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.

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.

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.

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.

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.

Follow-up after stage II breast cancer: a comparative study of relapsed versus nonrelapsed patients.

A retrospective study was undertaken to compare the frequency of scheduled and unscheduled (extra) visits and the signs and symptoms reported on such visits for 31 patients with relapse and 31 matched relapse-free patients all of whom had completed adjuvant treatment for stage II breast cancer. All patients had been treated with the same identical adjuvant therapy program and all had the same regular follow-up schedule, including clinic visits for history and physical examination every 6 months and chest x-ray, complete blood profile, bone scan, and mammogram yearly. Almost all (29/31) relapsed patients had signs or symptoms as the first indicator of recurrence. During a follow-up period of 13-16 months, the relapsed and nonrelapsed patients had a total of 89 and 81 visits, respectively, with an unscheduled visit occurring for almost every two routine visits. Almost all of the 89 total visits for relapsed patients and almost 75% for nonrelapsed patients were associated with signs or symptoms, a majority of which could have been due to cancer recurrence. We conclude that history and physical examination generally provide the first clues to recurrence but that such symptoms and signs are frequently reported by nonrelapsed patients as well as those with recurrence.

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)

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.

Impact of anal manipulation and pouch design on ileal pouch function.

The frequency of defecation, leakage, maximum resting pressure, and maximum squeeze pressure of the anal canal, maximum tolerated volume, and pouch compliance were evaluated in 116 consecutive patients following total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA) and after temporary ileostomy closure. Sixty-nine patients had a double ileal loop pouch ("J") and 47 a triple ("S") design. Seventy patients had mucosal proctectomy and hand-sewn IPAA (mucosectomy) and 46 a stapled IPAA without mucosal proctectomy (stapled). Fifty percent of the S and 30% of the J pouch patients did not have nocturnal defecations. The avoidance of anal manipulation in the stapled group resulted in higher anal canal resting pressures and a lower incidence of leakage. The maximum tolerated volume and compliance was greater in the S pouch group than in the J group. Although the median frequency of defecation was equal in both pouch groups, fewer S pouch patients had nocturnal defecations. Anal canal resting tone may be the primary factor affecting continence following TPC and IPAA, but a compliant pouch may prevent leakage if sphincter function is compromised.

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.

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.

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.

Effect of irrigation fluids on arterial and venous endothelium after ischemia.

This study examines the extent of endothelial damage following a period of irrigation with various crystalloid irrigation fluids. Both arteries and veins were evaluated after irrigation with normal saline, lactated Ringer's, Balanced Salt Solution (BSS), and Balanced Salt Solution Plus (BSS+). The arterial and venous endothelia were examined with the scanning electron microscope. Using a randomized blind observer scoring system, micrographs were evaluated for changes in nuclear shape, cell junction integrity, cytoplasm changes, and sloughing of the endothelial cell layer. BSS+ and BSS produced statistically significant (P less than .001) improvement over the other two irrigation fluids in the arteries. BSS+ and BSS were statistically superior (P less than .001) in the venous vessels. The compositions of BSS and BSS+ tend to maintain a physiologic environment in the presence of ischemia. These fluids maintained a morphologic appearance closer to that of perfusion-fixed controls. The data suggest a protective effect of such physiologic preparations on the endothelium. The preservation of intact endothelium may play a role in decreased platelet activation, continued production of prostacyclin, and maintenance of an intact barrier between the intracellular and extracellular spaces. This could enhance the survival of transplanted or transferred tissue, by helping to maintain nearly normal endothelium during surgery.

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.

A manometric study of anal fissure treated by subcutaneous lateral internal sphincterotomy.

A prospective, manometric trial of anal fissure treated by subcutaneous lateral internal sphincterotomy (SLIS) was designed to elucidate the pathophysiology of this condition. Anorectal manometry with a closed, precalibrated, water-filled microballoon using the station pull-through technique was performed on 13 patients with anal fissure before, and at one and 150 days after SLIS. The results were compared with 13 control subjects, matched for age and sex, who had no history of anal disease. Both resting pressure (RP) and maximum voluntary contraction pressure (MVCP) were measured at centimeter intervals of the anal canal. At all levels RP was significantly higher in the preoperative patients compared with controls (p less than 0.0001). After operation RP fell significantly at all levels with the result that there was no significant difference in RP between postoperative patients and controls, except at 4 cm from the anal verge, where there remained a significant elevation in RP in the postoperative group. There was no significant difference in the two sets of postoperative manometric results. All patients underwent rapid healing and resolution of their symptoms. MVCP did not change significantly after operation, nor did it differ from the control values. This suggests that the increase in RP is due to activity of the internal anal sphincter. This over-activity is present throughout the entire length of the internal anal sphincter and sphincterotomy of its lowest portion returns RP to normal values throughout most of the anal canal.