Effect of crutch and walking-boot use on whole-body angular momentum during gait.

Crutches are the most prescribed ambulatory assistive device and are used for mobility and maintaining weight-bearing restrictions after injury or surgery. However, standard axillary crutches (SACs) can lead to overuse and other injuries and restrict upper limb movement. Hands-free crutches (HFC) do not restrict upper limb movement but their effect on balance control, with or without commonly prescribed walking boots, is poorly understood. The purpose of this study was to compare the effect of crutch type (SACs vs. HFC) and boot use on whole-body angular momentum (RAM), a measure of balance control. Participant's balance confidence, pain, comfort, and device preference were assessed. Seventeen participants were evaluated while walking without a crutch (NONE), with SACs, and with an HFC, and walked with and without a walking boot in each crutch condition. The gait pattern used with SACs resulted in significantly greater limb angular velocity (p < .05), and an 84% increase in RAM (p < .001) as compared to the HFC. There were no differences between the SAC and HFC for balance confidence, pain, or comfort, however most (71.1%) participants preferred the HFCs. These results suggest that individuals can better control angular momentum with the HFCs and thus may be less susceptible to loss of balance.

Substantial Loss of Skeletal Muscle Mass Occurs After Femoral Fragility Fracture.

BACKGROUND: Femoral fragility fractures in older adults can result in devastating loss of physical function and independence. Skeletal muscle atrophy likely contributes to disability. The purpose of this study was to characterize the change in skeletal muscle mass, investigate the relationship with malnutrition and physical function, and identify risk factors for skeletal muscle loss. METHODS: Adults ≥65 years of age who were treated with operative fixation of an isolated femoral fragility fracture were enrolled in this multicenter, prospective observational study. Skeletal muscle mass was assessed within 72 hours of admission using multifrequency bioelectrical impedance analysis, which was repeated at 6 weeks, 3 months, and 6 months. Sarcopenia was defined by sex-specific cutoffs for the appendicular skeletal muscle mass index. The Mini Nutritional Assessment was used to measure nutritional status at the time of injury. Physical function was measured using the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function domain. Linear mixed models were used to evaluate changes in skeletal muscle mass and PROMIS Physical Function scores over time and to evaluate factors associated with skeletal muscle mass changes. RESULTS: Ninety participants (74% female) with a mean age of 77.6 ± 9.0 years were enrolled. At the time of injury, 30 (33%) were sarcopenic and 44 (49%) were at risk for malnutrition or had malnutrition. Older age was associated with lower skeletal muscle mass (age of ≥75 versus <75 years: least squares mean [and standard error], -3.3 ± 1.6 kg; p = 0.042). From the time of injury to 6 weeks, participants lost an average of 2.4 kg (9%) of skeletal muscle mass (95% confidence interval [CI] = ‒3.0 to ‒1.8 kg; p < 0.001). This early loss did not recover by 6 months (1.8 kg persistent loss compared with baseline [95% CI = ‒2.5 to ‒1.1 kg]; p < 0.001). Participants with normal nutritional status lost more skeletal muscle mass from baseline to 6 weeks after injury compared with those with malnutrition (1.3 kg more loss [standard error, 0.6 kg]; p = 0.036). A 1-kg decrease in skeletal muscle mass was associated with an 8-point decrease in the PROMIS Physical Function (model parameter estimate, 0.12 [standard error, 0.04]; p = 0.002). CONCLUSIONS: We found that older adults with femoral fragility fractures lost substantial skeletal muscle mass and physical function. Participants with adequate baseline nutrition actually lost more muscle mass than those who were malnourished, indicating that future investigations of interventions to prevent muscle loss should focus on older adults regardless of nutritional status. LEVEL OF EVIDENCE: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence.

Does tibialis posterior dysfunction correlate with a worse radiographic overall alignment in progressive collapsing foot deformity? A retrospective study.

BACKGROUND: Posterior Tibial Tendon (PTT) dysfunction is considered to have an important role in Progressive Collapsing Foot Deformity (PCFD). The objective of our study was to assess the relationship between PTT status and three-dimensional foot deformity in PCFD. METHODS: Records from 25 patients with PCFD were included for analysis. The PTT was considered deficient in patients with a positive single heel rise test or a deficit in inversion strength. Three-dimensional foot deformity was assessed using the Foot and Ankle Offset (FAO) from Weight-Bearing-CT imaging. Hindfoot valgus, midfoot abduction and medial longitudinal arch collapse were assessed on X-Rays using hindfoot moment arm, talonavicular coverage angle and Meary's angle respectively. Deland and Rosenberg MRI classifications were used to classify PTT degeneration. RESULTS: PCFD with PTT deficit (13/25) had a mean FAO of 7.75 + /- 3.8% whereas PCFD without PTT deficit had a mean FAO of 6.68 + /- 3.9% (p = 0.49). No significant difference was found between these groups on the hindfoot moment arm and the talonavicular coverage angle (respectively p = 0.54 and 0.32), whereas the Meary's angle was significantly higher in case of PCFD with PTT deficit (p = 0.037). No significant association was found between PTT degeneration on MRI and FAO. CONCLUSION: PCFD associated three-dimensional deformity, hindfoot valgus and midfoot abduction were not associated with PTT dysfunction. PTT dysfunction was only associated with a worse medial longitudinal arch collapse in our study. Considering our results, it does not appear that PTT is the main contributor to PCFD. LEVEL OF EVIDENCE: Level III, Retrospective Comparative Study.

Physical Performance Tests Correlate With Patient-reported Outcomes After Periacetabular Osteotomy: A Prospective Study.

INTRODUCTION: Individuals with hip dysplasia report significant functional disability that improves with periacetabular osteotomy (PAO). Four physical performance measures (PPMs) have been recently validated for use with nonarthritic hip conditions; however, their ability to detect functional improvement and correlate with improvements in popular hip-specific patient-reported outcome (PRO) instruments after PAO is unknown. The purpose of this study was to evaluate the responsiveness of four PPMs up to 1 year after PAO, compare PPMs with established PRO measures at these time points, and report the acceptability and utility of PPMs for assessing outcomes after PAO. METHODS: Twenty-two participants aged 15 to 39 years completed the timed stair ascent (TSA), sit-to-stand five times (STS5), self-selected walking speed, four-square-step test, and seven hip-specific PRO measures before surgery and at approximately 6 months and 1 year after PAO. They completed questions regarding acceptability and utility of both types of testing. Wilcoxon rank sum test and unpaired Student t-tests were used to assess differences between time points; Spearman correlation and generalized linear modeling were used to determine the relationship between PPMs and PRO measures. RESULTS: Six months after PAO, participants showed significant improvements on all seven PRO instruments (P < 0.001) and on the STS5 (P = 0.01). At one year, these improvements were maintained and TSA also improved (P = 0.03). Improvement in other PPMs did not reach significance (P = 0.07 and 0.08). The STS5 test demonstrated moderate to strong correlation (|r| = 0.43 to 0.76, P < 0.05) with all PRO measures, and the TSA test demonstrated moderate to strong correlation with almost all measures (|r| = 0.43 to 0.58, P < 0.05). Correlations strengthened on subanalysis of participants with unilateral disease (n = 11) (|r| = 0.56 to 0.94, P < 0.05). All participants (100%) found PPM testing acceptable despite disability; 25% preferred PPMs to PRO measures, whereas 75% of participants found them equal in usefulness. DISCUSSION: The STS5 and TSA tests demonstrated moderate to very strong correlation with PRO measures at six and 12 months after PAO for dysplasia. These tests could be used as a functional outcome to supplement PRO instruments after PAO.

Assessment of Disability Related to Hip Dysplasia Using Objective Measures of Physical Performance.

BACKGROUND: Lower extremity physical performance measures (PPMs), which can objectively quantify functional ability, are an attractive adjuvant to patient-reported outcome (PRO) instruments. However, few tests have been validated for use in hip instability. PURPOSE: To evaluate 4 different PPMs for their ability to differentiate between young adults with hip dysplasia indicated for treatment with periacetabular osteotomy (PAO) and asymptomatic controls and to test inter- and intratest reliability and relationship with popular hip PRO instruments. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: A total of 24 symptomatic patients aged 15 to 39 years (100% female) with hip dysplasia (lateral center-edge angle <25°) indicated for treatment with PAO completed the visual analog scale (VAS) for pain, Hip disability and Osteoarthritis Outcome (HOOS) Pain subscale, HOOS Short Version (HOOS PS), International Hip Outcome Tool Short Version (iHOT-12), modified Harris Hip Score (mHHS), Patient Reported Outcome Measurement Information System (PROMIS) physical function (PF) and pain interference (PI), and 4 physical function tests: (1) self-selected walking speed (SSWS), sit-to-stand 5 times (STS5), (3) 4-square step test (FSST), and (4) timed stair ascent (TSA). A further 21 young, asymptomatic adults aged 18 to 39 years (91% female) also underwent testing. Between-group comparisons were made with unpaired t test with Bonferroni-Holm correction. Inter- and intrarater reliability was assessed in 38 participants by repeating PPMs at a second visit and using 2 raters. Spearman rank correlation coefficients were used to determine associations between PPMs and PRO instruments. RESULTS: Significant differences between patients with hip dysplasia and controls were observed for all PRO instruments (HOOS Pain, 47.8 vs 99.2; HOOS PS, 61.9 vs 99.2; iHOT-12, 32.2 vs 99.2; mHHS, 54.5 vs 90.6; PROMIS PF, 41.4 vs 65.6; and PROMIS PI, 62.0 vs 39.1 [all P < .001]), and all PPMs (SSWS, 1.21 vs 1.53 m/s; STS5, 10.85 vs 5.95 s; FSST, 6.59 vs 4.03 s [all P < .001]; and TSA, 4.58 vs 3.29 s [P = .002]). All 4 PPMs demonstrated excellent intra- and intertest reliability (intraclass correlation coefficient, 0.83-0.99). STS5, FSST, and TSA were correlated highly (r > 0.5) with physical function PRO instruments, including PROMIS PF, mHHS, and iHOT-12. CONCLUSION: Patients with symptomatic hip dysplasia demonstrated significant impairment on functional testing compared with asymptomatic controls, and performance measure testing demonstrated excellent test-retest reliability. Timed stair ascent and sit-to-stand testing in particular were correlated strongly with physical function PRO instruments. PPMs may be a viable and well-received adjuvant to PRO instrument administration for patients with nonarthritic hip conditions, and investigation of the ability of PPMs to assess surgical outcomes for hip dysplasia is warranted.

Local Anesthetic Injection Resolves Movement Pain, Motor Dysfunction, and Pain Catastrophizing in Individuals With Chronic Achilles Tendinopathy: A Nonrandomized Clinical Trial.

OBJECTIVES: Peripherally directed treatments (targeted exercise, surgery) can reduce, but not fully eliminate, pain for up to 40% of patients with Achilles tendinopathy. The objectives of the present study were (1) to identify indicators of altered central processing in participants with Achilles tendinopathy compared to controls, and (2) to determine which indicators of altered central processing would persist after a local anesthetic injection in patients with Achilles tendinopathy. DESIGN: Mechanistic clinical trial. METHODS: Forty-six adults (23 with chronic Achilles tendinopathy, 23 matched controls) repeated (1) a movement-evoked pain rating, (2) motor performance assessment, (3) pain psychology questionnaires, and (4) quantitative sensory testing. Participants with Achilles tendinopathy received a local anesthetic injection before repeat testing and controls did not. Mixed-effects analyses of variance examined the effects of group, time, and group by time. RESULTS: The Achilles tendinopathy group had movement-evoked pain, motor dysfunction, and higher pain psychological factors (pain catastrophizing, kinesiophobia) compared to controls (P<.05). The Achilles tendinopathy group did not have indicators of nociplastic pain with quantitative sensory testing (P>.05). In those with Achilles tendinopathy, local anesthetic injection eliminated pain and normalized the observed deficits in heel-raise performance and pain catastrophizing (group-by-time effect, P<.01), but not in kinesiophobia (P = .45). Injection did not affect measures of nociplastic pain (P>.05). CONCLUSION: People with Achilles tendinopathy had elevated pain psychological factors and motor dysfunction but no signs of nociplastic pain with quantitative sensory testing. Removal of nociceptive input normalized movement-evoked pain and some indicators of altered central processing (motor dysfunction, pain catastrophizing), but not kinesiophobia. J Orthop Sports Phys Ther 2020;50(6):334-343. Epub 29 Apr 2020. doi:10.2519/jospt.2020.9242.

Severe Lung Injury Associated With Use of e-Cigarette, or Vaping, Products-California, 2019.

Importance: Since August 2019, more than 2700 patients have been hospitalized with e-cigarette, or vaping, product use-associated lung injury (EVALI) across the United States. This report describes the outbreak in California, a state with one of the highest case counts and with a legal adult-use (recreational) cannabis market. Objective: To present clinical characteristics and vaping product exposures of patients with EVALI in California. Design, Setting, and Participants: Case series describing epidemiologic and laboratory data from 160 hospitalized patients with EVALI reported to the California Department of Public Health by local health departments, who received reports from treating clinicians, from August 7 through November 8, 2019. Exposures: Standardized patient interviews were conducted to assess vaping products used, frequency of use, and method of product acquisition. Vaping products provided by a subset of patients were tested for active ingredients and other substances. Main Outcomes and Measures: Demographic and clinical characteristics, level of care, and outcomes of hospitalization were obtained from medical record review. Results: Among 160 patients with EVALI, 99 (62%) were male, and the median age was 27 years (range, 14-70 years). Of 156 patients with data available, 71 (46%) were admitted to an intensive care unit, and 46 (29%) required mechanical ventilation. Four in-hospital deaths occurred. Of 86 patients interviewed, 71 (83%) reported vaping tetrahydrocannabinol (THC)-containing products, 36 (43%) cannabidiol (CBD)-containing products, and 39 (47%) nicotine-containing products. Sixty-five of 87 (75%) THC-containing products were reported as obtained from informal sources, such as friends, acquaintances, or unlicensed retailers. Of 87 vaping products tested from 24 patients, 49 (56%) contained THC. Vitamin E or vitamin E acetate was found in 41 (84%) of the THC-containing products and no nicotine products. Conclusions and Relevance: Patients' clinical outcomes and vaping behaviors, including predominant use of THC-containing products from informal sources, are similar to those reported by other states, despite California's legal recreational cannabis market. While most THC products tested contained vitamin E or vitamin E acetate, other underlying cause(s) of injury remain possible. The California Department of Public Health recommends that individuals refrain from using any vaping or e-cigarette products, particularly THC-containing products from informal sources, while this investigation is ongoing.

Multisite Evaluation of a Custom Energy-Storing Carbon Fiber Orthosis for Patients with Residual Disability After Lower-Limb Trauma.

BACKGROUND: The Intrepid Dynamic Exoskeletal Orthosis (IDEO) is a custom energy-storing carbon fiber ankle-foot orthosis developed for lower-extremity trauma patients. Studies conducted at the military treatment facility where the IDEO was developed demonstrated benefits of the IDEO when used with the Return to Run Physical Therapy (RTR PT) program. The current study was designed to determine if results could be replicated at other military treatment facilities and to examine whether early performance gains in patient-reported functional outcomes remained at 12 months. METHODS: Study participants included service members who had functional deficits that interfered with daily activities at least 1 year after a traumatic unilateral lower-extremity injury at or below the knee. Participants were evaluated before receiving the IDEO, immediately following completion of RTR PT, and at 6 and 12 months. Agility, strength/power, and speed were assessed using well-established performance tests. Self-reported function was measured using the Short Musculoskeletal Function Assessment (SMFA). The Orthotics and Prosthetics Users' Survey was administered to assess satisfaction with the IDEO. Of 87 participants with complete baseline data, 6 did not complete any physical therapy and were excluded from the analysis. Follow-up rates immediately following completion of the RTR PT and at 6 and 12 months were 88%, 75%, and 79%, respectively. RESULTS: Compared with baseline, improvement at completion of RTR PT was observed in all but 1 performance test. SMFA scores for all domains except hand and arm function were lower (improved function) at 6 and 12 months. Satisfaction with the IDEO was high following completion of RTR PT, with some attenuation at the time of follow-up. CONCLUSIONS: This study adds to the evidence supporting the efficacy of the IDEO coupled with RTR PT. However, despite improvement in both performance and self-reported functioning, deficits persist compared with population norms. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The influence of limb alignment and transfemoral amputation technique on muscle capacity during gait.

Many factors influence successful outcomes following transfemoral amputation. One factor is surgical technique. In this study, the influence of limb alignment and surgical technique on a muscle's capacity to generate force was examined using musculoskeletal modeling. Non-amputee and transfemoral amputee models were analyzed while hip adduction, femur length, and reattached muscle wrap position, tension and stabilization technique were systematically varied. With muscle tension preserved, wrap position and femur length had little influence on muscle capacity. However, limb alignment, muscle tension and stabilization technique notably influenced muscle capacity. Overall, myodesis stabilization provided greater muscle balance and function than myoplasty stabilization.

Gait biomechanics following lower extremity trauma: Amputation vs. reconstruction.

BACKGROUND: Surgical advances have substantially improved outcomes for individuals sustaining traumatic lower extremity injury. Injuries once requiring lower limb amputation are now routinely managed with limb reconstruction surgery. However, comparisons of functional outcomes between the procedures are inconclusive. PURPOSE: To compare gait biomechanics after lower limb reconstruction and transtibial amputation. METHODS: Twenty-four individuals with unilateral lower limb reconstruction wearing a custom ankle-foot orthosis (Intrepid Dynamic Exoskeletal Orthosis), 24 with unilateral, transtibial amputation, and 24 able-bodied control subjects underwent gait analysis at a standardized Froude speed based on leg length. Lower extremity joint angles, moments, and powers, and ground reaction forces were analyzed on the affected limb of patients and right limb of able-bodied individuals. ANOVA with Tukeys post-hoc tests determined differences among groups and post-hoc paired t-tests with Bonferroni-Holm corrections determined differences between limbs. RESULTS: The ankle, knee, and hip exhibited significant kinematic differences between amputated, reconstructed and able-bodied limbs. The reconstruction group exhibited less ankle power and range of motion while the amputee group exhibited lower knee flexor and extensor moments and power generation. CONCLUSION: Gait deficiencies were more pronounced at the ankle following limb reconstruction with orthosis use and at the knee following transtibial amputation with prosthesis use. Although both groups in the cohorts tested can replicate many key aspects of normative gait mechanics, some deficiencies still persist. These results add to the growing body of literature comparing amputation and limb reconstruction and provide information to inform the patient on functional expectations should either procedure be considered.

Blood Flow Restriction Training After Knee Arthroscopy: A Randomized Controlled Pilot Study.

INTRODUCTION: Quadriceps strength after arthroscopic knee procedures is frequently diminished several years postoperation. Blood flow restriction (BFR) training uses partial venous occlusion while performing submaximal exercise to induce muscle hypertrophy and strength improvements. The purpose of this study was to evaluate BFR as a postoperative therapeutic intervention after knee arthroscopy. METHODS: A randomized controlled pilot study comparing physical therapy with and without BFR after knee arthroscopy was conducted. Patients underwent 12 sessions of supervised physical therapy. Subjects followed the same postoperative protocol with the addition of 3 additional BFR exercises. Outcome measures included thigh girth, physical function measures, Knee Osteoarthritis Outcome Score (KOOS), Veterans RAND 12-Item Health Survey (VR12), and strength testing. Bilateral duplex ultrasonography was used to evaluate for deep venous thrombosis preintervention and postintervention. RESULTS: Seventeen patients completed the study. Significant increases in thigh girth were observed in the BFR group at 6-cm and 16-cm proximal to the patella (P = 0.0111 and 0.0001). All physical outcome measures significantly improved in the BFR group, and the timed stair ascent improvements were greater than conventional therapy (P = 0.0281). The VR-12 and KOOS subscales significantly improved in the BFR group, and greater improvement was seen in VR-12 mental component score (P = 0.0149). The BFR group displayed approximately 2-fold greater improvements in extension and flexion strength compared with conventional therapy (74.59% vs 33.5%, P = 0.034). No adverse events were observed during the study. CONCLUSIONS: This study suggests that BFR is an effective intervention after knee arthroscopy. Further investigation is warranted to elucidate the benefits of this intervention in populations with greater initial impairment.

Assessment of emergency responders after a vinyl chloride release from a train derailment - New Jersey, 2012.

On November 30, 2012, at approximately 7:00 am, a freight train derailed near a small town in New Jersey. Four tank cars, including a breached tank car carrying vinyl chloride, landed in a tidal creek. Vinyl chloride, a colorless gas with a mild, sweet odor, is used in plastics manufacture. Acute exposure can cause respiratory irritation and headache, drowsiness, and dizziness; chronic occupational exposure can result in liver damage, accumulation of fat in the liver, and tumors (including angiosarcoma of the liver). Because health effects associated with acute exposures have not been well studied, the New Jersey Department of Health requested assistance from the Agency for Toxic Substances and Disease Registry (ATSDR) and CDC. On December 11, teams from these agencies deployed to assist the New Jersey Department of Health in conducting an assessment of exposures in the community as well as the occupational health and safety of emergency personnel who responded to the incident. This report describes the results of the investigation of emergency personnel. A survey of 93 emergency responders found that 26% of respondents experienced headache and upper respiratory symptoms during the response. A minority (22%) reported using respiratory protection during the incident. Twenty-one (23%) of 92 respondents sought medical evaluation. Based on these findings, CDC recommended that response agencies 1) implement the Emergency Responder Health Monitoring and Surveillance (ERHMS) system for ongoing health monitoring of the emergency responders involved in the train derailment response and 2) ensure that in future incidents, respiratory protection is used when exposure levels are unknown or above the established occupational exposure limits.

How does ankle-foot orthosis stiffness affect gait in patients with lower limb salvage?

BACKGROUND: Ankle-foot orthoses (AFOs) are commonly prescribed during rehabilitation after limb salvage. AFO stiffness is selected to help mitigate gait deficiencies. A new custom dynamic AFO, the Intrepid Dynamic Exoskeletal Orthosis (IDEO), is available to injured service members but prescription guidelines are limited. QUESTIONS/PURPOSES: In this study we ask (1) does dynamic AFO stiffness affect gait parameters such as joint angles, moments, and powers; and (2) can a given dynamic AFO stiffness normalize gait mechanics to noninjured control subjects? METHODS: Thirteen patients with lower limb salvage (ankle arthrodesis, neuropathy, foot/ankle reconstruction, etc) after major lower extremity trauma and 13 control subjects who had no lower extremity trauma and wore no orthosis underwent gait analysis at a standardized speed. Patients wore their custom IDEO with posterior struts of three different stiffnesses: nominal (clinically prescribed stiffness), compliant (20% less stiff), and stiff (20% stiffer). Joint angles, moments, powers, and ground reaction forces were compared across the varying stiffnesses of the orthoses tested and between the patient and control groups. RESULTS: An increase in AFO compliance resulted in 20% to 26% less knee flexion relative to the nominal (p = 0.003) and stiff (p = 0.001) conditions, respectively. Ankle range of motion and power generation were, on average, 56% (p < 0.001) and 63% (p < 0.001), respectively, less than controls as a result of the relatively fixed ankle position. CONCLUSIONS: Patients with limb salvage readily adapted to different dynamic AFO stiffnesses and demonstrated few biomechanical differences among conditions during walking. None of the stiffness conditions normalized gait to controls. CLINICAL RELEVANCE: The general lack of differences across a 40% range of strut stiffness suggests that orthotists do not need to invest large amounts of time identifying optimal device stiffness for patients who use dynamic AFOs for low-impact activities such as walking. However, choosing a stiffer strut may more readily translate to higher-impact activities and offer less chance of mechanical failure.

Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab.

Soluble epidermal growth factor receptor (sEGFR) is a circulating serum biomarker in cancer patients. Recent studies suggest that baseline serum sEGFR concentrations may predict responsiveness to EGFR-targeted therapy. Here, we demonstrate that sEGFR is generated through proteolytic cleavage of a cell surface precursor of an alternately spliced EGF receptor isoform and that sEGFR binds to EGF with high affinity. Proteolytic cleavage is stimulated by an anti-α5/ß1 integrin antibody and 4-aminophenylmercuric acetate, and inhibited by fibronectin. Two FDA-approved therapeutic anti-EGFR antibodies also inhibit shedding of sEGFR, thus implicating the cell surface precursor of sEGFR as a competing target for anti-EGFR antibodies in human tissues. These observations parallel trastuzumab regulation of HER2 shedding and have implications for patient stratification in future clinical trials of EGFR-targeted antibodies.

A phase II evaluation of gefitinib in the treatment of persistent or recurrent endometrial cancer: a Gynecologic Oncology Group study.

BACKGROUND: A phase II trial was performed to evaluate the efficacy and safety of gefitinib in patients with persistent/recurrent endometrial cancer. METHODS: Women with histologically confirmed persistent/recurrent endometrial cancer were treated with 500mg oral gefitinib daily until progression or severe toxicity, with progression-free survival (PFS) at six months as the primary endpoint. Tumor expression of total epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor A (PRA) and B (PRB), Ki67, pEGFR and activated extracellular signal-regulated kinase (pERK) were examined pre- and post-treatment. EGFR was sequenced, and serum concentrations of soluble EGFR (sEGFR) at baseline also were examined. RESULTS: Of 29 patients enrolled, 26 were evaluable for efficacy and toxicity. Four patients experienced PFS ≥6 months, and one had a complete response which was not associated with an EGFR mutation. The concentration of sEGFR in pretreatment serum was positively correlated with overall survival (OS), but not with responsiveness to gefitinib in this small patient cohort. Expression of tumor biomarkers was not associated with PFS or OS. Co-expression of ER with PRA in primary and recurrent tumors, and pEGFR with pERK in primary tumors was observed. CONCLUSIONS: This treatment regimen was tolerable but lacked sufficient efficacy to warrant further evaluation in this setting. The possible association between serum sEGFR concentrations and OS, and temporal changes in expression of pEGFR and pERK and the documented CR of one patient are interesting and warrant additional investigation.

A comparison of limb-socket kinematics of bone-bridging and non-bone-bridging wartime transtibial amputations.

BACKGROUND: While there are proponents of both bone-bridging and non-bone-bridging transtibial amputation techniques, there is a lack of evidence describing functional differences between these two techniques. The goal of the present investigation was to objectively compare the techniques of bone-bridging and non-bone-bridging with respect to limb socket displacement during physiologic loading. METHODS: Fifteen male subjects with an average age of twenty-seven years (range, twenty-two to thirty-two years) who had undergone a unilateral transtibial amputation secondary to a traumatic wartime injury were prospectively evaluated. Seven patients had undergone a bone-bridging amputation, and eight had undergone a non-bone-bridging amputation. Digital fluoroscopic video was used to measure the vertical displacement of the limb within a total-surface-bearing socket with weight-bearing from 0% to 100% of body weight. RESULTS: There was no difference in limb-socket displacement between amputation techniques with initial loading (12.78 mm for the bone-bridging group, compared with 12.43 mm for the non-bone-bridging group; p = 0.88) or with total loading (p = 0.98). Similarly, there was no difference between suspension mechanisms in limb-socket displacement with initial loading (12.15 mm for patients with pin lock suspension, compared with 12.98 mm for those with suction sleeve suspension; p = 0.72) or with total loading (18.24 mm for patients with pin lock suspension, compared with 21.42 mm for those with suction sleeve suspension, p = 0.21). CONCLUSIONS: The current study demonstrated no difference between surgical techniques with respect to bone-socket displacement. These data provide no evidence to support statements that bone-bridging contributes to a more efficient platform in the total-surface-bearing socket.

EGFR/HER-targeted therapeutics in ovarian cancer.

Despite decades of research and evolving treatment modalities, survival among patients with epithelial ovarian cancer has improved only incrementally. During this same period, the development of biologically targeted therapeutics has improved survival for patients with diverse malignancies. Many of these new drugs target the human epidermal growth factor receptor (EGFR/HER/ErbB) family of tyrosine kinases, which play a major role in the etiology and progression of many carcinomas, including epithelial ovarian cancer. While several HER-targeted therapeutics are US FDA approved for the treatment of various malignancies, none have gained approval for the treatment of ovarian cancer. Here, we review the published literature on HER-targeted therapeutics for the treatment of ovarian cancer, including novel HER-targeted therapeutics in various stages of clinical development, as well as the challenges that have limited the use of these inhibitors in clinical settings.

Comparative effect of orthosis design on functional performance.

BACKGROUND: High-energy extremity trauma is common in combat. Orthotic options for patients whose lower extremities have been salvaged are limited. A custom energy-storing ankle-foot orthosis, the Intrepid Dynamic Exoskeletal Orthosis (IDEO), was created and used with high-intensity rehabilitation as part of the Return to Run clinical pathway. We hypothesized that the IDEO would improve functional performance compared with a non-custom carbon fiber orthosis (BlueRocker), a posterior leaf spring orthosis, and no brace. METHODS: Eighteen subjects with unilateral dorsiflexion and/or plantar flexion weakness were evaluated with six functional tests while they were wearing the IDEO, BlueRocker, posterior leaf spring, or no brace. The brace order was randomized, and five trials were completed for each of the functional measures, which included a four-square step test, a sit-to-stand five times test, tests of self-selected walking velocity over level and rocky terrain, and a timed stair ascent. They also completed one trial of a forty-yard (37-m) dash, filled out a satisfaction questionnaire, and indicated whether they had ever considered an amputation and, if so, whether they still intended to proceed with it. RESULTS: Performance was significantly better with the IDEO with respect to all functional measures compared with all other bracing conditions (p < 0.004), with the exception of the sit-to-stand five times test, in which there was a significant improvement only as compared with the BlueRocker (p = 0.014). The forty-yard dash improved by approximately 35% over the values for the posterior leaf spring and no-brace conditions, and by 28% over the BlueRocker. The BlueRocker demonstrated a significant improvement in the forty-yard dash compared with no brace (p = 0.033), and a significant improvement in self-selected walking velocity on level terrain compared with no brace and the posterior leaf spring orthosis (p < 0.028). However, no significant difference was found among the posterior leaf spring, BlueRocker, and no-brace conditions with respect to any other functional measure. Thirteen patients initially considered amputation, but after completion of the clinical pathway, eight desired limb salvage, two were undecided, and three still desired amputation. CONCLUSIONS: Use of the IDEO significantly improves performance on validated tests of agility, power, and speed. The majority of subjects initially considering amputation favored limb salvage after this noninvasive intervention.

Identification of immunoreactive regions of homology between soluble epidermal growth factor receptor and α5-integrin.

Proteins encoded by the epidermal growth factor receptor (EGFR/HER1/ERBB1) gene are being studied as diagnostic, prognostic, and theragnostic biomarkers for numerous human cancers. The clinical application of these tissue/tumor biomarkers has been limited, in part, by discordant results observed for epidermal growth factor receptor (EGFR) expression using different immunological reagents. Previous studies have used EGFR-directed antibodies that cannot distinguish between full-length and soluble EGFR (sEGFR) expression. We have generated and characterized an anti-sEGFR polyclonal antiserum directed against a 31-mer peptide (residues 604-634) located within the unique 78-amino acid carboxy-terminal sequence of sEGFR. Here, we use this antibody to demonstrate that sEGFR is coexpressed with EGFR in a number of carcinoma-derived cell lines. In addition, we show that a second protein of ~140 kDa (p140) also is detected by this antibody. Rigorous biochemical characterization identifies this second protein to be α5-integrin. We show that a 26-amino acid peptide in the calf domain of α5-integrin (residues 710-735) is 35% identical in sequence with a 31-mer carboxy-terminal sEGFR peptide and exhibits an approximately 5-fold lower affinity for anti-sEGFR than the homologous 31-mer sEGFR peptide does. We conclude that the carboxy terminus of sEGFR and the calf-1 domain of α5-integrin share a region of sequence identity, which results in their mutual immunological reactivity with anti-sEGFR. We also demonstrate that anti-sEGFR promotes three-dimensional tissue cohesion and compaction in vitro, further suggesting a functional link between sEGFR and α5-integrin and a role of the calf-1 domain in cell adhesion. These results have implications for the study of both EGFR and sEGFR as cancer biomarkers and also provide new insight into the mechanisms of interaction between cell surface EGFR isoforms and integrins in complex processes such as cell adhesion and survival signaling.