A phase I/IIa clinical trial of a recombinant Rho protein antagonist in acute spinal cord injury

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(?)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or cervical (C4-T1) SCI were sequentially recruited for this dose-ranging (0.3?mg to 9?mg Cethrin), multi-center study of 48 patients with complete American Spinal Injury Association assessment (ASIA) A. Vital signs; clinical laboratory tests; computed tomography (CT) scans of the spine, head, and abdomen; magnetic resonance imaging (MRI) of the spine, and ASIA assessment were performed in the pre-study period and in follow-up periods out to 1 year after treatment. The treatment-emergent adverse events that were reported were typical for a population of acute SCI patients, and no serious adverse events were attributed to the drug. The pharmacokinetic analysis showed low levels of systemic exposure to the drug, and there was high inter-patient variability. Changes in ASIA motor scores from baseline were low across all dose groups in thoracic patients (1.8±5.1) and larger in cervical patients (18.6±19.3). The largest change in motor score was observed in the cervical patients treated with 3?mg of Cethrin in whom a 27.3±13.3 point improvement in ASIA motor score at 12 months was observed. Approximately 6% of thoracic patients converted from ASIA A to ASIA C or D compared to 31% of cervical patients and 66% for the 3-mg cervical cohort. Although the patient numbers are small, the observed motor recovery in this open-label trial suggests that BA-210 may increase neurological recovery after complete SCI. Further clinical trials with Cethrin in SCI patients are planned, to establish evidence of efficacy.     

Neuroendocrine tumors of the rectum: a 10-year review of management

Neuroendocrine tumors of the rectum constitute approximately 19 per cent of gastrointestinal neuroendocrine tumors (NETs). The histologic characteristics of the tumor seem to be an indicative prognostic factor. Optimal treatment of NETS of the rectum has been widely debated, but more recent studies suggest that treatment depends upon the size. The medical records of 37 patients with NETS of the rectum were retrospectively reviewed. We reviewed their presentation, surgical treatment, pathology, and outcome. All pathological specimens were reviewed. Neuroendocrine tumors of the rectum were classified as either well-differentiated tumors, well-differentiated neuroendocrine carcinoma, or poorly differentiated neuroendocrine carcinoma. Evaluating tumor size, we found 35/37 patients had tumors less than 1 cm, 1 patient had a tumor between 1 and 2 cm, and one had a tumor greater than 2 cm. Pathologic evaluation of the tumors revealed that 35 of the tumors invaded the submucosa only, one invaded the muscularis propria, and one invaded the perirectal adipose tissue. The histopathologic features of the tumors revealed that 34 of the tumors were well-differentiated NETS with benign features, one tumor had invaded the submucosa, with angioinvasion, and two tumors were neuroendocrine carcinoma. Thirty-five patients underwent local excision. Eleven had reexcisions for positive margins. Two patients had local excision for recurrence, and one patient underwent low anterior resection (4 cm). Twelve patients had negative margins, 25 had positive margins. Eleven patients underwent reexcision. Six had no evidence of residual disease, and five had persistent positive margins and were offered no further treatment. Nineteen patients had positive margins and did not have reexcision. They all had tumors < 1 cm. Despite half of the lesions being resected with final pathologic positive margins, we have seen no significant influence on recurrence or overall survival. This raises the question of margin clearance in early lesions.     

Closed midshaft femur fractures: are they only for trauma centers?

Trauma centers are limited resources, particularly in rural areas, and availability of emergency care in some parts of the United States may be inadequate. The declining number of orthopedic surgeons willing to care for injured patients has limited access to fracture repair in some communities. We studied the management of closed midshaft femur fractures in both trauma centers (TCs) and nontrauma centers (NTCs) to evaluate outcome for this common orthopedic injury and determine if these issues have affected fracture care in Kentucky. All patients 16-years-old and older who suffered femur fractures in Kentucky from 2004 and 2005 were identified. There were 334 TC patients and 341 NTC patients with closed, midshaft femur fractures. The mean age of TC patients (33 ± 17 years) was significantly lower than that of NTC patients (59 ± 25 years). TC patients were more likely men (71% vs 44%), had more associated injuries (2.4 ± 2.1 vs 0.5 ± 1.2), and had longer lengths of stay (8.3 ± 9.8 vs 6.4 ± 7.1 days) (TCs vs NTCs, all P < 0.005). Although both groups ultimately underwent internal fixation (97% vs 99%, TCs vs NTCs), TC patients were more likely (2.7% vs 0.3%) to receive external fixation than the NTC patients (P < 0.05). There was no significant difference in the percentage of patients that received only a closed reduction. There was no significant difference in hospital mortality (0.3% vs 0.9%, TCs vs NTCs, P = 0.62). Although differences in patient populations exist between TCs and NTCs, both TCs and NTCs manage substantial numbers of patients with closed, midshaft femur fractures with low mortality in this state database.     

Individualized functional restoration as an adjunct to advice for lumbar disc herniation with associated radiculopathy. A preplanned subgroup analysis of a randomized controlled trial

Background Context

Physical therapy is commonly sought by people with lumbar disc herniation and associated radiculopathy. It is unclear whether physical therapy is effective for this population.

Prevalence,Risk Factors,and Management of Proximal Femoral Remodeling in Revision Hip Arthroplasty

The prevalence of, risk factors, and management of proximal femoral remodeling in revision total hip arthroplasty is unknown. Therefore, we reviewed the files of 200 consecutive femoral revision arthroplasties to study this phenomenon. Remodeling was considered present if a properly sized diaphyseal-engaging acrylic template had appropriate distal canal fill but lied within 2 mm of the proximal lateral endosteal cortex (definition 1) or completely outside the femoral canal (definition 2) on anteroposterior femoral radiographs. The prevalence of remodeling was 42% by definition 1 and 21% by definition 2. The strongest risk factors were loose femoral components and more severe femoral bone loss. Orthopedic surgeons performing revision arthroplasty should be prepared to encounter remodeling as its presence can complicate femoral component revision.     

Isolated Transcalcaneal Talonavicular Dislocation: A Severe Injury Related to a Low-energy Mechanism

Transcalcaneal talonavicular dislocation is a rare injury, with very few reported cases. Of these, most have been the result of high-energy mechanisms such as road traffic collisions or falls from a height. The management of this injury is challenging, and treatment is fraught with a high rate of disability, infection, and amputation. We describe the successful management of the first reported case of a low-energy transcalcaneal talonavicular dislocation in a 71-year-old female. Combined external and internal fixation was used to reduce and maintain the injury, with a resultant good functional and complication-free outcome at 1 year after the injury. Our experience highlights the prevalence of these devastating injuries caused by relatively benign mechanisms in an increasingly older population with osteoporotic bone. It also indicates that operative stabilization of a low-energy injury can be more successful than that with the traditional high-velocity trauma.     

Urothelial carcinoma at the uretero-enteric junction: Multi-center evaluation of oncologic outcomes after radical nephroureterectomy

ObjectiveThe natural history of urothelial carcinoma arising at the uretero-enteric junction (UEJ) is poorly defined, and the data guiding clinical management of these patients is limited. Therefore, we evaluated oncologic outcomes of patients treated for urothelial carcinoma at the UEJ.MethodsUtilizing a multi-institutional database of patients treated with radical nephroureterectomy (RNU), we assessed the clinicopathologic parameters and oncologic outcomes of UEJ tumors compared with other upper tract urothelial carcinomas (UTUC). Survival analyses were performed to determine independent predictors of disease recurrence and cancer-specific mortality after RNU.ResultsThe study included 1,363 patients, 921 men and 442 women with 36 months median follow-up after RNU. Compared with UTUC in the kidney or ureter, UEJ tumors (n = 22) were more likely to demonstrate features of advanced disease, which were proved to be independent predictors of disease recurrence and cancer-specific mortality after RNU. The 5 year disease-free survival (DFS) and cancer-specific survival (CSS) rates were 25% and 39% in those with UEJ tumors vs. 69% and 73% in those with UTUC in the kidney or ureter (P = 0.001 and P = 0.008, respectively).ConclusionsUEJ tumors harbor features of locally advanced disease associated with high risk of systemic recurrence and death from cancer after RNU. Our findings suggest the need for integration of systemic therapy into the management paradigm of these patients.     

Utilizing milk from pooling facilities as a novel approach for foot‐and‐mouth disease surveillance

This study investigated the potential of pooled milk as an alternative sample type for foot‐and‐mouth disease (FMD) surveillance. Real‐time RT‐PCR (rRT‐PCR) results of pooled milk samples collected weekly from five pooling facilities in Nakuru County, Kenya, were compared with half‐month reports of household‐level incidence of FMD. These periodic cross‐sectional surveys of smallholder farmers were powered to detect a threshold household‐level FMD incidence of 2.5% and collected information on trends in milk production and sales. FMD virus (FMDV) RNA was detected in 9/219 milk samples, and using a type‐specific rRT‐PCR, serotype SAT 1 was identified in 3/9 of these positive samples, concurrent with confirmed outbreaks in the study area. Four milk samples were FMDV RNA‐positive during the half‐months when at least one farmer reported FMD; that is, the household‐level clinical incidence was above a threshold of 2.5%. Additionally, some milk samples were FMDV RNA‐positive when there were no reports of FMD by farmers. These results indicate that the pooled milk surveillance system can detect FMD household‐level incidence at a 2.5% threshold when up to 26% of farmers contributed milk to pooling facilities, but perhaps even at lower levels of infection (i.e., below 2.5%), or when conventional disease reporting systems fail. Further studies are required to establish a more precise correlation with estimates of household‐level clinical incidence, to fully evaluate the reliability of this approach. However, this pilot study highlights the potential use of this non‐invasive, routinely collected, cost‐effective surveillance tool, to address some of the existing limitations of traditional surveillance methods.