMS) predicted 3-month, 6-month, and 1-year survival of non-surgical lung cancer spinal metastases. OVERVIEW OF LITERATURE: There has been no study assessing the performance of prognostic scores for non-surgical lung cancer spinal metastases. METHODS: Data analysis was carried out to identify the variables that had a significant impact on survival. For all patients with spinal metastasis from lung cancer who received non-surgical treatment, the Tomita score, revised Tokuhashi score, modified Bauer score, Van der Linden score, classic SORG algorithm, SORG nomogram, and NESMS were calculated. The performance of the scoring systems was assessed by using receiver operating characteristic (ROC) curves at 3 months, 6 months, and 12 months. The predictive accuracy of the scoring systems was quantified using the area under the ROC curve (AUC). RESULTS: A total of 127 patients are included in the present study. The median survival of the population study was 5.3 months (95% confidence interval [CI], 3.7-9.6 months). Low hemoglobin was associated with shorter survival (hazard ratio [HR], 1.49; 95% CI, 1.00-2.23; p =0.049), while targeted therapy after spinal metastasis was associated with longer survival (HR, 0.34; 95% CI, 0.21-0.51; p <0.001). In the multivariate analysis, targeted therapy was independently associated with longer survival (HR, 0.3; 95% CI, 0.17-0.5; p <0.001). The AUC of the time-dependent ROC curves for the above prognostic scores revealed all of them performed poorly (AUC <0.7). CONCLUSIONS: The seven scoring systems investigated are ineffective at predicting survival in patients with spinal metastasis from lung cancer who are treated non-surgically.

Suction drainage in total knee replacement does not influence early functional outcomes or blood loss: a randomized control trial.

INTRODUCTION: The use of wound drainage following total knee arthroplasty (TKA) remains controversial. The purpose of this study was to evaluate the impact of suction drainage on early postoperative outcomes in patients who underwent TKA with concomitant administration of intravenous tranexamic acid (TXA). METHOD: One hundred forty-six patients undergoing primary TKA with systematic intravenous TXA were prospectively selected and randomly divided into two groups. The first "Study group" (n = 67) received no suction drain and the second "Control" group (n = 79) had a suction drain. Perioperative hemoglobin levels, blood loss, complications, and length of hospital stay were assessed in both groups. Preoperative and postoperative range of motion and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were also compared at a 6-week follow-up. RESULTS: The study group was found to have higher hemoglobin levels preoperatively and during the first two days following surgery, and no difference was found between the groups on the third day. No significant discrepancies at any time were found between groups in terms of blood loss, length of hospitalization, knee range of motion, and KOOS score. Complications requiring further treatment were observed in one patient from the study group and ten patients from the control group. CONCLUSION: The use of suction drains after TKA with TXA did not alter early postoperative outcomes.

Bicruciate-retaining total knee arthroplasty non-inferior to posterior-stabilized prostheses after 5 years: a randomized, controlled trial.

PURPOSE: Bicruciate-retaining (BCR) prostheses may improve satisfaction of patient undergoing total knee arthroplasty (TKA). The objective of this randomized controlled trial was to assess whether BCR prostheses provide better clinical outcomes than posterior-stabilized (PS) prostheses. MATERIALS AND METHODS: This is a randomized single-blind control trial involving a total of 77 patients with knee osteoarthritis, randomly assigned to undergo TKA with a BCR or PS implant between 2015 and 2019. Mean follow-up period was 39 months. Clinical and demographic data were extracted manually from medical records. Data acquisition included patient demographics, knee range of motion, and patient-reported outcomes via KSS, KOOS, WOMAC, and SF-12 scores. RESULTS: A total of 38 patients were randomized to the PS group and 39 to the BCR group. At the 5-year follow-up, no statistical differences were noted for knee range of motion or patient-reported outcomes between the two groups, except for a greater knee flexion in the early follow-up period in the PS group. Five adverse events occurred in the BCR group compared to none in the PS group (p = 0.02). CONCLUSION: BCR TKA yield similar clinical and patient-reported outcomes 5 years following the intervention compared with PS TKA. The BCR TKA had more complications. LEVEL OF EVIDENCE: I (Randomized Controlled Trial).

Which Scoring System Is the Most Accurate for Assessing Survival Prognosis in Patients Undergoing Surgery for Spinal Metastases from Lung Cancer? A Single-Center Experience.

OBJECTIVE: To compare different survival prognosis scores among patients operated on for spinal metastasis from lung cancer. METHODS: A single-center retrospective review of patients with lung cancer and spinal metastases who underwent spinal surgery at our institution from January 2008 to October 2020 was conducted. We calculated the prognostic value of the following scoring systems: revised Tokuhashi, revised Bauer, Skeletal Oncology Research Group classic, and New England Spinal Metastatic Score. For each scoring system, discrimination was assessed by computing the area under the curve. RESULTS: The study included 94 patients operated on for spinal metastasis from lung cancer. Mean patient age was 62 years (range, 32-79 years); 51% of patients were male. The 1-year survival rate was 18%, and the median survival time was 4 months. The 6- and 12-month area under the curve was 60% and 76%, respectively, for revised Tokuhashi, 55% and 58% for revised Bauer, 58% and 63% for Skeletal Oncology Research Group classic, and 61% and 69% for New England Spinal Metastatic Score. CONCLUSIONS: The revised Tokuhashi score seemed to be the most accurate scoring system for assessing survival prognosis in patients operated on for spinal metastasis from lung cancer. Newer scores including biological parameters did not add further precision among this specific population.

Spinal Metastasis in Multiple Primary Malignancies Involving Lung Cancer: Clinical Characteristics and Survival.

OBJECTIVE: The incidence of multiple primary malignancies (MPM) has increased in recent decades. Our aim was to evaluate incidence, clinical features, and survival in cases of spinal metastases from MPM in which one of the malignancies is lung cancer. METHODS: We retrospectively reviewed an institutional database of lung cancer patients with spinal metastasis and extracted all cases of MPM. RESULTS: Among 275 patients who had spinal metastasis with lung cancer as one of the diagnoses, 21 (7.6%) patients with MPM were identified. Mean patient age was 68.5 years (95% confidence interval [CI], 65.3-71.7). The most common cancers diagnosed in addition to lung cancer were breast cancer (5 patients, 24%), upper aerodigestive tract cancer (4 patients, 19%), and prostate cancer (4 patients, 19%). Eighteen (86%) patients walked independently, and 3 (14%) patients walked with help. Seventeen (80.9%) patients had a good Karnofsky performance scale score. The median survivals from the date of first cancer diagnosis, last cancer diagnosis, and spinal metastasis diagnosis were 109.8 months (95% CI, 23.5-196.1), 17.8 months (95% CI, 5.8-29.8), and 10.3 months (95% CI, 5.4-15.2), respectively. Actual rates of survival at 6 months, 12 months, and 24 months from the date of spinal metastasis diagnosis were 81%, 42.9%, and 23.8%, respectively. CONCLUSIONS: The present study is the first series to our knowledge to show that survival of patients with spinal metastasis and MPM involving lung cancer is not clearly inferior to that of patients with spinal metastasis and lung cancer alone.

Single-Stage Posterior Approach for the En Bloc Resection and Spinal Reconstruction of T4 Pancoast Tumors Invading the Spine.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to evaluate the outcomes of patients who had T4 Pancoast tumors invading the spine and underwent en bloc resection and spinal stabilization through a single-stage posterior approach. OVERVIEW OF LITERATURE: Surgical resection for Pancoast tumors affecting the spine has been successfully performed in two stages involving spinal reconstruction and tumor resection. However, reports have rarely presented the results of en bloc resection combined with spinal stabilization for T4 Pancoast tumors invading the spine through a single-stage posterior approach. METHODS: Patients who had T4N0M0 Pancoast tumors invading the spine and underwent a single-stage posterior approach were retrospectively recruited. The following data were obtained and examined: demographics, tumor histology, preoperative and postoperative therapy, complications, spinal reconstruction technique, tumor resection extent, survival time, and disease recurrence. RESULTS: Eighteen patients were included. The mean population age was 61±17 years, and the most common pathological type was adenocarcinoma (61.1%). Complete resection (R0) was obtained in 15 patients (83.3%), positive surgical margins (R1) were found in three patients (16.7%), and the 90-day mortality rate was 0%. Postoperative major complications were detected in 12 patients (66.7%), who required reoperation. The mean survival time was 67±24 months, but the median survival time was not reached. Among the patients, 10 (55.6%) are still alive at the end of the study. The 2- and 5-year actual survival rates were 59% (95% confidence interval [CI], 35.7%-82.3%) and 52.5% (95% CI, 28.4%-76.6%), respectively. CONCLUSIONS: En bloc resection and spinal stabilization through a single-stage posterior approach might be effective for T4 Pancoast tumors invading the spine.

Does the Region of the Spine Involved with Metastatic Tumor Affect Outcomes of Surgical Treatments?

OBJECTIVE: Spinal metastases occur primarily in the thoracic spine (50%-60%), less commonly in the lumbar (30%-35%), and, infrequently, in the cervical spine (10%-15%). There has been only 1 study with a limited population comparing the postoperative outcome among cervical, thoracic, and lumbar spine metastasis. The aim of this study is to identify whether the region of surgically treated spinal metastasis affects postoperative outcomes. METHODS: A retrospective study of patients with spinal metastasis was performed. The collected data were as follows: age, gender, smoking history, tumor histology, revised Tokuhashi score, preoperative and postoperative American Spinal Injury Association score, region of spinal metastasis, ambulatory status, surgical approach, surgery time, blood loss, complications, length of hospital stay, postoperative pain relief, postoperative adjuvant therapy, and survival. Data were analyzed to identify the factors affecting the survival and postoperative functional outcome. RESULTS: We studied 191 patients with spinal metastasis including 47 cervical spine metastases, 96 thoracic spine metastases, and 48 lumbar spine metastases, with a mean age of 60.91 ± 9.72 years. The overall median survival was 7 months (95% confidence interval, 2.9-20.63 months). Univariate analysis showed that region of the spine involved with metastasis did not significantly affect the survival and postoperative motor function improvement. Multivariate analysis showed that revised Tokuhashi score, postoperative radiotherapy, and postoperative chemotherapy were independent factors affecting survival. The rate of 30-day complications among patients with different regions of spine metastasis did not reach significance. CONCLUSIONS: The postoperative outcomes of patients undergoing surgery for metastases are not affected by the region of the spine.

Medial Opening Wedge Proximal Tibial Osteotomy: Lessons Learned from a Series of 175 Consecutive Cases.

INTRODUCTION: High tibial osteotomy (HTO) is a surgical procedure aimed at inhibiting the progression of osteoarthritis of the knee joint. The aim of this study was to identify factors influencing the functional outcome after opening wedge valgus HTO. METHODS: A total of 175 cases (155 patients) of varus-correcting high tibial open-wedge osteotomies using the Tomofix plate were reviewed retrospectively. Patients answered the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire and 4 survey follow-up questions. RESULTS AND DISCUSSION: A total of 76 of the 155 patients studied (84 of the 175 knees) completed the KOOS questionnaire, on average 3.1 years (SD 1.8 years) after the surgery. The median scores (with median absolute deviations [MAD]) for the KOOS pain, symptoms, daily activities, sports, and quality of life sections were, respectively, 76.4 (MAD 12.5), 75.0 (MAD 14.3), 85.3 (MAD 11.8), 50.0 (MAD 25.0), and 59.4 (MAD 21.9). No cases of nonunion were observed throughout the length of the study. Identified predictors of worse outcomes were higher weight and body mass index, limited knee flexion, genu varum and tibial varus of small magnitude, active smoking status at the time of surgery, further surgery for plate removal, and some grades of chondropathy in the patellofemoral, medial tibial, and femoral compartments. Patient gender, joint obliquity and over- or undercorrection were not associated with any of the outcomes. CONCLUSION: This study shows good results following valgus HTO that are comparable to outcomes following total knee arthroplasty, reinforcing the option of HTO as a valid alternative for total knee arthroplasty.

Surgical Intervention for Patients With Spinal Metastasis From Lung Cancer: A Retrospective Study of 87 Cases.

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.

Enhanced Visualization of the Cervical Vertebra during Intraoperative Fluoroscopy Using a Shoulder Traction Device.

STUDY DESIGN: A retrospective, matched cohort study of a prospective database. PURPOSE: To evaluate the efficacy and safety of the Cervision system (Spinologics, Montreal, Canada), a new shoulder traction device that improves the fluoroscopic visualization of the lower cervical spine using caudal traction of the shoulders out of the radiographic field. OVERVIEW OF LITERATURE: Operating at a wrong level is a common error that may be committed by nearly 50% of surgeons during their career. Intraoperative fluoroscopy of the cervical vertebrae is an extremely important step in cervical spine surgery. Optimal lateral cervical radiography of the C1-T1 vertebrae is not always possible due to overlap of the shoulders. METHODS: In this study, a group of patients (n=33, device group) underwent surgery with the new device used to apply caudal traction to both shoulders, and another group of patients (n=33, matched control group) had surgery with the tape traction. Data about the lowest vertebra visible on lateral fluoroscopic view, installation time, skin irritation under the traction area, and postoperative brachial palsy were recorded, and these parameters were analyzed using the t-test. RESULTS: The mean numbers of visible cervical vertebra were 6.3±0.41 in the device group and 5.6±0.32 in the matched control group (p <0.01, unpaired t-test). The mean installation times were 83.9±5.15 minutes in the device group and 73.7±6.32 minutes in the matched control group (p <0.02). Seven patients from the matched control group presented with skin irritation. However, none of the patients from the device group had the condition (p =0.005, Pearson chi-square test). Postoperative brachial palsy was not observed in both groups. CONCLUSIONS: The Cervision system is more effective and superior to tape traction in pulling the shoulders down to improve the visualization of the cervical vertebra on lateral fluoroscopic view during cervical spine surgery.

Postoperative Stiffening after Bicruciate-Retaining Total Knee Arthroplasty.

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.

DNA variants in region for noncoding interfering transcript of dihydrofolate reductase gene and outcome in childhood acute lymphoblastic leukemia.

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.