Leigh A. Gray

Vertebroplasty in Multiple Myeloma: Outcomes in a Large Patient Series

BACKGROUND AND PURPOSE: Despite the literature supporting the efficacy of vertebroplasty for treatment of osteoporotic vertebral compression fractures, few reports exist documenting its use in the treatment of compression fractures in multiple myeloma patients. Accordingly, we sought to characterize the imaging characteristics, clinical course, and outcomes in myeloma patients treated with vertebroplasty. MATERIALS AND METHODS: We performed a retrospective review of clinical outcome data from 67 multiple myeloma patients treated with vertebroplasty since October 2000. Quantitative outcome data including the Roland Morris Disability Questionnaire (RDQ) and Visual Analog Scales for pain and qualitative outcome data (self-reported pain, mobility, and narcotic use) were collected preoperatively, immediately after vertebroplasty, and at 1 week, 1 month, 6 months, and 1 year after treatment. RESULTS: Significant improvements in all of the outcome measures were observed postoperatively and throughout the duration of follow-up. Quantitative outcome measures (RDQ, analog pain scale 0–10, with rest and activity) improved by 11.0 (48%; P < .0001), 2.7 (25%; P < .001), and 5.3 (48%; P < .0001) points, respectively, with persistent improvement at 1 year (P < .01; P < .03; P < .001). Eighty-two percent and 89% of patients experienced a significant improvement in subjective rest pain and activity pain, respectively. Subjective scores achieved durable improvements, with 65% of patients requiring fewer narcotics after vertebroplasty and 70% having improved mobility. CONCLUSION: Vertebroplasty provides significant and durable pain relief for patients with intractable spinal pain secondary to compression fractures resulting from multiple myeloma.

INvestigational Vertebroplasty Efficacy and Safety Trial (INVEST): a randomized controlled trial of percutaneous vertebroplasty

BackgroundThe treatment of painful osteoporotic vertebral compression fractures has historically been limited to several weeks of bed rest, anti-inflammatory and analgesic medications, calcitonin injections, or external bracing. Percutaneous vertebroplasty (the injection of bone cement into the fractured vertebral body) is a relatively new procedure used to treat these fractures. There is increasing interest to examine the efficacy and safety of percutaneous vertebroplasty and to study the possibility of a placebo effect or whether the pain relief is from local anesthetics placed directly on the bone during the vertebroplasty procedure.Methods/DesignsOur goal is to test the hypothesis that patients with painful osteoporotic vertebral compression fractures who undergo vertebroplasty have less disability and pain at 1 month than patients who undergo a control intervention. The control intervention is placement of local anesthesia near the fracture, without placement of cement. One hundred sixty-six patients with painful osteoporotic vertebral compression fractures will be recruited over 5 years from US and foreign sites performing the vertebroplasty procedure. We will exclude patients with malignant tumor deposit (multiple myeloma), tumor mass or tumor extension into the epidural space at the level of the fracture.We will randomly assign participants to receive either vertebroplasty or the control intervention.Subjects will complete a battery of validated, standardized measures of pain, functional disability, and health related quality of life at baseline and at post-randomization time points (days 1, 2, 3, and 14, and months 1, 3, 6, and 12). Both subjects and research interviewers performing the follow-up assessments will be blinded to the randomization assignment. Subjects will have a clinic visit at months 1 and 12. Spine X-rays will be obtained at the end of the study (month 12) to determine subsequent fracture rates. Our co-primary outcomes are the modified Roland score and pain numerical rating scale at 1 month.DiscussionAlthough extensively utilized throughout North America for palliation of pain, vertebroplasty still has not undergone rigorous study. The study outlined above represents the first randomized, controlled study that can account for a placebo effect in the setting of vertebroplasty.Trial RegistrationCurrent Controlled Trials ISRCTN81871888

Balloon-Assisted Coiling of Intracranial Aneurysms: Evaluation of Local Thrombus Formation and Symptomatic Thromboembolic Complications

BACKGROUND AND PURPOSE: Remodeling balloons are used to assist in endovascular coiling of aneurysms. We evaluated our experience with balloon-assisted coiling (BAC) in an attempt to determine whether this technique increased the rate of thrombus formation or symptomatic thromboembolic complications. MATERIALS AND METHODS: In 3 years, we treated 221 patients with intracranial aneurysms. Statistical analysis was performed to assess whether BAC increased the rate of thrombus formation or symptomatic thromboembolic complications. Patient demographics, aneurysm size, location, neck width, antiplatelet therapy, and rupture status were evaluated. RESULTS: We detected no statistically significant difference in rates of thrombus formation (14% versus 9% with and without BAC, respectively, P = 0.35) or symptomatic thromboembolic events (7% versus 5% with and without BAC, respectively, P = 0.76), though our power to detect small differences was limited. There was also no correlation with age, sex, rupture status, aneurysm size, or location. There was a significant increase in the rates of thrombus formation (6% versus 16%, P = 0.02) and symptomatic thromboembolic complications (3% versus 10%, P = 0.04) in aneurysms that were classified as narrow- or wide-necked, respectively. The use of clopidogrel was associated with a decrease in the rate of complications (P = 0.01). CONCLUSION: In this series, we detected no significant increase in the rates of either intraprocedural thrombus formation or symptomatic thromboembolic events in patients treated with BAC. Larger studies are required to confirm our observations. Wide-necked aneurysms were independently associated with increased rates of thrombus formation and symptomatic thromboembolic complications, whereas the use of clopidogrel was protective (P = 0.01).

A Prospective Trial of 3T and 1.5T Time-of-Flight and Contrast-Enhanced MR Angiography in the Follow-Up of Coiled Intracranial Aneurysms

BACKGROUND AND PURPOSE: Endovascularly coiled intracranial aneurysms are increasingly being followed up with noninvasive MRA imaging to evaluate for aneurysm recurrences. It has not been well-established which MRA techniques are best for this application, however. Our aim was to prospectively compare 4 MRA techniques, TOF and CE-MRA at 1.5T and 3T, to a reference standard of DSA in the evaluation of previously endovascularly coiled intracranial aneurysms. MATERIALS AND METHODS: Fifty-eight subjects with 63 previously coiled intracranial aneurysms underwent all 4 MRA techniques within 8 days of DSA. There were 2 outcome variables: coil occlusion class (class 1, complete; class 2, dog ear; class 3, residual neck; class 4, aneurysm filling) and change in degree of occlusion since the previous comparison. Sensitivity and specificity were computed for each MRA technique relative to the reference standard of DSA. Differences among the MRA techniques were evaluated in pair-wise fashion by using the McNemar test. RESULTS: For the detection of any aneurysm remnant, the sensitivity was 85%–90% for all MRA techniques. Sensitivity dropped to 50%–67% when calculated for the detection of only the class 3 and 4 aneurysm remnants, because several class 3 and 4 remnants were misclassified as class 2 by MRA. CE-MRA at 1.5T and 3T misclassified fewer of the class 3 and 4 remnants than did TOF-MRA at 1.5T, as reflected by the significantly greater sensitivity for larger aneurysm remnants with CE-MRA relative to TOF-MRA at 1.5T (P = .0455 for both comparisons). CONCLUSIONS: CE-MRA is more likely than TOF-MRA to classify larger aneurysm remnants appropriately. We recommend performing both CE-MRA and TOF-MRA in the follow-up of coiled intracranial aneurysms and at 3T if available.

A phase II trial of pirfenidone (5-methyl-1-phenyl-2-[1H]pyridone), a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia

The anti‐fibrotic and cytokine modulatory properties of pirfenidone suggest its usefulness in the treatment of myelofibrosis with myeloid metaplasia (MMM). In a prospective study, 28 patients with MMM were treated with oral pirfenidone. Twelve patients completed 1 year of therapy; 13 were withdrawn because of disease progression and three because of drug intolerance. Only one patient experienced a clinically relevant benefit with respect to anaemia and splenomegaly. The overall lack of clinical benefit correlated with no significant improvement in the bone marrow morphological features of the disease. We conclude that pirfenidone has no significant clinical or biological activity in MMM.

Cerebral venous sinus density on noncontrast CT correlates with hematocrit.

BACKGROUND AND PURPOSE: A positive correlation between HCT and CT attenuation of intravascular blood has long been assumed but has never been established by using substantial patient numbers and modern CT equipment. The purpose of this study was to determine whether apparent increased attenuation on CT in cerebral venous sinuses can be attributed to hemoconcentration alone and to assess whether sinus thrombosis can be differentiated from hemoconcentrated blood based on attenuation values alone. MATERIALS AND METHODS: We measured HUs in a region of interest within the confluence of dural venous sinuses in 166 unenhanced head CTs and correlated these data with HCT and HGB values in male and female patients aged 2 to 100 years. We then compared these data with similar measurements in 8 patients with recent venous sinus thrombosis. Two-tailed t test and linear regression analyses were performed to evaluate HGB and HCT between groups and with measured CT attenuation of intravascular blood, respectively. RESULTS: A statistically significant relationship was noted between both HCT and HGB with CT attenuation. Seven of 8 patients with sinus thrombosis had attenuation values >70, but none of the normal subjects had HUs >70. CONCLUSIONS: Hemoconcentration correlates with CT attenuation in cerebral venous sinuses. Our findings suggest that comparing the ratio of HUs to HCT may be useful in gauging concern for sinus thrombosis.

In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia.

R115777 is an orally bioavailable farnesyltransferase inhibitor (FTI) that has displayed encouraging activity in patients with acute myeloid leukemia. To determine whether R115777 might exert similar activity in myelofibrosis with myeloid metaplasia (MMM), we evaluated its effects on circulating myeloid progenitor cells from patients with MMM (n=25) using in vitro colony-forming assays. The median R115777 concentrations that inhibited colony formation by 50% were 34 and 2.7 nM for myeloid and megakaryocytic colonies from MMM patients, respectively. Progenitors from normal controls and patients with other myeloproliferative disorders demonstrated similar sensitivity. Since the ras polypeptides are one putative target of FTIs, the potential role of ras effectors was examined by incubating parallel progenitor assays with the phosphatidyl-inositol-3 (PI-3) kinase inhibitor LY294002 and the mitogen-activated protein kinase 1 inhibitor PD98059. MMM progenitor colonies (n=7) were highly sensitive to LY294002 but not to PD98059, implying that the PI-3 kinase pathway may be critical for survival and proliferation of these cells. In addition to indicating that MMM progenitors are sensitive to clinically achievable R115777 concentrations in vitro, these results provide a potential explanation for the thrombocytopenia observed with R115777 during the treatment of other hematologic malignancies.

Radiation therapy for symptomatic hepatomegaly in myelofibrosis with myeloid metaplasia

Abstract: Objective: To describe the experience with liver irradiation in advanced cases of myelofibrosis with myeloid metaplasia (MMM). Methods: Over a 20‐yr period, 14 patients with MMM were treated with a total of 25 courses of liver, abdominal, or abdominal and pelvic irradiation for symptomatic hepatomegaly with (5 patients) or without (9 patients) ascites. All 14 patients had advanced disease and 11 (79%) had previous splenectomy. The median radiation therapy (RT) dose per course was 150 cGy (range 50–1000) administered at a median of six fractions. Four patients received two to six courses. Results: Twelve of the 14 patients (86%) had a transient (median 3 months) subjective response from RT. However, in only 35% of these was there a transient (median 3 months) decrease in palpable liver size. Four of the five patients with ascites experienced a short‐term response from RT. Eight of the 13 patients suitable for evaluation (62%) had treatment‐associated cytopenia, often in the form of anemia and/or thrombocytopenia. At last follow‐up, 10 patients (71%) had died after a median of 7 months (range 0.1–23) and 4 were alive at 3, 20, 33, and 57 months after RT. Conclusions: Low‐dose abdominal RT for symptomatic hepatomegaly or ascites associated with advanced‐stage MMM is myelosuppressive and provides only temporary and mainly subjective and short‐lived relief.

Baseline Pain and Disability in the Investigational Vertebroplasty Efficacy and Safety Trial

BACKGROUND AND PURPOSE: Multiple case series of vertebroplasty outcomes have been published, though no large, placebo controlled trial has yet been performed. Our aim was to report baseline characteristics for the Investigational Vertebroplasty Efficacy and Safety Trial (INVEST), a randomized blinded controlled study of vertebroplasty. MATERIALS AND METHODS: We compared baseline demographics, pain scores, and scores on the modified Roland-Morris Disability Scale (RMDS), a back pain−specific metric, between 2 groups. One group included subjects enrolled at the lead INVEST site (n = 27 to date). The second group consisted of eligible patients seen concurrently at the lead INVEST site, who declined enrollment (n = 70). Comparisons were made by using 2-sample t tests. RESULTS: Mean ages were similar between groups, averaging approximately 74 years among study participants and 77 years among nonenrolled eligible patients (P = .17). Approximately 75% of subjects were female in both groups. RMDS scores of enrolled patients at the lead site (18.0 ± 4.2) were not statistically different from those of eligible nonenrolled patients at the lead site (18.6 ± 3.6, P = .49). Pain scores in the enrolled subjects were measured as “average intensity over the prior 24 hours” with mean scores of 7.6 ± 2.1 among enrolled patients at the lead site. Pain scores in eligible nonenrolled patients were measured as “pain at rest,” with mean score of 3.4 ± 3.3, and “pain with activity,” with mean score of 8.5 ± 2.0. CONCLUSIONS: Patient demographics among subjects enrolled in the INVEST are similar to those in a cohort of eligible nonenrolled patients. Back pain−specific disability was similar between subjects enrolled in the INVEST study and eligible nonenrolled patients at the lead site.

Mortality in the Vertebroplasty Population

More controversy with regard to vertebroplasty: Do vertebroplasties affect mortality rates? These well-seasoned investigators compared 524 vertebroplasty patients with refractory osteoporotic fractures with 589 patients not treated by the procedure. When compared with the general population, vertebroplasty patients showed 77% of the expected survival and when compared with patients with symptomatic or asymptomatic vertebral fractures, vertebroplasty recipients retained a 17% greater mortality risk. Conclusion: mortality rates were worse for vertebroplasty patients when compared with those of patients with untreated asymptomatic fractures, and similar if compared with patients with untreated symptomatic fractures. BACKGROUND AND PURPOSE: Vertebroplasty is an effective treatment for painful compression fractures refractory to conservative management. Because there are limited data regarding the survival characteristics of this patient population, we compared the survival of a treated with an untreated vertebral fracture cohort to determine whether vertebroplasty affects mortality rates. MATERIALS AND METHODS: The survival of a treated cohort, comprising 524 vertebroplasty recipients with refractory osteoporotic vertebral compression fractures, was compared with a separate historical cohort of 589 subjects with fractures not treated by vertebroplasty who were identified from the Rochester Epidemiology Project. Mortality was compared between cohorts by using Cox proportional hazards models adjusting for age, sex, and Charlson indices of comorbidity. Mortality was also correlated with pre-, peri-, and postprocedural clinical metrics (eg, cement volume use, RDQ score, analog pain scales, frequency of narcotic use, and improvement in mobility) within the treated cohort. RESULTS: Vertebroplasty recipients demonstrated 77% of the survival expected for individuals of similar age, ethnicity, and sex within the US population. Compared with individuals with both symptomatic and asymptomatic untreated vertebral fractures, vertebroplasty recipients retained a 17% greater mortality risk. However, compared with symptomatic untreated vertebral fractures, vertebroplasty recipients had no increased mortality following adjustment for differences in age, sex, and comorbidity (HR, 1.02; 95% CI, 0.82–1.25). In addition, no clinical metrics used to assess the efficacy of vertebroplasty were predictive of survival. CONCLUSIONS: Vertebroplasty recipients have mortality rates similar to those of individuals with untreated symptomatic fractures but have worse mortality compared with those with asymptomatic vertebral fractures.