Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Hypoxaemia during open-airway apnoea: a computational modelling analysis.

Hypoxaemia during open-airway apnoea, e.g. during brainstem death testing, may cause organ damage. The effect of ambient oxygen fraction on the extent of hypoxaemia has not been established. We validated the Nottingham Physiology Simulator in this context by reproducing the methodologies and results of four published clinical studies. We then used the simulator to examine the effects of different ambient oxygen fractions (0.21-1.0) and shunt fractions (1-30% of cardiac output) during apnoea. Increasing ambient oxygen fraction from 0.9 to 1.0 more than doubled the time to haemoglobin desaturation at all shunt fractions, and extended apnoea longer than when the ambient oxygen fraction was increased from 0.21 to 0.9. When ambient oxygen fraction and shunt fraction were large, arterial oxygen tension transiently increased during apnoea. A very high ambient oxygen fraction and a patent airway are likely to delay dangerous hypoxaemia during apnoea.

The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.

To assess the influence of the presenilin 1 (PS1) and 2 (PS2) mutations on amyloid deposition, neurofibrillary tangle (NFT) formation and neuronal loss, we performed stereologically based counts in a high-order association cortex, the superior temporal sulcus, of 30 familial Alzheimer's disease cases carrying 10 different PS1 and PS2 mutations, 51 sporadic Alzheimer's disease cases and 33 non-demented control subjects. All the PS1 and PS2 mutations assessed in this series led to enhanced deposition of total Abeta and Abeta(x-42/43) but not Abeta(x-40) senile plaques in the superior temporal sulcus when compared with brains from sporadic Alzheimer's disease patients. Some of the PS1 mutations studied (M139V, I143F, G209V, R269H, E280A), but not others, were also associated with faster rates of NFT formation and accelerated neuronal loss in the majority of the patients who harboured them when compared with sporadic Alzheimer's disease patients. In addition, our analysis showed that dramatic quantitative differences in clinical and neuropathological features can exist even among family members with the identical PS mutation. This suggests that further individual or pedigree genetic or epigenetic factors are likely to modulate PS phenotypes strongly.

Risk factors associated with methicillin-resistant staphylococcal wound infection after spinal surgery.

We used the data from a retrospective case controlled study to identify risk factors for methicillin-resistant staphylococcal wound infection after spinal surgery. Thirty-five cases and 35 uninfected control patients were matched for indication for initial surgery and approximate operative date. Preoperative, intraoperative, and postoperative risk factors were examined. At our institution between 1989 and 1995, 35 adult patients developed spinal wound infection requiring operative debridement; 16 infections were caused by methicillin-resistant staphylococci (MRS). Significant risk factors for MRS infection were lymphopenia, history of chronic infections, alcohol abuse, recent hospitalization, and prolonged postoperative wound drainage. Patients with MRS infections were also somewhat less likely to have received vancomycin prophylaxis. In contrast, the only factor associated with infection caused by other pathogens was alcohol abuse. A number of preoperative risk factors were significantly associated with subsequent MRS spinal wound infection. Chemoprophylaxis with vancomycin should be targeted to patients at increased risk, because overuse may promote the emergence of vancomycin-resistant pathogens.

Immunohistochemical and in situ analysis of amyloid precursor-like protein-1 and amyloid precursor-like protein-2 expression in Alzheimer disease and aged control brains.

Amyloid precursor protein (APP) is a ubiquitously expressed membrane spanning glycoprotein which is endoproteolytically processed to Abeta, a 39-43 amino acid peptide that is the main component of senile plaques in Alzheimer Disease (AD). APP is a member of a highly conserved gene family, including Amyloid Precursor-Like Proteins (APLPs) APLP1 and APLP2. We now characterize APLP1 and APLP2 mRNA and protein expression in AD and aged control brains. Using in situ hybridization in hippocampal tissue from control and AD brain, we show that APLP1 and APLP2 mRNA are expressed primarily in the granule cells of the dentate gyrus, in areas CA1-CA3, and subiculum. Immunohistochemistry reveals staining for both APLP1 and APLP2 in neurons and blood vessels in AD and control cases. In addition, in AD brain, large dystrophic neurites in a subset of senile plaques are conspicuously labeled with APLP1 and APLP2 antibodies. The aged control brains have significantly fewer immunoreactive plaques and dystrophic neurites. The regional, cellular, and subcellular distribution of APLP1 and APLP2 overlap with each other and with APP. These observations support the hypothesis that the members of this family of proteins may perform similar functions.

Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease.

OBJECTIVE: To examine the differential deposition of amyloid beta (Abeta) peptide isoforms Abeta40 and Abeta42 in the Alzheimer disease (AD) brain in relation to the apolipoprotein E (APOE) genotype. BACKGROUND: The APOE epsilon4 genotype is an inherited risk factor for AD and is associated with increased deposition of Abeta protein in the cerebral cortex. Previous data from familial AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein suggest that the long form of Abeta peptide, Abeta42, is selectively increased in these circumstances. Herein, we examine whether APOE genotype influenced the species of Abeta peptide deposited. DESIGN AND METHODS: The amount of Abeta40, Abeta42, and total Abeta deposited in immunostained temporal lobe tissue of 28 cases of AD of known APOE genotype was determined. RESULTS: Individuals with the APOE epsilon4 genotype (APOE epsilon4/4) were associated with both increased Abeta40 (P<.05) and Abeta42 (P<.05) compared with individuals without the APOE epsilon4/4 genotype. CONCLUSION: Our results differ from the data from AD due to mutations in presenilin 1 and presenilin 2 genes and the amyloid precursor protein and suggest that the APOE epsilon4 genotype mediates increased Abeta deposition by a mechanism that differs from that found in other genetic causes of AD.

Neuronal expression of class II major histocompatibility complex (HLA-DR) in 2 cases of Pick disease.

BACKGROUND: Pick disease is a progressive form of dementia characterized by personality changes, speech disturbances, inattentiveness, and occasionally extrapyramidal phenomena. Although several variants have been recognized, the pathological profile of Pick disease includes focal frontotemporal atrophy, neuronal loss, astrocytosis, Pick bodies, and Pick cells. To date, little is known about the etiology of Pick disease. OBJECTIVE: To evaluate the possibility of inflammatory processes occurring in Pick disease pathophysiology. DESIGN: Immunohistochemistry for HLA-DR and related molecules was performed in brain tissue from individuals with Pick disease, Alzheimer disease, and diffuse Lewy body disease, as well as from neurologically normal controls. RESULTS: We report the unusual expression of the class II major histocompatibility complex protein Ia (HLA-DR) on neurons in 2 cases of Pick disease. In addition, both cases exhibited a dramatic microglial response. Neuronal HLA-DR immunostaining was not observed in 12 other cases of Pick disease or cases of Alzheimer disease, cases of diffuse Lewy body disease, or in control cases run con-currently. In addition, the pattern of HLA-DR staining observed in Pick disease was confirmed with another monoclonal antibody to HLA-DR. Frequent in vitro inducers of HLA-DR expression and enhanced class I major histocompatibility expression, interferon gamma, and tumor necrosis factor alpha were not detected. CD4-positive T lymphocytes were also not present and class I major histocompatibility complex expression was not detected on neurons or glia from brain tissue with Pick disease. CONCLUSIONS: These results are the first to demonstrate class II major histocompatibility complex expression on neurons. Based on these preliminary results, we suggest that some cases of Pick disease may be complicated by or involve in inflammatory process.

Late-onset sternomanubrial dislocation with progressive kyphotic deformity after a thoracic burst fracture.

Fractures and dislocations of the sternum may be associated with flexion-compression injuries of the thoracic spine. Sternal injuries most commonly occur at or near the sternomanubrial joint. We present a patient with a known thoracic spine fracture who developed a subsequent late-onset, symptomatic sternomanubrial dislocation and progression of thoracic kyphosis, ultimately requiring operative fixation of both the sternum and the spine. Internal fixation of these sternal injuries should be considered in the setting of a flexion-compression thoracic spine fracture to possibly prevent a worsening kyphosis and neurological decline.

Acute appendicitis and the use of intraperitoneal cultures.

We reviewed the charts of 200 patients with a preoperative diagnosis of acute appendicitis (AA) to evaluate the influence and use of intraoperative culture results on patient management and antibiotic selection. Cultures were obtained in 66 percent of patients; 16 percent of the cultures in patients with AA yielded positive results versus 88 percent of cultures in patients with perforated or gangrenous appendicitis (complicated appendicitis [CA]) and in nine patients, positive cultures were used to adjust antibiotic therapy. Patients with CA who had antibiotic changes based on culture results had a complication rate of 25 percent versus a 29 percent rate for this group as a whole. We conclude that intraoperative cultures in patients with AA are rarely positive and do not influence antibiotic therapy or patient management. In CA, antibiotic changes based on culture results do not seem to alter patient outcome. Surgeons tend to rely on the proved efficacy of empiric antibiotic therapy and other basic surgical principles to afford the best outcome for their patients. The routine practice of obtaining peritoneal cultures in patients operated upon for AA and CA should be abandoned.

Passive immunization of mice against D factor blocks lethality and cytokine release during endotoxemia.

D factor, also known as leukemia inhibitory factor, is a pleiotropic cytokine whose role during acute injury and inflammation is not known. Intraperitoneal administration of Escherichia coli endotoxin induced D factor gene expression in mice, and passive immunization against D factor protected them from the lethal effects of endotoxin and blocked endotoxin-induced increases in serum levels of interleukin 1 and 6. Peak levels of tumor necrosis factor and interferon gamma were not affected. These results indicate that D factor is an essential early mediator of the inflammatory cytokine response and therefore may be important in the pathogenesis of the many inflammatory conditions, such as sepsis, arthritis, allograft rejection, and cancer immunotherapy.

Lumbar spinal stenosis and lower extremity arthroplasty.

Because of their prevalence in elderly patients, the clinical symptoms of acquired lumbar spinal stenosis and degenerative joint disease of the lower extremity can often be present in the same patient. This study reports 14 patients who had diagnoses of both lower extremity degenerative disease and acquired lumbar spinal stenosis. Five of the 14 patients presented with concomitant symptoms, while 9 of 14 patients presented with clinical symptoms of spinal stenosis an average of 9.3 months following joint arthroplasty surgery. Comparison of the preoperative hip and knee scores between the concomitant and sequential groups demonstrated no differences. Seven of the nine patients in the sequential group required subsequent decompression for their spinal stenosis. Stenosis of the lumbar spine must be considered in patients who complain of continuing symptoms of neurogenic claudication in the postoperative period. In addition, these patients should be specifically counseled before their arthroplasty procedures that subsequent spinal surgery may be necessary.

Biomechanical analysis of three surgical approaches for lumbar burst fractures using short-segment instrumentation.

Burst fractures of the lumbar spine that are located below the thoracolumbar junction present a challenge when operative management is indicated. Short-segment instrumentation offers the advantage of incorporating fewer motion segments in the fusion, but may not provide adequate long-term stabilization. The goal of this study was to assess the axial stiffness and torsional rigidity of several short-segment instrumentation procedures. Compressive axial stiffness and torsional rigidity were measured in six intact porcine lumbar spines (L1-L5). A corpectomy was performed to simulate a burst fracture injury and decompression. Posterior instrumentation, posterior instrumentation with an anterior strut (a wood block), and anterior instrumentation with an anterior strut one level above and one level below the fracture site were applied as treatment strategies. VSP plates (Acromed, Cleveland, OH) for posterior instrumentation and the Kaneda system (Acromed, Cleveland, OH) for anterior instrumentation were used. Load-displacement and torque-angle plots were generated and used to calculate 144 estimates of axial stiffness and 144 estimates of torsional rigidity for these constructs. These analyses showed that, in comparison with the intact spine, posterior instrumentation alone was an average of 76% less stiff axially, posterior instrumentation with an anterior strut was 3% more stiff (not significantly different from intact), and anterior instrumentation with an anterior strut was 15% more stiff. Posterior instrumentation alone was an average of 30% less rigid in torsion, posterior instrumentation with an anterior strut was 26% less rigid, and anterior instrumentation with an anterior strut was 24% less rigid than the intact spine.(ABSTRACT TRUNCATED AT 250 WORDS)

Short segment transpedicular Cotrel-Dubousset instrumentation: a porcine corpectomy model.

This study examines changes in stiffness in a three-level spinal construct utilizing transpedicular Cotrel-Dubousset instrumentation. In addition, we evaluated the effect of adding offset laminar hooks at the same level as the superior transpedicular fixation. Porcine lumbar spines (L-1 to L-5) were tested as: (a) intact spine, (b) intact spine with instrumentation, and (c) instrumented spine after L-3 corpectomy. Instrumented constructs were tested with and without laminar hooks placed at the level of superior transpedicular fixation. Constructs were tested in modes of axial compression and torsion in a MTS materials testing machine. The fully instrumented intact spines demonstrated a 28.0% stiffness increase over the intact spines in torsion (p < 0.005) and a 23.1% increase in the mode of axial compression (p < 0.0002). There was no statistically significant difference in axial or torsional stiffness in the instrumented intact spine constructs when hooks were added. In the corpectomy model, addition of the laminar hooks increased stiffness in axial compression an average of 26.9% (p < 0.002) and in torsion an average of 28.1% (p < 0.0005). This increase in stiffness may aid in preventing the postoperative progression of kyphosis noted in studies utilizing similar constructs in clinical application for the treatment of lumbar burst fractures.

Interleukin-1 receptor antibody (IL-1rab) protection and treatment against lethal endotoxemia in mice.

Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 +/- 25, IL-1rab, 41 +/- 8; 4 h after LPS: IgG, 46 +/- 13, IL-1rab, 8 +/- 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokines and their role in the pathophysiology of cancer cachexia.

Cancer cachexia describes a syndrome that consists of weight loss, and abnormalities in carbohydrate, protein, and lipid metabolism, which result in a state of persistent net negative energy balance. Patients suffering from cancer cachexia have a significantly shortened survival after cancer treatment. Recent experimental studies have focused on the belief that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which through broad physiologic actions ultimately lead to a chronic state of wasting, malnourishment, and death. Cytokines that have been thought to play a role in the pathophysiology of cachexia include tumor necrosis factor, interleukin-1, interleukin-6, interferon-gamma and differentiation factor. It has become clear that these cytokines have overlapping physiologic activities, which makes it likely that no single substance is the sole cause of cachexia in most cancer patients. Only further investigation may make it possible to more clearly define the role of cytokines in the pathophysiology of cancer cachexia. Specific strategies to reverse the cachectic effects of these substances may then be developed to ultimately improve cancer treatment.

Segmental fixation of lumbar burst fractures with Cotrel-Dubousset instrumentation.

A retrospective review of 17 patients who underwent bilateral transpedicular decompression, instrumentation with a Cotrel-Dubousset construct, and posterolateral fusion with iliac crest bone graft for treatment of lumbar burst fracture is presented. All patients were followed to fusion with an average follow-up of 18.9 months. Fifteen of sixteen patients returned to preinjury occupation and/or activity. All patients reported good to excellent clinical results. The average postoperative progression of kyphosis was 11.9 degrees. There was no significant change in anterior vertebral height between the preoperative and postoperative periods. We conclude that although excellent early clinical results can be obtained using this operative strategy, the long-term effect of residual kyphosis at the fracture site is unknown.

Transpedicular short-segment fusions for treatment of lumbar burst fractures.

A retrospective review of 13 patients who underwent decompression and transpedicular instrumentation for lumbar burst fractures is presented. Average follow-up was 22.5 months. Eighty-four percent of patients reported little or no pain at follow-up. Sixty-nine percent of patients returned to full preinjury activity. Radiographic review demonstrated an average postoperative progression of kyphosis of 8.7%. Anterior vertebral body height was unchanged between preoperative evaluation and follow-up. Although short-segment posterior transpedicular instrumentation with VSP plates did not reestablish or maintain anatomic alignment of the lumbar spine after burst fractures, the clinical outcome was excellent.

Circumferential fusion for the management of acute cervical spine trauma.

Combined, single-stage anterior and posterior approaches for acute surgical management of cervical spine injury allows for early restoration of anatomic alignment and decompression. Six patients underwent single-stage anterior decompression and posterior instrumentation and fusion at Vanderbilt University Medical Center between 1984-1989. There was no late deformity. Five patients had incomplete neurologic deficits, and each improved a minimum of one Frankel classification. One patient had complete neurologic deficit at the C5 level. The procedure is lengthy, with an average time under anesthesia of 7.7 hs. Since this procedure allows for immediate mobilization, it should be considered for the management of cervical spine fractures with both anterior and posterior column instability.