Robert Elashoff

Pancreatitis, Pancreatic, and Thyroid Cancer With Glucagon-Like Peptide-1–Based Therapies

BACKGROUND & AIMSnGlucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. There are also concerns that dipeptidyl peptidase-4 inhibitors could cause cancer, given their effects on immune function.nnnMETHODSnWe examined the US Food and Drug Administrations database of reported adverse events for those associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide, from 2004-2009; data on adverse events associated with 4 other medications were compared as controls. The primary outcomes measures were rates of reported pancreatitis, pancreatic and thyroid cancer, and all cancers associated with sitagliptin or exenatide, compared with other therapies.nnnRESULTSnUse of sitagliptin or exenatide increased the odds ratio for reported pancreatitis 6-fold as compared with other therapies (P<2×10(-16)). Pancreatic cancer was more commonly reported among patients who took sitagliptin or exenatide as compared with other therapies (P<.008, P<9×10(-5)). All other cancers occurred similarly among patients who took sitagliptin compared with other therapies (P=.20).nnnCONCLUSIONSnThese data are consistent with case reports and animal studies indicating an increased risk for pancreatitis with glucagon-like peptide-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.

Sentinel node biopsy for early-stage melanoma - Accuracy and morbidity in MSLT-I, an international multicenter trial

Objective:The objective of this study was to evaluate, in an international multicenter phase III trial, the accuracy, use, and morbidity of intraoperative lymphatic mapping and sentinel node biopsy (LM/SNB) for staging the regional nodal basin of patients with early-stage melanoma. Summary Background Data:Since our introduction of LM/SNB in 1990, this technique has been widely adopted and has become part of the American Joint Committee on Cancer (AJCC) staging system. Eleven years ago, the authors began the international Multicenter Selective Lymphadenectomy Trial (MSLT-I) to compare 2 treatment approaches: wide excision (WE) plus LM/SNB with immediate complete lymphadenectomy (CLND) for sentinel node (SN) metastases, and WE plus postoperative observation with CLND delayed until the subsequent development of clinically evident nodal metastases. Methods:After each center achieved 85% accuracy of SN identification during a 30-case learning phase, patients with primary cutaneous melanoma (≥1 mm with Clark level ≥III, or any thickness with Clark level ≥IV) were randomly assigned in a 4:6 ratio to WE plus observation (WEO) with delayed CLND for nodal recurrence, or to WE plus LM/SNB with immediate CLND for SN metastasis. The accuracy of LM/SNB was determined by comparing the rates of SN identification and the incidence of SN metastases in the LM/SNB group versus the subsequent development of nodal metastases in the regional nodal basin of those patients with tumor-negative SNs. Early morbidity of LM/SNB was evaluated by comparing complication rates between the 2 treatment groups. Trial accrual was completed on March 31, 2002, after enrollment of 2001 patients. Results:Initial SN identification rate was 95.3% overall: 99.3% for the groin, 95.3% for the axilla, and 84.5% for the neck basins. The rate of false-negative LM/SNB during the trial phase, as measured by nodal recurrence in a tumor-negative dissected SN basin, decreased with increasing case volume at each center: 10.3% for the first 25 cases versus 5.2% after 25 cases. There were no operative mortalities. The low (10.1%) complication rate after LM/SNB increased to 37.2% with the addition of CLND; CLND also increased the severity of complications. Conclusions:LM/SNB is a safe, low-morbidity procedure for staging the regional nodal basin in early melanoma. Even after a 30-case learning phase and 25 additional LM/SNB cases, the accuracy of LM/SNB continues to increase with a centers experience. LM/SNB should become standard care for staging the regional lymph nodes of patients with primary cutaneous melanoma.

Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI

Objective: To compare the efficacy of step training with body weight support on a treadmill (BWSTT) with over-ground practice to the efficacy of a defined over-ground mobility therapy (CONT) in patients with incomplete spinal cord injury (SCI) admitted for inpatient rehabilitation. Methods: A total of 146 subjects from six regional centers within 8 weeks of SCI were entered in a single-blinded, multicenter, randomized clinical trial (MRCT). Subjects were graded on the American Spinal Injury Association Impairment Scale (ASIA) as B, C, or D with levels from C5 to L3 and had a Functional Independence Measure for locomotion (FIM-L) score <4. They received 12 weeks of equal time of BWSTT or CONT. Primary outcomes were FIM-L for ASIA B and C subjects and walking speed for ASIA C and D subjects 6 months after SCI. Results: No significant differences were found at entry between treatment groups or at 6 months for FIM-L (n = 108) or walking speed and distance (n = 72). In the upper motor neuron (UMN) subjects, 35% of ASIA B, 92% of ASIA C, and all ASIA D subjects walked independently. Velocities for UMN ASIA C and D subjects were not significantly different for BWSTT (1.1 ± 0.6 m/s, n = 30) and CONT (1.1 ± 0.7, n = 25) groups. Conclusions: The physical therapy strategies of body weight support on a treadmill and defined overground mobility therapy did not produce different outcomes. This finding was partly due to the unexpectedly high percentage of American Spinal Injury Association C subjects who achieved functional walking speeds, irrespective of treatment. The results provide new insight into disability after incomplete spinal cord injury and affirm the importance of the multicenter, randomized clinical trial to test rehabilitation strategies.

Phase II Study of Bevacizumab Plus Temozolomide During and After Radiation Therapy for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSEnThis open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity.nnnPATIENTS AND METHODSnSeventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison.nnnRESULTSnThe overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials.nnnCONCLUSIONnPatients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer

Purpose: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. Experimental Design: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA >0.2 and <5 ng/mL and Gleason score ≤7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. Results: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. Conclusions: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases.

Objective: Lymphatic mapping and sentinel lymphadenectomy (LM/SL) have been applied to virtually all solid neoplasms since our original description of LM/SL for melanoma. Our objectives were to determine the diagnostic and therapeutic utility of LM/SL, investigate carbon dye for mapping the microanatomy of lymphatic flow within the sentinel node (SN), and determine the prognostic accuracy of molecular assessment of the SN. Methods: Since 1985, 1599 patients with AJCC Stage I/II melanoma have been treated by LM/SL at our institution and 4590 have been treated by wide excision (WE) without nodal staging. We examined the incidence of clinical nodal recurrence after WE alone, the incidence of subclinical nodal metastases found by LM/SL, and the incidence of nodal recurrence in basins with histopathology-negative SNs. Results: In 1514 LM/SL patients with a primary of known Breslow thickness, the incidence of metastasis in nodes claimed to be sentinel was 7.3%, 19.7%, 33.2%, and 39.7% for primary lesions ≤1.0, 1.01–2.0, 2.01–4.0, and >4.0 mm, respectively. In 3652 WE-only patients, the corresponding rates of nodal recurrence were 12.0%, 32.0%, 34.4%, and 30.1%. Thus, LM/SL detected only 60% of expected nodal metastases from primary melanomas <2.01 mm. Forty of 1599 (3.1%) patients developed recurrence in basins with immunohistochemistry (IH)-negative SNs. To determine whether nonrandom intranodal distribution of tumor cells could explain missed SN metastases, we coinjected carbon particles and blue dye during LM/SL in 166 patients: 25 (16%) patients had nodal metastases, all of which were found only in nodal subsectors containing carbon particles. When paraffin-embedded SNs from a subset of 162 IH-negative patients were re-examined by quantitative multimarker reverse-transcriptase polymerase chain reaction (qRT) assay, 49 (30%) gave positive signals. These patients had a significantly higher risk of disease recurrence and death than did patients whose IH and qRT results were negative (p < 0.0001). Comparison of 287 prognostically matched pairs of patients who underwent immediate (after LM/SL) versus delayed (after observation) dissection of nodal metastases revealed 5-, 10-, and 15-year survival rates of 73%, 69%, and 69% versus 51%, 37%, and 32%, respectively (P ≤ 0.001). Conclusions: SN assessment based on intranodal compartmentalization of lymphatic flow (carbon dye mapping) should increase the accuracy of IH and, in combination with multimarker qRT assessment, will allow confident identification of most patients for whom surgery alone is curative. Our data suggest a significant therapeutic benefit for immediate dissection based on identification of a tumor-involved SN.

Coronary vasomotor abnormalities in insulin-resistant individuals.

Context Cardiovascular abnormalities are not known to be present in early-stage insulin resistance. Contribution The authors tested endothelial and vascular smooth-muscle function in 22 insulin-sensitive controls and 50 young, insulin-resistant adults with no glucose intolerance or other cardiac risk factors. Insulin-resistant patients had normal vascular smooth-muscle function but had abnormal endothelial function. Administering thiazolidinediones to a sample of the insulin-resistant patients normalized endothelial function. Cautions These observations must be confirmed. Furthermore, the results do not indicate that pharmacologic intervention improves the long-term cardiovascular health of insulin-resistant but otherwise healthy patients. The Editors Diabetes mellitus is associated with a 2- to 4-fold increased rate of death from coronary artery disease (1). However, vascular disease is present before diabetes, as shown by the 2- to 3-fold increased rate of death from coronary artery disease in the prediabetic state, that is, impaired glucose tolerance (2). Endothelial dysfunction, a precursor of atherosclerosis, is also present in both prediabetes and diabetes (3, 4). We hypothesize that coronary vasomotor dysfunction is present before carbohydrate abnormalities develop in persons with insulin resistance, possibly even before the onset of the metabolic syndrome (as defined by the National Cholesterol Education Program [5]). To address this hypothesis, we used positron emission tomography to noninvasively measure coronary blood flow in insulin-sensitive versus insulin-resistant patients without glucose intolerance or other cardiovascular risk factors associated with endothelial dysfunction. Flow responses to the vascular smooth-muscle vasorelaxant dipyridamole reflect the total integrated coronary vasodilator capacity, while flow responses to cold pressor test are modulated largely by endothelial function (6-9). In some insulin-resistant patients, myocardial blood flow was measured again after thiazolidinedione therapy to determine whether improvements in insulin action affected coronary vasomotor function. This investigation was conducted in a single ethnic sample of Mexican-American participants, who are reported to have the highest prevalence of adiposity, the metabolic syndrome, and glucose intolerance in the United States (10-12). Methods Patients and Study Design The Mexican-American Coronary Artery Disease (MACAD) project is an ongoing study that recruits families from the Los Angeles area and aims to identify genes common to insulin resistance and atherosclerosis. Families, recruited from University of California, Los Angeles (UCLA), and Olive View-UCLA Medical Center and by flyer at local community organizations, are ascertained through a parental case of coronary artery disease (proband). All proband offspring and offspring spouses undergo a medical history, physical examination, and blood collection for DNA extraction and routine testing. Fasting serum creatinine, urea nitrogen, liver enzyme, and thyroid-stimulating hormone levels are measured and routine urinalysis is performed by the UCLA Medical Center Clinical Pathology Laboratory. Total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and free fatty acid levels are determined by enzymatic colorimetric assays, as previously described (13). Low-density lipoprotein (LDL) cholesterol level is estimated by using the equation of Friedewald and colleagues (14). Serum levels of apolipoprotein A-I and apolipoprotein B are determined by using rate kinetic nephelometry, and apolipoprotein A-II levels are determined by end point nephelometry. Offspring and their spouses undergo a 75-g, 2-hour oral glucose tolerance test (Sun-Dex 75, Fisherbrand, Houston, Texas) with blood collection at 30, 15, 0, 30, 60, 90, and 120 minutes to determine plasma glucose levels (glucose oxidase technique; YSI, Inc., Yellow Springs, Ohio) and insulin levels (Human Insulin-Specific RIA Kit; Linco Research, Inc., St. Charles, Missouri; <0.2% cross-reactivity with proinsulin). Patients insulin sensitivity is then assessed by hyperinsulinemic glucose clamp. Hyperinsulinemic Euglycemic Clamp A modified hyperinsulinemic glucose clamp is used to quantitate insulin sensitivity (15). Regular human insulin (Novolin, Novo Nordisk Pharmaceuticals, Princeton, New Jersey; 60 mU/m2 per minute) is infused for 120 minutes, while 20% dextrose is co-infused to maintain normoglycemia (5 to 5.55 mmol/L [90 to 100 mg/dL]). Plasma is sampled for glucose at 5-minute intervals. The rate of glucose infusion at steady state (mg/kg of body weight per minute) during the last 30 minutes of the clamp is a measure of insulin action. Patients with a rate of glucose infusion at steady state of 4.0 mg/kg of body weight per minute or less are considered to be insulin-resistant, and patients with a rate of glucose infusion at steady state of 7.5 mg/kg per minute or more are considered to be insulin-sensitive. These criteria were based on upper and lower tertiles of 182 clamp procedures that were completed in the MACAD project at the time our study began and are now verified in 824 patients who underwent clamping to date. A total of 126 consecutive patients who underwent clamp procedure and met these criteria were candidates for participation in this study. Nine patients declined to participate. After thorough review of patients medical history, physical examination findings, laboratory values, and electrocardiograms in the remaining 117 patients, 39 patients were excluded for the following reasons: hypertension (3 patients); type 2 diabetes mellitus (2 patients); impaired fasting glucose level (8 patients), as classified by the American Diabetes Association (16); hypercholesterolemia (9 patients), fasting triglyceride levels greater than 3.39 mmol/L (300 mg/dL) (15 patients), and smoking (2 patients). These changes could adversely affect endothelial function. Six patients taking oral contraceptives were also excluded, and no female patient was postmenopausal. A total of 72 (50 insulin-resistant and 22 insulin-sensitive) patients met all entry criteria and underwent myocardial blood flow measurements. All participants signed an informed consent form, which was approved by the UCLA Medical Institutional Review Board. No participant had coronary artery disease or liver or renal abnormalities. Myocardial Blood Flow Measurements by Positron Emission Tomography Myocardial blood flow was measured at rest, during cold pressor testing, and during dipyridamole administration by using nitrogen-13-ammonia and positron emission tomography (ECAT EXACT HR+, Siemens/CTI, Knoxville, Tennessee) (9). Beginning with the first intravenous injection of nitrogen-13-ammonia, serial transaxial positron emission tomography images were acquired at rest, during cold pressor test, and then during dipyridamole administration (0.56 mg/kg infused intravenously over 4 minutes) with 45 minutes between each maneuver, as previously described (9). Cold pressor test was performed with the patients left hand immersed in ice water; nitrogen-13-ammonia was injected at 45 seconds, while cold pressor test was maintained for another minute. Heart rate, blood pressure, and 12-lead electrocardiograms were recorded continuously. The ratepressure product (RPP), an index of cardiac work, was derived as the heart rate multiplied by systolic blood pressure averaged over the first 2 minutes after tracer injection. From the serially acquired images, time activity curves for the left ventricular myocardium and the arterial blood pool were generated and myocardial blood flow (mL/g per minute) was estimated by using a previously validated tracer kinetic model (17, 18). Images of myocardial perfusion were also visualized and underwent polar map analysis to rule out rest- or stress-induced perfusion defects. Since no regional flow defects were present during stress or at rest and myocardial blood flow values were similar among the 3 coronary territories, myocardial blood flow values were estimated as averages for the entire left ventricular myocardium. The primary variables include percentages of myocardial blood flow response to cold pressor test ([myocardial blood flow response to cold pressor test myocardial blood flow response to rest]/myocardial blood flow response to rest) and response to dipyridamole adminstration (myocardial blood flow response to dipyridamole myocardial blood flow response to rest]/myocardial blood flow response to rest) and percentages of RPP response to cold pressor test ([RPP response to cold pressor test RPP response to rest]/RPP response to rest) and response to dipyridamole administration ([RPP response to dipyridamole RPP response to rest]/RPP response to rest). Thiazolidinedione Treatment To determine whether improvements in insulin sensitivity would affect coronary vasomotion in insulin resistance, some insulin-resistant patients were assigned to receive troglitazone, 600 mg daily (n = 9), or rosiglitazone, 8 mg daily (n = 16), for 3 months. At the start of this study, 9 insulin-resistant patients entered and completed troglitazone treatment. In March 2000, troglitazone was withdrawn from the U.S. market; therefore, we discontinued the use of troglitazone in this study. Troglitazone was replaced with the thiazolidinedione rosiglitazone; 16 insulin-resistant patients completed this treatment phase. Liver enzyme levels, monitored every 2 (troglitazone) or 4 (rosiglitazone) weeks during treatment, were normal in all patients throughout the study. Patient adherence was assessed through monthly pill counts. Rates of glucose infusion at steady state and myocardial blood flow were measured again when thiazolidinedione therapy was completed and at least 3 months after completion. Statistical Analysis Descriptive statistics (mean [SD]) were calculated for age, insulin sensitivity, blood pressure, lipid levels, free fa

Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node.

Lymphatic mapping and sentinel node biopsy are well-established techniques for staging and managing patients with melanoma, breast cancer and other malignancies that spread initially to the regional lymph nodes. Identification of tumor in the sentinel node is the most precise staging technique currently available. The sentinel node is the site of metastatic melanoma in approximately 20% of melanoma patients and if tumor is present in the sentinel node it is customary to perform a complete dissection of the lymph nodes of the affected nodal basin. This may be overtreatment for some patients as tumor is identified in the nonsentinel nodes of only one-third of sentinel node-positive melanoma patients treated by completion lymphadenectomy. If it were possible accurately to identify the minority of patients with tumor in the nonsentinel nodes, the patients most likely to benefit from lymphadenectomy, the remaining patients could be spared a potentially morbid operation that is unlikely to confer clinical advantage. In 90 patients with a melanoma-positive sentinel node, who subsequently had a completion lymphadenectomy, we evaluated and compared the capacity of characteristics of the primary melanoma and of the sentinel node to predict individuals likely to have tumor in nonsentinel nodes. We assessed the Breslow thickness of the primary, the amount of tumor in the sentinel node (relative tumor area) and, as an index of immune modulation of the sentinel node, the density of dendritic leukocytes in the nodal paracortex. The relative area of tumor in the sentinel node and Breslow thickness of the primary melanoma most accurately predicted the presence of tumor in the nonsentinel nodes (P=0.0001 in both cases—Wilcoxon rank sums). The presence of melanoma in the nonsentinel nodes was also predicted by the density of dendritic leukocytes in the paracortex (P=0.008–Wilcoxon rank sums). These three observations assessed alone and in combination predict the presence of tumor in the nonsentinel nodes with high accuracy. The same characteristics also significantly correlated with tumor recurrence (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0007) and death from melanoma (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0026)

Levels of Expression of CYR61 and CTGF Are Prognostic for Tumor Progression and Survival of Individuals with Gliomas

The biological properties of CCN proteins include stimulation of cell proliferation, migration, and adhesion, as well as angiogenesis and tumorigenesis. We quantified CYR61, CTGF, WISP-1, and NOV mRNA expression levels in samples from sixty-six primary gliomas and five normal brain samples using quantitative real-time PCR assay. Statistical analysis was performed to explore the links between expression of the CCN genes and clinical and pathological parameters. Overexpression of CYR61, CTGF, WISP-1, and NOV occurred in 48% (32 of 66), 58% (38 of 66), 36% (24 of 66), and 15% (10 of 66) of primary gliomas, respectively. Interestingly, significant associations were found between CYR61 expression versus tumor grade, pathology, gender, and age at diagnosis. Also, a significant correlation existed between CTGF mRNA levels versus tumor grade, gender, and pathology. In contrast to CYR61 and CTGF, no significant association was found between expression of either WISP-1 or NOV versus any of the pathological features. Furthermore, Cox regression analysis showed that CYR61 and CTGF expression had a significant correlation with patient survival. These results suggest that CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance; and these proteins might serve as valuable targets for therapeutic intervention.

The evolution of walking-related outcomes over the first 12 weeks of rehabilitation for incomplete traumatic spinal cord injury: the multicenter randomized Spinal Cord Injury Locomotor Trial.

Background. The Spinal Cord Injury Locomotor Trial (SCILT) compared 12 weeks of step training with body weight support on a treadmill (BWSTT) that included overground practice to a defined but more conventional overground mobility intervention (CONT) in patients with incomplete traumatic SCI within 8 weeks of onset. No previous studies have reported walking-related outcomes during rehabilitation. Methods. This single-blinded, randomized trial entered 107 American Spinal Injury Association (ASIA) C and D patients and 38 ASIA B patients with lesions between C5 and L3 who were unable to walk on admission for rehabilitation. The Functional Independence Measure (FIM-L) for walking, 15-m walking speed, and lower extremity motor score (LEMS) were collected every 2 weeks. Results. No significant differences were found at entry and during the treatment phase (12-week mean FIM-L = 5, velocity = 0.8 m/s, LEMS = 35, distance walked in 6 min = 250 m). Combining the 2 arms, a FIM-L ≥ 4 was achieved in < 10% of ASIA B patients, 92% of ASIA C patients, and all of ASIA D patients. Walking speed of ≥ 0.6 m/s correlated with a LEMS near 40 or higher. Conclusions. Few ASIA B and most ASIA C and D patients achieved functional walking ability by the end of 12 weeks of BWSTT and CONT, consistent with the primary outcome data at 6 months. Walking-related measures assessed at 2-week intervals reveal that time after SCI is an important variable for entering patients into a trial with mobility outcomes. By about 6 weeks after entry, most patients who will recover have improved their FIM-L to >3 and are improving in walking speed. Future trials may reduce the number needed to treat by entering patients with FIM-L < 4 at > 8 weeks after onset if still graded ASIA B and at > 12 weeks if still ASIA C.