The embryonic transcription factor Brachyury blocks cell cycle progression and mediates tumor resistance to conventional antitumor therapies.

The T-box transcription factor Brachyury, a molecule frequently detected in human cancers but seldom found in normal adult tissue, has recently been characterized as a driver of the epithelial-to-mesenchymal switch of human carcinomas. In the current investigation, we present data demonstrating that in two different human lung carcinoma models expression of Brachyury strongly correlates with increased in vitro resistance to cytotoxic therapies, such as chemotherapy and radiation. We also demonstrate that chemotherapy treatment in vitro selects for tumor cells with high levels of Brachyury and that the degree of resistance to therapy correlates with the level of Brachyury expression. In vitro and in vivo, human lung carcinoma cells with higher levels of Brachyury divide at slower rates than those with lower levels of Brachyury, a phenomenon associated with marked downregulation of cyclin D1, phosphorylated Rb and CDKN1A (p21). Chromatin immunoprecipitation and luciferase reporter assays revealed that Brachyury binds to a half T-box consensus site located within the promoter region of the p21 gene, indicating a potential mechanism for the observed therapeutic resistance associated with Brachyury expression. Finally, we demonstrate that in vivo treatment of tumor xenografts with chemotherapy results in the selective growth of resistant tumors characterized by high levels of Brachyury expression. Altogether, these results suggest that Brachyury expression may attenuate cell cycle progression, enabling tumor cells to become less susceptible to chemotherapy and radiation in human carcinomas.

Management of the carotid artery in paraganglioma surgery.

Paragangliomas can be challenging to even the most experienced surgeon. Injuries to the carotid artery are not uncommon. To avoid injury, a careful preoperative assessment of the size and extent of the tumor and its relation to the internal carotid artery, external carotid artery, and common carotid artery is important for planning the procedure. For more extensive tumors, it is often helpful to have a multidisciplinary team available to handle all potential issues and complications.

Outcome of the acute abdomen in patients with previous spinal cord injury.

BACKGROUND: Patients with spinal cord injury (SCI) have always posed difficulties for the diagnosis of an acute abdomen. The aim of the present study was to define this problem retrospectively at Princess Alexandra Hospital and to assess the results of treatment for these patients. METHODS: A retrospective review was conducted of 133 SCI patients admitted with an acute abdomen in the 16 years prior to this analysis at the Spinal Injuries Unit (SIU) of Princess Alexandra Hospital. There were 21 patients who conformed to the study criteria. All the patients had sustained traumatic SCI at or above the level of T11, more than 1 month prior to admission. RESULTS: There were 13 male and eight female patients. The time lapse between SCI and the onset of an acute abdomen ranged from 1.5 months to 27 years. The age range was 26-79 years. The majority of patients had C6 injuries (six patients). There were 18 patients with injury levels above T6 and three patients with injuries below this level. The time taken to diagnose the cause of the acute abdomen ranged between I day and 3 months. Investigations were found to be useful in making the diagnoses in 61.9% of cases. There were 14 patients who had surgical interventions. Five patients had surgical complications and there were two deaths in the study. The length of follow up was 1-132 months. The mortality in the study was 9.5%. CONCLUSION: An aggressive approach to the diagnosis and treatment of the acute abdomen in SCI patients with suspicious symptoms is recommended. A high index of suspicion should be maintained in those patients with pre-existing SCI who present with abdominal trauma.

The trials, tribulations, and relative success of the ongoing clinical merger of two large academic hospital systems.

The North Shore Health System and the Long Island Jewish Medical Center merged in 1997 and now form the third largest not-for-profit academic health care system in the United States. The authors analyze the specific factors responsible for the relative success of the clinical merger, review their merger's initial failures and how they crafted a more pragmatic and appropriate set of guiding principles to continue the merger, and discuss the future of their institution's clinical integration strategy. In 2000, clinical integration of the 19 clinical departments at the two merged institutions was surveyed across five broad areas: conferences, residency programs, common faculty and support staff, finances, and research. Extents of clinical integration ranged from 20% to 72%. Six departments had more than 50% clinical integration, and overall clinical integration was 42%. Not surprisingly, clinical integration had occurred most frequently with conferences (50%) and least with finances (25%). The single-chairperson model for department leadership has been most successful in achieving significant clinical integration of the formerly separate departments. The relative success of the clinical merger has been guided by the principle that no clinical service should be integrated simply for the sake of merging, but rather that integration should be encouraged where and when it makes sense to achieve specific program goals. In addition, the merger would not have proceeded without constant communication among the leadership and staff, flexibility in building leadership models, patience in having events progress over a time course that developed trust among the senior leaders, and the presence of a senior executive structure whose authority to make decisions is accepted. The most important factor for achieving a reasonable level of clinical integration is the ability of the clinical leaders to collaborate and lead the change process.

A versatile assay for gelatinases using succinylated gelatin.

A spectrophotometric assay using succinylated gelatin as substrate is described for measuring the catalytic activity of gelatinases. The assay is based on measurement of primary amines exposed as a result of hydrolysis of the substrate by gelatinases. Comparison of hydrolysis by matrix metalloproteinase (MMP) 1, 2, 3, 7, 9 indicated that succinylated gelatin was primarily digested by MMP-2 and -9. The assay is rapid (<60 min), specific, suitable for measuring gelatinolytic activity of enzymes and high volume screening of MMP-2 and -9 inhibitors. Sensitivity of the assay is comparable to that of gelatin zymography, under similar experimental conditions. Thus, the assay combines ease and rapidity of assays based on synthetic peptide substrates with specificity of the gelatin zymography technique.

Cut or paste? The use of glyceryl trinitrate paste in the treatment of acute and chronic anal fissure.

BACKGROUND: Anal fissure unresponsive to conservative measures such as stool softeners frequently requires surgical intervention. The present study describes the use of glyceryl trinitrate (GTN) in the treatment of acute and chronic anal fissure. METHODS: Eighteen consecutive patients with anal fissure were treated with 0.5% GTN paste in soft white paraffin applied twice daily to the anus. These patients were followed at regular intervals to assess symptom control, rate of healing, adverse effects and recurrence rate. RESULTS: Two patients were lost to follow-up. Twelve of the remaining 16 were cured. Of these, symptomatic relief was obtained for most within 2 days, and for all within 1 week. No patient required cessation of treatment due to adverse effects. Treatment failed in four of 16 patients. Two of these patients subsequently underwent successful surgical procedures, and two patients (while not completely cured) had sufficient symptomatic relief to decide against surgery. CONCLUSIONS: The use of GTN paste in the treatment of acute and chronic anal fissure may be a safe and effective modality that can be considered as first-line treatment for this condition.

Minimal incision abdominal aortic aneurysm repair.

PURPOSE: The use of a limited incision for abdominal aortic aneurysm (AAA) repair was evaluated, and its outcome was analyzed in comparison to laparoscopic-assisted and standard open repair. METHODS: Eleven patients who had an AAA that required a tube graft underwent minimal incision (MINI) repair. The procedure consisted of a standard endoaneurysmorrhaphy performed through an 8- to 10-cm minilaparotomy. Clinical characteristics, in-hospital outcomes, and total in-hospital charges for this procedure were then compared with those of comparative groups of patients who had undergone repair of AAA by means of a laparoscopic-assisted (LAP) approach or a standard open (OPEN) technique. RESULTS: MINI repair was successfully completed in all 11 patients. Patients in the three groups were comparable for age, sex, risk factors, and aortic dimensions. The mean values for operative time, blood loss, length of hospital stay, and total hospital charges for the three comparison groups were: 129. 7 minutes (MINI) vs. 244.8 minutes (LAP)*, 209.9 minutes (OPEN)*; 522.7 mL (MINI) vs. 1214.7 mL (LAP), 1795.8 mL (OPEN)*; 5.18 days (MINI) vs. 18.7 days (LAP), 17.4 days (OPEN); $22,692 (MINI) vs. $59, 922 (LAP)*, $62,324 (OPEN)* (*P <.05). Local complications occurred in 18.2% of patients who underwent MINI repair, 23.5% of patients who underwent LAP repair, and 29.7% of patients who underwent OPEN repair (P = not significant). Patients undergoing minilaparotomy demonstrated decreased compromise of gastrointestinal function, with a decreased need for postoperative fluid resuscitation (6799.7 mL [MINI], 7781.8 mL [LAP] vs. 11061.1 mL [OPEN]*) and shortened nasogastric tube decompression (1.6 days [MINI], 1.5 days [LAP] vs. 4.1 days [OPEN]*; *P <.05). CONCLUSION: MINI repair is a technically feasible technique that combines the benefits of minimally invasive surgery with those of conventional open repair with few, if any disadvantages. Facility of the procedure, combined with the potential cost benefits, encourages further study for consideration of this technique as a viable alternative for the management of AAAs.

Laparoscopically assisted abdominal aortic aneurysm repair.

Since the advent of laparoscopy, the sweeping changes seen in general surgery have not been paralleled in vascular surgery. However, the application of laparoscopic techniques to intraabdominal vascular procedures has now progressed from the animal laboratory to the clinical arena. Initial experience with laparoscopically assisted aortic bypasses for occlusive disease has led to the development of procedures for aneurysmal disease. This article reviews the current clinical experience in the evolving technique of laparoscopically assisted abdominal aortic aneurysm repair.

In God's garden. Creation and cloning in Jewish thought.

The possibility of cloning-human beings challenges Western beliefs about creation and our relationship to God. If we understand God as the Creator and creation as a completed act, cloning will be a transgression. If, however, we understand God as the Power of Creation and creation as a transformative process, we may find a role for human participation, sharing that power as beings created in the image of God.

Laparoscopically assisted abdominal aortic aneurysm repair.

Since the first description of abdominal aortic aneurysms by sixteenth-century anatomist Vesalius, the history of this disease has reflected the remarkable progress of vascular surgery. From initial attempts of ligation and sclerosis to the recent advances of endovascular and laparoscopic repair, present-day vascular surgeons are supplied with a technically evolving choice of therapeutics. None of these procedures is mutually exclusive; currently, great interest lies in the use of laparoscopy to provide extraluminal control at the neck of aneurysms, to work with endoluminal grafts, and to control collateral vessel endoleaks. Laparoscopic vascular surgery must not be introduced into the clinical arena based only on the assumption that it is feasible. Clearly, it is a technically challenging procedure with a steep learning curve that requires specialized instrumentation and sophisticated laparoscopic suturing capability; however, with continued investigation, including prospective randomized trials, laparoscopic treatment of aortic aneurysms may become a standard option for high-risk patients.

Reduced capacity to inhibit elastase in abdominal aortic aneurysm.

BACKGROUND: Loss of elastin in the aortic wall is an early event in abdominal aortic aneurysm (AAA). An imbalance in the protease-antiprotease system is proposed to be one of the factors that promote connective tissue destruction. We hypothesize that plasma from AAA patients will have a reduced inhibitory capacity in comparison to normal controls. MATERIALS AND METHODS: Using an assay we developed, plasma (10 microliters), collected from AAA patients (n = 14) and normal controls (n = 13), was added to the elastase inhibition assay containing succinylated elastin substrate. The reaction was initiated with 13.9 units porcine pancreatic elastase (PPE). Elastase activity in the presence and absence of plasma was compared. Plasma elastase was also determined using the Merck PMN-elastase kit. RESULTS: The relative activity of exogenous elastase (%) in the presence of AAA plasma (n = 14, mean age 73.4 years +/- 1.7 SEM) was 42.59% +/- 4.3 SEM, while that in the presence of control plasma (n = 13, mean age 73.9 years +/- 2.1 SEM) was 10.23% +/- 2.1 SEM (P < 0.0001). Analysis of plasma elastase (microgram/L) indicated that there was no significant difference between normal (n = 9, 207.33 microgram/L +/- 58.67 SEM) and AAA (n = 9, 145.34 microgram/L +/- 29.54 SEM) (P = 0.359). CONCLUSION: There is a significant reduction in the plasma inhibitory capacity of elastase in AAA patients in comparison to normal controls, though plasma elastase level was not significantly different. The data presented here give experimental evidence to the protease-antiprotease imbalance in AAA patient plasma and may lead to the development of a measurable parameter to monitor AAA.

Warfarin anticoagulation in the perioperative period: is it safe?

This study was undertaken to determine if warfarin anticoagulation could be safely continued during surgery and in the perioperative period. An animal model was followed by a prospective human study of all patients on heparin or warfarin at the time of surgery. Twenty-four rabbits underwent laparotomy, during which a controlled liver injury was created and repaired. Group 1 (Warf) was anticoagulated with warfarin to raise the mean international normalization ratio (INR) to 2.5-3.0. Group 2 (Hep) was anticoagulated with heparin to raise the activated partial thromboplastin time to 1.5-2.0 times control. The heparin was then stopped 6 hr prior to surgery and resumed 6 hr postoperatively without a bolus. Group 3 (control) was not anticoagulated and received saline infusion. For the human study, data were collected on 40 patients undergoing 50 operations from October 1996 to January 1998. The results of this study reveal that (1) bleeding was less in the group anticoagulated with warfarin throughout surgery in the animal model, (2) bleeding complications were less in the patients continued on warfarin through surgery than those on heparin (3) older patients may have an increased risk of bleeding, and (4) an INR of >3 at the time of surgery may increase the risk of bleeding.

Relationship of protamine dosing with postoperative complications of carotid endarterectomy.

Protamine sulfate (PS) neutralization of heparin (HEP) given during carotid endarterectomy (CEA) has been previously associated with an increased postoperative stroke rate. Dosing regimens of PS have varied in previous studies. The accuracy of PS dosing and its effect on postoperative complications was analyzed. The medical records of all patients undergoing elective CEAs from January 1993 to June 1996 in our institution were reviewed. A hematoma was defined as either an event requiring return to the operating room or when repeatedly identified in the medical record. The accuracy of dosing PS was determined utilizing a formula calculating the logarithmic exponential decay of HEP, which determined the residual HEP at the time of PS dosing. An ideal PS dose was then calculated and compared to the dose given. Statistical analyses was performed using a Fisher's exact test as well as the Student's t-test. Four hundred-seven CEAs were performed in 365 patients. There were 10/407 (2.5%) postoperative strokes (STROKE) and 11/407 (2.7%) hematomas, 3 of which required reoperation. Results indicate that (1) the administration of PS significantly reduced the incidence of postoperative hematoma; (2) there appears to be an association between the administration of PS and STROKE; (3) the inaccuracy in dosing PS appears to be based on a decision to dose PS to the total HEP given rather than the residual HEP on board at the time of neutralization. The effect of PS overdosing is unclear, but it may play a role in STROKE.

Perioperative predictors of colonic ischemia after ruptured abdominal aortic aneurysm.

PURPOSE: Colonic ischemia and colonic resection occur frequently after ruptured abdominal aortic aneurysm (rAAA). The purpose of this study was to identify the perioperative risk factors that might help to determine earlier in the postoperative period which patients are at risk for colonic ischemia and colonic resection. METHODS: The medical records of the 43 patients who underwent repair of rAAA from January 1989 to November 1997 were reviewed. The data were reviewed for the following factors: acidosis, pressor agents, lactate levels, guaiac status, cardiac index, coagulopathy, early postoperative bowel movement, the lowest intraoperative pH level, the temperature at the conclusion of the case, the location and duration of aortic cross clamping, the amount of fluid boluses administered after surgery, the amount of packed red blood cells administered during the case, and the average systolic blood pressure at admission and during surgery. Univariate analysis was performed with Fisher exact test, chi2 test, and Student t test. Multivariate analyses also were performed with the variables that were found to be significant on the univariate analysis. RESULTS: Thirteen of the 43 patients (30. 2%) had colonic ischemia, and seven of the 13 underwent colonic resection (53.8%). The overall mortality rate was 51.2% (22/43) five of the deaths were intraoperative and excluded from the study. In a comparison of the patients who had colonic ischemia with those who did not, statistically significant differences were found in the following variables: average systolic blood pressure at admission 90 mm Hg or less, hypotension of more than 30 minutes' duration, temperature less than 35 degreesC, pH less than 7.3, fluid boluses administered after surgery 5 L or more, and packed red blood cells 6 units or more. Multivariate analysis indicated that the number of these variables present correlated significantly with the positive predicted probability of colonic ischemia occurring. No patient with two factors or fewer had an ischemic bowel, and the positive predictive probability of colonic ischemia for those patients with six factors was 80%. CONCLUSION: The results of this study show that: (1) colonic ischemia after rAAA may be predicted with the presence of two or more specific perioperative factors, (2) the lack of a guaiac-positive bowel movement may be misleading for the early diagnosis of colonic ischemia, and (3) more than 50% of the patients with colonic ischemia will require a colonic resection. We recommend that any patient with rAAA with more than two perioperative factors undergo sigmoidoscopy every 12 hours after surgery for 48 hours to rule out colonic ischemia without waiting for early or guaiac-positive bowel movement.

Diagnostic failure in colonoscopies for malignant disease.

BACKGROUND: While colonoscopy has become established as more accurate than double contrast barium enema for detecting colonic polyps and cancers, as well as offering the opportunity for therapy, there are occasional instances where colonoscopy is misleading. The present study is to determine what problems occur, with a view to finding a solution. METHODS: The records of the Colorectal Project at the Princess Alexandra Hospital indicate retrospectively that 346 patients have been correctly diagnosed with cancer of the colon and rectum by colonoscopy in the 5 years up to October 1996. During the same time eight patients (2.3%) were recorded at the same hospital as being misdiagnosed by colonoscopy, the lesion being either missed completely or misplaced. RESULTS: In five of these patients there was failure to recognize that the whole colon had not been examined endoscopically, thereby missing a more proximal lesion. In two patients the lesion was missed although the entire colon was examined. In one patient the lesion was discovered but inaccurately sited. Six of these mistakes would have been obviated by the routine use of fluoroscopy to confirm the totality of the colonoscopy and to site any lesions found. The other two cases occurred because of failure to remember that colonic examination during withdrawal should be performed meticulously back as far as the anal canal. Failure to diagnose a colon cancer on the initial colonoscopy led to an average delay of 6 months for definitive care. CONCLUSIONS: It is recommended that fluoroscopy be used routinely during colonoscopy to site accurately any lesions found, and to confirm the completeness of insertion if reliable landmarks, including terminal ileum, are not clearly identified.

Laparoscopically assisted abdominal aortic aneurysm repair: first 20 cases.

PURPOSE: Laparoscopic surgery decreases postoperative pain, shortens hospital stay, and returns patients to full functional status more quickly than open surgery for a variety of surgical procedures. This study was undertaken to evaluate laparoscopic techniques for application to abdominal aortic aneurysm (AAA) repair. METHODS: Twenty patients who had AAAs that required a tube graft underwent laparoscopically assisted AAA repair. The procedure consisted of transperitoneal laparoscopic dissection of the aneurysm neck and iliac vessels. A standard endoaneurysmorrhaphy was then performed through a minilaparotomy using the port sites for the aortic and iliac clamps. Data included operative times, duration of nasogastric suction, intensive care unit days, and postoperative hospital days. Pulmonary artery catheters and transesophageal echocardiography were used in seven patients. For these patients data included heart rate, pulmonary artery systolic and diastolic pressures, mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, cardiac index, and end diastolic area. Data were obtained before induction, during and after insufflation, during aortic cross-clamp, and at the end of the procedure. RESULTS: Laparoscopically assisted AAA repair was completed in 18 of 20 patients. Laparoscopic and total operative times were 1.44 +/- 0.44 and 4.1 +/- 0.92 hours, respectively. Duration of nasogastric suction was 1.3 +/- 0.7 days. Intensive care unit stay was 2.2 +/- 0.9 days. The mean length of hospital stay was 5.8 days excluding three patients who underwent other procedures. There were two minor complications, one major complication (colectomy after colon ischemia), and no deaths. For the eight patients who had intraoperative transesophageal echocardiographic monitoring, no changes were noted in heart rate, pulmonary artery systolic pressure, pulmonary capillary wedge pressure, and cardiac index. Pulmonary artery diastolic pressure and central venous pressure were greatest during insufflation without changes in end-diastolic area. Volume status, as reflected by end-diastolic area and pulmonary capillary wedge pressure, did not change. CONCLUSIONS: Laparoscopically assisted AAA repair is technically challenging but feasible. Potential advantages may be early removal of nasogastric suction, shorter intensive care unit and hospital stays, and prompt return to full functional status. The hemodynamic data obtained from the pulmonary artery catheter and transesophageal echocardiogram during pneumoperitoneum suggest that transesophageal echocardiography may be sufficient for evaluation of volume status along with the added benefit of detection of regional wall motion abnormalities and aortic insufficiency. Further refinement in technique and instrumentation will make total laparoscopic AAA repair a reality.

Control of proximal hypertension during aortic cross-clamping: its effect on cerebrospinal fluid dynamics and spinal cord perfusion pressure.

Postoperative paraplegia remains the most devastating complication of surgery of the descending and thoraco-abdominal aorta. Control of the proximal hypertension that follows cross-clamping of the thoracic aorta to repain aneurysms of the descending and thoraco-abdominal aorta is necessary to prevent left ventricular failure, myocardial infarction, and hemorrhagic cerebral events. Both pharmacological and mechanical modalities used to control central hypertension during aortic occlusion affect cerebrospinal fluid dynamics and spinal cord perfusion pressure. Sodium nitroprusside (doses >5 microg/kg/min), the most widely used pharmacological agent, decreases spinal cord perfusion pressure because it increases cerebrospinal fluid pressure and decreases blood pressure distal to the aortic cross-clamp. This effect cannot be prevented by drainage of cerebrospinal fluid. Nitroglycerin also decreases spinal cord perfusion pressure, but its effects on cerebrospinal fluid dynamics can be countered by drainage of cerebrospinal fluid. Active distal perfusion with left atrial-femoral artery bypass can provide adequate perfusion of the circulation distal to the aortic cross-clamp while simultaneously reducing cerebrospinal fluid pressure. This approach can maintain mesenteric and spinal cord blood flow, therefore preventing the multiple organ dysfunction syndrome caused by release of cytokines from the splanchnic district and decreasing the incidence of postoperative paraplegia from spinal cord ischemia. In cases of limited retroperfusion, partial exsanguination and cerebrospinal fluid drainage can be used in conjunction with left atrial-femoral artery bypass to prevent rises in cerebrospinal fluid pressure and maintain spinal cord blood flow above the threshold necessary to prevent neurological injury. The use of oxygenated perfluorocarbons in the subarachnoid space to provide passive oxygenation of the spinal cord during aortic occlusion remains experimental and requires further investigation.