Meaningful Symptomatic Change in Patients With Myelofibrosis From the SIMPLIFY Studies.

OBJECTIVES: Patients with myelofibrosis develop symptoms due to bone marrow fibrosis, systemic inflammation, and/or organomegaly. Alleviating symptoms improves overall quality of life. Clinical trials have historically defined symptom response as a reduction of at least 50% in Total Symptom Score at week 24 compared with baseline. Whether 50% constitutes a meaningful benefit has not been established. This study determined the meaningful change threshold (MCT) for 2 momelotinib phase III trials, SIMPLIFY-1 and SIMPLIFY-2. METHODS: The absolute and percentage MCT was determined using anchor-based methods applied to the modified Myeloproliferative Neoplasm Symptom Assessment Form v2.0 and Patient Global Impression of Change. MCTs were applied retrospectively to determine responder rates. Generalized estimating equations estimated the treatment-related difference in likelihood of improvement. RESULTS: In SIMPLIFY-1, a Janus kinase inhibitor-naive population, the MCT was 8 points. In SIMPLIFY-2, a previously Janus kinase inhibitor-treated population, the MCT was 6 points. A 32% MCT was determined in both studies, showing that the historic 50% reduction threshold may be a conservative choice. In SIMPLIFY-1, a similar proportion of patients achieved responder status with 24 weeks of momelotinib or ruxolitinib therapy based on the absolute MCT (39% vs 41%, respectively). In SIMPLIFY-2, a significantly greater proportion of patients treated with momelotinib achieved responder states compared with best available therapy based on absolute and percent change MCTs. CONCLUSIONS: This study demonstrates that momelotinib provided clinically meaningful symptom benefit for patients with myelofibrosis and provides insight into the appropriateness of the symptom change threshold used in historical studies.

Anemia-related response end points in myelofibrosis clinical trials: current trends and need for renewed consensus.

JAK inhibitors are the current standard of care in myelofibrosis, but many do not address and may worsen anemia; thus, anemia-related responses have traditionally been overlooked as efficacy end points in pivotal clinical trials, leading to a lack of consistency and analytic detail in their reporting. Here we apply our experiences in the phase III trials of momelotinib, a JAK1/JAK2/ACVR1 inhibitor and the first therapy indicated by the US FDA for myelofibrosis patients with anemia, to highlight how application of different criteria impacts the anemia-related benefits reported for any potential treatment in myelofibrosis. We advocate for a convention of a new expert consensus panel to bring consistency and transparency to the definition of anemia-related response in myelofibrosis.

What is this Perspective about? Anemia (too few healthy red blood cells) is common in patients with myelofibrosis. While it is becoming more common to measure the anemia benefits associated with potential treatments for myelofibrosis in clinical trials, different definitions of anemia benefit are available. This Perspective reviews these definitions, the differences between them, and why consistency and clarity in measuring anemia benefit matter. The definitions used in clinical trials of momelotinib, a treatment for patients with myelofibrosis and anemia, are also explained to show how the anemia benefit observed in these trials could have changed if different definitions were used. What does this Perspective show? Definitions of anemia benefit may include the number of red blood cell transfusions a patient receives, the amount of hemoglobin (a red blood cell protein) in their blood, or a combination thereof. Considerations such as timing, the types of patients included, and other factors are not consistent across definitions and not always clearly reported. Results when different definitions of anemia benefit were followed in the momelotinib clinical trials show that the amount of benefit observed with treatments changes depending on which definition is used. What conclusions can be drawn from this Perspective? More consistency and clarity in the definitions of anemia benefit in myelofibrosis clinical trials are needed, suggesting that a new panel of experts should come together to discuss this topic.

Patient-reported Outcomes and Quality of Life in Anemic and Symptomatic Patients With Myelofibrosis: Results From the MOMENTUM Study.

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm that typically manifests with debilitating symptoms that progressively worsen, negatively impacting patients' quality of life. Fatigue is a multifactorial and burdensome MF-related symptom due to its severity, persistence, and prevalence, with anemia a contributing factor and major unmet need. Clinical trials of the Janus kinase (JAK)1/JAK2/activin A receptor type 1 inhibitor momelotinib have shown consistent anemia benefits, in addition to improvements in MF-related symptoms. The phase 3 MOMENTUM trial in symptomatic and anemic patients met its primary end point, with a greater proportion having a Myelofibrosis Symptom Assessment Form (MFSAF) Total Symptom Score (TSS) reduction ≥50% at week 24 with momelotinib versus danazol. To support the positive primary end point result, we conducted longitudinal, responder, and time-to-event analyses of patient-reported outcomes from MOMENTUM, as measured by the MFSAF, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Patient-Reported Outcomes Measurement Information System (PROMIS) assessments. These analyses demonstrated rapid and durable response benefits with momelotinib, with achievement of first TSS response by day 29 and continued improvement over time. Improvements favored momelotinib versus danazol for each MFSAF individual item, and greater improvements were observed for disease- and cancer-related fatigue and physical functioning at week 24, with significant results for multiple items/domains across the 3 assessments. These findings are consistent in demonstrating that momelotinib provides substantial symptom benefit.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study.

BACKGROUND: The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48. METHODS: MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1-4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib. The primary endpoint, which has already been reported, was Myelofibrosis Symptom Assessment Form TSS response rate at week 24. Predefined secondary endpoints were duration of week 24 TSS and transfusion independence responses, safety, and survival, which are summarised post hoc at the week 48 data cutoff (May 17, 2022). TSS, transfusion independence, and splenic responses at week 48 were defined post hoc and assessed in all evaluable patients who entered the open-label period and provided sufficient data. The timing of this updated analysis was defined post hoc after all patients had the opportunity to complete their week 48 assessments, as most patients entered an extended access study (NCT03441113) after week 48. This study is registered with ClinicalTrials.gov, number NCT04173494, and is now complete. FINDINGS: Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6-55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3-4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia). INTERPRETATION: Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia. FUNDING: Sierra Oncology, a GSK company.

Symptomatic benefit of momelotinib in patients with myelofibrosis: Results from the SIMPLIFY phase III studies.

BACKGROUND: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. METHODS: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. RESULTS: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. CONCLUSIONS: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. FUNDING: Sierra Oncology.

Recombinant Human Platelet-Derived Growth Factor BB in Combination With a Beta-Tricalcium Phosphate (rhPDGF-BB/ß-TCP)-Collagen Matrix as an Alternative to Autograft.

BACKGROUND: Joint arthrodesis often employs autograft to promote union; graft harvesting can lead to perioperative morbidity. A Canadian randomized controlled trial (RCT) demonstrated that recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB) combined with beta-tricalcium phosphate (ß-TCP)-collagen was a safe, effective alternative to autograft. This multicenter North American RCT compared the safety and efficacy of rhPDGF-BB/ß-TCP-collagen with autograft for ankle and hindfoot fusion. Subclassification using propensity scores (PS) incorporated patients from previous trials for enhanced statistical power for noninferiority testing and broader review of treatments. METHODS: Patients requiring ankle or hindfoot arthrodesis and supplemental bone graft were treated with rhPDGF-BB/ß-TCP-collagen (n = 69) or autograft (n = 35). Outcomes included joint fusion on computed tomography (24 weeks), clinical healing status, visual analog scale (VAS) pain, Short-Form 12 (SF-12), American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale, and Foot Function Index (FFI) scores over 52 weeks. PS methodology addressed potential selection bias arising from pooling data among these patients and 2 previous RCTs with similar inclusion criteria, surgical techniques, graft harvest techniques, and outcomes. All 132 rhPDGF-BB/ß-TCP-collagen-treated patients and 167 of 189 candidate autograft-treated controls were selected for comparison by an independent statistician blinded to outcomes. RESULTS: In the PS subclassification, 68.1% treatment patients and 68.4% controls achieved >50% osseous bridging at fusion sites. Clinical healing status was achieved in 84.8% of treated patients and 90.7% of controls at 52 weeks. Clinical, functional, and quality of life results demonstrated noninferiority of rhPDGF-BB/ß-TCP-collagen to autograft. Safety-related outcomes were equivalent. CONCLUSION: PS subclassification analysis of 3 RCTs demonstrated that rhPDGF-BB/ß-TCP-collagen was as effective as autograft for ankle and hindfoot fusions, with less pain and morbidity than treatment with autograft. LEVEL OF EVIDENCE: Level I, prospective randomized study.

Clinical Outcomes of Nonunions of Hindfoot and Ankle Fusions.

BACKGROUND: While nonunion after foot and ankle fusion surgery has been associated with poor outcomes, we are not aware of any longitudinal study on this subject. Thus, we prospectively evaluated the impact of nonunion on clinical outcomes of foot and ankle fusions and identified potential risk factors for nonunion after these procedures. METHODS: Using data from a randomized clinical trial on recombinant human platelet-derived growth factor-BB (rhPDGF-BB; Augment Bone Graft, BioMimetic Therapeutics), union was defined either by assessment of computed tomography (CT) scans at 24 weeks by a reviewer blinded to the type of treatment or by the surgeon's composite assessment of clinical and radiographic findings at 52 weeks and CT findings at 24 or 36 weeks. The nonunion and union groups (defined with each assessment) were then compared in terms of clinical outcome scores on the American Orthopaedic Foot & Ankle Society Ankle-Hindfoot Scale (AOFAS-AHS), Foot Function Index (FFI), and Short Form-12 (SF-12) as well as age, sex, body mass index (BMI), smoking status, diabetes status, work status, and arthrodesis site. RESULTS: Blinded CT assessment identified nonunion in 67 (18%) of 370 patients, and surgeon assessment found nonunion in 21 (5%) of 389 patients. Postoperatively, the nonunion group scored worse than the union group, regardless of the method used to define the nonunion, on the AOFAS-AHS and FFI, with mean differences of 10 and 12 points, respectively, when nonunion was determined by blinded CT assessment and 19 and 20 points when it was assessed by the surgeon. The nonunion group also had worse SF-12 Physical Component Summary scores. Differences between the union and nonunion groups were clinically meaningful for all outcome measures, regardless of the nonunion assessment method. The concept of an asymptomatic nonunion (i.e., imaging indicating nonunion but the patient doing well) was not supported. Patients with nonunion were more likely to be overweight, smokers, and not working. CONCLUSIONS: This prospective longitudinal study demonstrated poorer functional outcomes in patients with a nonunion after foot and ankle fusion, regardless of whether the diagnosis of nonunion was based on CT only or on combined clinical, radiographic, and CT assessment. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Importance of Sufficient Graft Material in Achieving Foot or Ankle Fusion.

BACKGROUND: Nonunion, an important complication following foot and ankle arthrodesis, causes substantial morbidity and disability. In patients undergoing hindfoot and ankle arthrodesis, autogenous bone graft (autograft) or a suitable alternative is often used to promote osseous fusion across the joint. This study assessed the importance of adequate graft material in the fusion space to achieve joint fusion during ankle and hindfoot arthrodesis. METHODS: This study used data from a previously published clinical trial of grafting material (recombinant human platelet-derived growth factor-BB with beta-tricalcium phosphate [rhPDGF-BB/ß-TCP] or autograft) for healing in hindfoot and ankle arthrodesis to correlate the amount of graft fill at 9 weeks with ultimate healing. Patients who received supplemental graft material for ankle or hindfoot arthrodesis for end-stage ankle or hindfoot arthritis were stratified according to nonunion risk factors and surgical fusion site. Patients underwent arthrodesis using standard rigid internal fixation. Graft fill was defined as "adequate" if the material occupied ≥50% of the cross-sectional area of the fusion space on a computed tomography (CT) scan made at 9 weeks. Fusion was defined as osseous bridging of ≥50% of each articulation on a CT scan made at 24 weeks. Three hundred and seventy-nine patients with 573 joints (383 managed with rhPDGF-BB/ß-TCP and 190 managed with autograft) that underwent arthrodesis had complete follow-up with 9-week and 24-week CT scans available. RESULTS: Overall, 472 (82%) of 573 joints had adequate graft fill; of those, 383 (81%) were successfully fused at 24 weeks compared with 21 (21%) of 101 joints without adequate graft fill (p < 0.0001). Absolute fusion rate differences (joints with adequate fill minus those without adequate fill) were consistent across joints (61% to 63%) and for graft materials. The overall odds ratio (OR) of successful fusion in joints with adequate graft fill compared with those without adequate graft fill was 16.4 (95% confidence interval, 9.6 to 27.9). CONCLUSIONS: This study demonstrates an association between the amount of graft material and successful hindfoot and ankle arthrodesis. Graft material filling of ≥50% of the fusion space at 9 weeks, regardless of type or origin, was associated with significantly higher fusion rates at 24 weeks. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Does autogenous bone graft work? A logistic regression analysis of data from 159 papers in the foot and ankle literature.

BACKGROUND: While autogenous cancellous iliac crest bone graft is the gold standard for foot and ankle surgery, it lacks Level I evidence. Although one third of all graft cases performed in the United States today rely on allograft, some surgeons believe no graft is necessary. We hypothesized that a systematic review of the foot and ankle literature would reveal that (1) autogenous bone graft during foot and ankle arthrodesis would demonstrate healing rates that were superior to the use of either using allograft or no bone graft at all, and (2) these differences would be even more dramatic in patients having risk factors that impair bone healing. To our knowledge, neither of these assessments to date has ever been performed with this body of literature. The goal of this study was to review the use and union rates of bone graft during foot and ankle arthrodesis and determine if autogenous bone graft was superior. METHODS: A literature search was performed to include articles between 1959 and 2012 using autograft, allograft, and/or no bone graft for foot and/or ankle arthrodesis. Case reports involving fewer than four patients, investigations failing to incorporate outcome data, those involving orthobiologic augmentation, and those including vascularized graft, xenograft, or pediatric patients were excluded. Recorded search results included patient demographics, comorbidities, pre-operative diagnosis, surgical procedure, bone graft type and indication, union rate, method of fixation, patient satisfaction, all outcome scores, definition of healing/success, and any listed complications including revision. Final data were stratified based upon the type of graft material. RESULTS: This search generated 953 related articles, of which 159 studies (5327 patients) met inclusion criteria. The majority (153/159) were retrospective case series. Systematic review demonstrated a trend toward higher union rates for cancellous autograft (OR 1.39, p=0.11), structural autograft (OR 1.52, p=0.09), and cancellous allograft (OR 1.31, p=0.52) relative to no graft material, but none reached statistical significance. Compared to no graft, structural allograft trended toward worse performance (OR 0.62, p=0.17). The overall probability of union was 93.7% for cancellous autograft, 94.2% for structural autograft, 93.3% for cancellous allograft, 91.4% for no graft, and 86.9% for structural allograft. When only comparing the 19 papers that included a no graft arm (91.9% union rate), data revealed the highest union using cancellous autograft (95.1%, OR 1.73, p=0.09) and structural autograft (96.3%, OR 2.33, p=0.06) while only 76% for structural allograft. No significant statistical association existed between union rates and other recorded variables. CONCLUSION: Systematic analysis of bone graft use in foot and ankle fusions favors the use of autograft and cancellous allograft for optimized healing rates, although no differences were statistically significant. If we assume that graft material been chosen for more complex procedures having lower anticipated union rates, then these data lend further support to the use of autograft and cancellous allograft. LEVEL OF EVIDENCE: Level IV.

Site selection and pain outcome after autologous bone graft harvest.

BACKGROUND: In foot and ankle surgery, there are multiple sites used for autologous bone graft, including the proximal (PT) or distal tibia (DT), calcaneus (C), and iliac crest (ICBG). There has been no comparison between these anatomic areas and the potential for acute or persistent pain at 1 year. The purpose of this study was to prospectively compare patient-reported outcomes of acute and persistent pain at 1 year after surgery to determine if harvest site selection made a difference. METHODS: As part of a clinical trial examining ankle and hindfoot fusion rates with autograft compared with synthetic graft, the autologous bone graft harvest sites were assessed with visual analog pain outcome scores at 3, 24, 36, and 52 weeks after surgery. Patients with a score of 20+ defined clinically significant pain. Four harvest sites were compared: ICBG, PT, DT, and C. Fisher exact test was used to compare the graft site pain between locations. RESULTS: Twelve percent of subjects reported clinically significant pain at 24 weeks and 8.5% at 52 weeks postoperatively. Each lower extremity harvest site (C, DT, PT) showed higher rates of clinically significant graft harvest site pain than the ICBG at 52 weeks. CONCLUSIONS: Autologous bone graft harvest carried a risk of persistent pain at up to 1 year (weeks 24-52) in 18% of patients. Lower-extremity bone graft sites had the greatest risk for persistent pain at 1 year. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Establishing the relationship between clinical outcome and extent of osseous bridging between computed tomography assessment in isolated hindfoot and ankle fusions.

BACKGROUND: Determining the success of joint fusion operations is often a diagnostic dilemma, and many factors may be considered. Most would agree that the broad categories of clinical success and radiographic success are likely most useful to determine the overall success of a joint fusion operation. Very little evidence exists to assist the surgeon in determining what constitutes a successful radiographic fusion. The aim of this study was to determine the extent of osseous bridging as measured by computed tomography (CT) that was associated with a good clinical outcome as measured by the 12-Item Short Form (SF-12), Foot Function Index (FFI), and American Orthopaedic Foot & Ankle Society (AOFAS) clinical outcomes questionnaires at 24 weeks. METHODS: Patients who had isolated joint fusions were evaluated (n = 275) to determine the correlation of extent of osseous bridging with clinical outcome. The extent of osseous bridging across the joint in question was categorized as absent (0%-24%), minimal (25%-49%) moderate (50%-74%), or complete (75%-100%). Clinical outcome scores included the SF-12, FFI, and AOFAS outcomes score. RESULTS: Patients evaluated to have at least minimal osseous bridging at fusion sites (25%-49%) on CT reported a clinically important improvement in SF-12, FFI, and AOFAS, whereas those with "absent" osseous bridging (0%-24%) did not report a clinically important improvement in outcome scores. CONCLUSION: This study suggests that osseous bridging of greater than 25% to 49% at the fusion site measured by CT may be necessary to consider a hindfoot or ankle fusion clinically successful. LEVEL OF EVIDENCE: Level IV, case series.

Survey on the need for bone graft in foot and ankle fusion surgery.

BACKGROUND: Generally, autologous bone graft is felt to be an important treatment adjunct in the presence of structural deformity, surface irregularities, defects (due to trauma, surgery, or degenerative changes), or underlying comorbidities that predispose the patient to healing challenges. This study assessed the prognostic and predictive factors used in the clinical decision making for bone graft supplementation in foot and ankle fusion surgery. METHODS: Utilizing standard survey research methodology, key-informant interviews, pretesting, and pilot testing; a survey was constructed. The survey consisted of a web-based 5-point Likert-type scale (never, seldom, sometimes, almost always, always) listing 14 clinical and 11 radiologic criteria that may influence the use of autologous bone grafting or other biologic augmentation in foot and ankle surgery. This survey was sent to Orthopaedic Foot and Ankle Surgeons in North America and Canada. RESULTS: A total of 48 foot and ankle surgeons completed the blinded survey (73% response rate). More than 70% of responders felt bone graft was almost always (AA) or always (A) indicated in prior nonunion of the indicated joint (96%). Fewer than 50% of respondents felt poor soft tissue integrity (20%), prior foot and ankle infection (20%), and current foot and ankle infection (4%) needed bone graft. Radiologic factors marked as AA or A in over 70% of responders include radiographic evidence of nonunion (96%), avascular necrosis (87%), and others. Factors chosen as AA or A by fewer than 50% of surgeons include prior adjacent joint fusions (47%), intra-articular deformity (31%), and extra-articular deformity (13%). CONCLUSIONS: There was some uniformity of agreement on the number of both clinical and radiologic factors that prompt a surgeon to utilize autologous bone graft to try to avoid the complication of nonunion. Surgeons may wish to consider these factors when making a decision on the use of bone graft to supplement fusion.

The impact of reduction mammaplasty on breast sensation: an analysis of multiple surgical techniques.

Our prospective clinical trial collected sensory data using a computerized pressure-specified sensory device comparing 4 procedures for reduction mammaplasty. A total of 48 patients were assessed at baseline, 6 weeks (n = 42), 6 months (n = 15), and 1 year (n = 24) postoperatively. The findings of our study showed pressure sensitivity for women <43 years of age improved by pressure-specified sensory device assessment; whereas, outcome data merely indicated return to baseline in pressure sensitivity for women ≥ 43 years of age. Improved sensitivities for moving and static pressures were found in patients receiving vertical or inferior pedicle reduction mammaplasties. Reductions based on superior pedicles exhibited sensory loss as compared with baseline measurements while those receiving free nipple grafts showed negligible change. Moving and static sensation showed differential return after breast reduction irrespective of the specific surgical approach but sensation was uniquely conserved for the nipple. In the total cohort, the type of breast reduction procedure did not produce significant differences in breast sensation.

Multi-institutional experience using human acellular dermal matrix for ventral hernia repair in a compromised surgical field.

BACKGROUND: A complex ventral hernia repair (CVHR) involves a compromised surgical field where gastrointestinal, biliary, and genitourinary procedures are performed. Complex ventral hernia is a significant problem in trauma, emergency, and elective general surgery in which prosthetic material is contraindicated. In this clinical scenario, primary fascia closure carries a 50% risk of developing a hernia. The other option is a planned ventral hernia with delayed repair. HYPOTHESIS: Human acellular dermal matrix is a suitable implant for CVHR in a compromised surgical field. DESIGN: Multi-institutional, 5-year retrospective review. SETTING: Four academic medical centers. PATIENTS AND METHODS: Each center obtained institutional review board approval. Patients included in the review had undergone CVHR with human acellular dermal matrix. Data collected included age, body mass index (calculated as weight in kilograms divided by height in meters squared), comorbidities, size of fascial defect, wound classification, hospital length of stay, length of follow-up, and mortality. Primary outcomes were surgical site infection, fistula recurrence, and hernia recurrence. Both chi2 and logistic regression analyses were performed. RESULTS: Two hundred forty patients met the study criteria. Their mean (SD) age was 52.2 (15.0) years, and 132 (55.0%) were men. The most common comorbidity was hypertension (115 patients [47.9%]), and the mean defect size was 201 cm2. The mean hospital length of stay was 17.2 days, and the mean follow-up was 317 days. The overall mortality was 2.9%. The hernia recurrence rate was 17.1% (41 patients). Repair of a fistula or stoma was associated with hernia recurrence (P = .03) and with fistula recurrence (P < .001). Logistic regression analysis demonstrated surgical site infection and body mass index of greater than 30 to be independent risks of hernia recurrence. CONCLUSIONS: Human acellular dermal matrix is a suitable alternative for CVHR in a compromised surgical field. The hernia recurrence rate with human acellular dermal matrix in a compromised surgical field is less than that seen with primary repair, offering additional and improved surgical options for CVHR in this group of patients. Stoma or fistula takedown at the time of CVHR continues to be associated with significant complications.

Intensive insulin therapy in practice: can we do it?

BACKGROUND: Intensive insulin therapy (IIT) is the standard of care in the ICU, but precise implementation of insulin protocols has been difficult in clinical practice. The authors' objective was to quantify adherence to an IIT protocol in a practice setting, and to describe how adherence impacts overall blood glucose (BG) control. METHODS: A retrospective analysis of a cohort of critically ill patients treated with IIT was performed. Protocol adherence was evaluated by assessing the timing of BG measurements. Each measurement was categorized according to the time from the previous reading: early (<1 hour), on time (1-3 hours), and late (>3 hours). Outcome measures included mean and median BG for each time category as well as the proportion of values within the target range. RESULTS: In 1106 trauma and surgical ICU patients, 54,139 measurements were available for analysis. The overall mean BG (116 mg/dL) was near the target (80-110 mg/dL), but only 46% of values were within this range. There were 45,806 (86%) measurements on time, 2749 (5%) early, and 4478 (9%) were late. BG values of late measurements were less likely to be within range (34% vs 46% for on time measurements, P<.001). Of late measurements, 19% were >200 mg/dL, 13% were 150-200 mg/dL, and 16% were <60 mg/dL. CONCLUSIONS: IIT is difficult to implement precisely in a complex ICU environment. Measurement timing impacts overall BG control, with late measurements more often associated with severe hyperglycemic (BG>150 mg/dL) and hypoglycemic (BG<60 mg/dL) episodes.

Hepatitis B and hepatitis C in Pakistan: prevalence and risk factors.

BACKGROUND: Pakistan carries one of the world's highest burdens of chronic hepatitis and mortality due to liver failure and hepatocellular carcinomas. However, national level estimates of the prevalence of and risk factors for hepatitis B and hepatitis C are currently not available. METHODS: We reviewed the medical and public health literature over a 13-year period (January 1994-September 2007) to estimate the prevalence of active hepatitis B and chronic hepatitis C in Pakistan, analyzing data separately for the general and high-risk populations and for each of the four provinces. We included 84 publications with 139 studies (42 studies had two or more sub-studies). RESULTS: Methodological differences in studies made it inappropriate to conduct a formal meta-analysis to determine accurate national prevalence estimates, but we estimated the likely range of prevalence in different population sub-groups. A weighted average of hepatitis B antigen prevalence in pediatric populations was 2.4% (range 1.7-5.5%) and for hepatitis C antibody was 2.1% (range 0.4-5.4%). A weighted average of hepatitis B antigen prevalence among healthy adults (blood donors and non-donors) was 2.4% (range 1.4-11.0%) and for hepatitis C antibody was 3.0% (range 0.3-31.9%). Rates in the high-risk subgroups were far higher. CONCLUSIONS: Data suggest a moderate to high prevalence of hepatitis B and hepatitis C in different areas of Pakistan. The published literature on the modes of transmission of hepatitis B and hepatitis C in Pakistan implicate contaminated needle use in medical care and drug abuse and unsafe blood and blood product transfusion as the major causal factors.

Autologous breast reconstruction: the Vanderbilt experience (1998 to 2005) of independent predictors of displeasing outcomes.

BACKGROUND: Optimal surgical outcomes are dependent on an appreciation of comorbid conditions that may handicap results. The purpose of this retrospective analysis was to delineate risk factors for complications after autologous breast reconstruction. STUDY DESIGN: An institutional database was constructed of patients who underwent autologous breast reconstruction from 1998 to 2005. Variables captured included age, diabetes and smoking status, prereconstruction radiation therapy, concomitant breast resection, preoperative albumin, flap type, and body mass index (BMI; based on World Health Organization classifications: BMI>25, overweight; >30, obese). The primary outcome was noninfectious wound complications (NIWC), a novel classification based on the extent of tissue derangement and need for operative intervention. Secondary outcomes were wound infection, hematoma, hernia, and fat necrosis. Statistical analysis was performed using chi-square tests and multiple logistic regression. RESULTS: The analysis included 200 flaps (transverse rectus abdominis myocutaneous [TRAM]=171; latissimus dorsi=29) in 180 patients. There were 19 infections (9.5%), 3 total flap losses (1.5%), 14 hematomas (7%), and 11 donor-site hernias (6%). The incidences of fat necrosis and any NIWC were 18% and 36%, respectively. Mean followup was 13.1 months (range 1.1 to 51.7 months). Multiple logistic regression demonstrated that obesity (BMI>30) is a statistically significant independent risk factor for any NIWC (hazards ratio=6.58; 95% CI, 2.85 to 15.18; p < 0.01) and for NIWC requiring operative treatment (NIWC>or=3; hazard ratio=6.23; 95% CI 2.15 to 18.05; p < 0.01). Increased BMI predicts NIWC, NIWC requiring operative intervention, and wound infection (p < 0.01). CONCLUSIONS: These data suggest that obesity is a strong predictor of simple and complex NIWC and of wound infection after autologous breast reconstruction. Obese patients should be counseled about their significantly increased risk of experiencing these unwanted outcomes.

Tibial artery calcification as a marker of amputation risk in patients with peripheral arterial disease.

OBJECTIVES: The purpose of this study was to evaluate the relationship between calcification in tibial arteries, the degree of limb ischemia, and the near-term risk of amputation. BACKGROUND: Determining the amputation risk in patients with peripheral arterial disease (PAD) remains difficult. Developing new measures to identify patients who are at high risk for amputation would allow for targeted interventions and focused trials aimed at limb preservation. METHODS: Two hundred twenty-nine patients underwent evaluation by history, arterial Doppler, and multislice computed tomography of the lower extremities. We then explored the relationship between a tibial artery calcification (TAC), traditional risk factors for PAD, limb status at presentation, and near-term amputation risk. RESULTS: Increased age and traditional atherosclerosis risk factors were associated with higher TAC scores. Patients with critical limb ischemia had the highest TAC scores, and increasing TAC scores were associated with worsening levels of limb ischemia in ordinal regression analysis. Receiver-operator characteristic analysis suggested that the TAC score predicted amputation better than the ankle-brachial index (ABI). Symptomatic patients with a TAC score greater than 400 had a significantly increased risk of amputation. In Cox regression analysis, there was a strong association between the TAC score and the risk of major amputation that remained after adjustment for traditional risk factors and the ABI. CONCLUSIONS: In patients presenting with PAD, the TAC score is associated with the stage of disease and it identifies those who are at high risk for amputation better than traditional risk factors and an abnormal ABI.