John J. Nigro

Occult Esophageal Adenocarcinoma: Extent of Disease and Implications for Effective Therapy

OBJECTIVE The need for esophagectomy in patients with Barretts esophagus, with no endoscopically visible lesion, and a biopsy showing high-grade dysplasia or adenocarcinoma has been questioned. Recently, endoscopic techniques to ablate the neoplastic mucosa have been encouraged. The aim of this study was to determine the extent of disease present in patients with clinically occult esophageal adenocarcinoma to define the magnitude of therapy required to achieve cure. METHODS Thirty-three patients with high-grade dysplasia (23 patients) or adenocarcinoma (10 patients) and no endoscopically visible lesion underwent repeat endoscopy and systematic biopsy followed by esophagectomy. The surgical specimens were analyzed to determine the biopsy error rate in detecting occult adenocarcinoma. In those with cancer, the depth of wall penetration and the presence of lymph node metastases on conventional histology and immunohistochemistry staining was determined. The findings were compared with those in 12 patients (1 with high-grade dysplasia, 11 with adenocarcinoma) who had visible lesions on endoscopy. RESULTS The biopsy error rate for detecting occult adenocarcinoma was 43%. Of 25 patients with cancer and no visible lesion, the cancer was limited to the mucosa in 22 (88%) and to the submucosa in 3 (12%). After en bloc esophagectomy, one patient without a visible lesion had a single node metastasis on conventional histology. No additional node metastases were identified on immunohistochemistry. The 5-year survival rate after esophagectomy was 90%. Patients with endoscopically visible lesions were significantly more likely to have invasion beyond the mucosa (9/12 vs. 3/25, p = 0.01) and involvement of lymph nodes (5/9 vs. 1/10, p = 0.057). CONCLUSIONS Endoscopy with systematic biopsy cannot reliably exclude the presence of occult adenocarcinoma in Barretts esophagus. The lack of an endoscopically visible lesion does not preclude cancer invasion beyond the muscularis mucosae, cautioning against the use of mucosal ablative procedures. The rarity of lymph node metastases in these patients encourages a more limited resection with greater emphasis on improved alimentary function (esophageal stripping with vagal nerve preservation) to provide a quality of life compatible with the excellent 5-year survival rate of 90%.

Prevalence and location of nodal metastases in distal esophageal adenocarcinoma confined to the wall: Implications for therapy

OBJECTIVE The purpose of this study was to characterize the prevalence and location of regional lymph node metastases in adenocarcinoma confined to the esophagal wall, to determine the extent of dissection required, and to investigate the applicability of nonoperative therapy. METHODS Histologic evaluation of the resected specimens after en bloc esophagogastrectomy with mediastinal and abdominal lymphadenectomy was performed on 37 patients with adenocarcinoma confined to the esophageal wall. Follow-up was complete in all patients (median 24 months). RESULTS Fifteen patients (41%) had intramucosal tumors. Twelve (32%) had submucosal tumors and 10 (27%) had muscular invasion. The prevalence of regional lymph node metastases (15/37 patients, 41%) increased progressively with depth of tumor invasion, with involved nodes identified in 80% of patients with muscular invasion. Lymph node metastases were also more common at distant node stations in intramuscular tumors (5/10, 50%). Actuarial survival for the entire group was 63% at 5 years. Recurrence was identified in 6 of the 37 patients (16%), with the risk of recurrence correlating with tumor depth. CONCLUSIONS Tumor depth is a strong predictor of the probabilities of regional lymph node metastases, the likelihood of involvement of distant node groups, and the risk of recurrence. Patients with invasion of the muscular wall are at particularly high risk. En bloc esophagectomy with mediastinal and abdominal lymphadenectomy has the highest likelihood of achieving an R0 resection. The long-term survival and low recurrence rate achieved with an en bloc esophagectomy emphasizes the importance of an aggressive lymph node dissection to remove all potentially involved nodes.

Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy

OBJECTIVE Adenocarcinoma has replaced squamous cell as the most common esophageal cancer in the United States. The purpose of this study was to determine the prevalence and location of lymph node metastases, the feasibility of performing an R0 resection, and disease recurrence and survival in patients with transmural adenocarcinoma of the lower esophagus and gastroesophageal junction. METHODS Forty-four patients with transmural adenocarcinoma underwent en bloc esophagectomy with systematic thoracic and abdominal lymphadenectomy. They were followed up for a median of 23 months. RESULTS Actuarial survival for the entire group was 26% at 5 years. The most important predictors of the likelihood of recurrent disease and 5-year survival were the presence and number of lymph node metastases and the ratio of involved to total removed nodes. Seven patients (16%) were found to have no lymph node metastases and had an 85% 5-year survival. In contrast, patients with more than 4 involved nodes or a node ratio greater than 0.1 had a high likelihood of recurrence and death. Location of involved lymph nodes did not predict the likelihood of recurrence or death. Despite all patients having transmural tumors, recurrence within the field of the en bloc resection occurred in only 1 patient (2%). CONCLUSIONS En bloc esophagectomy in patients with transmural esophageal adenocarcinoma is required to obtain the survival benefit of an R0 resection, to adequately assess lymphatic tumor burden, and to be able to predict the likelihood of recurrence and death and thereby guide the use of postoperative adjuvant therapy.

The extent of Barrett's esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure

OBJECTIVE The purpose of this study was to assess whether the extent of intestinal metaplasia is related to the severity of the gastroesophageal reflux disease. METHODS A total of 556 consecutive patients with symptoms suggestive of foregut disease had upper gastrointestinal endoscopy with extensive biopsies from the gastroesophageal junction and the esophagus. All patients had esophageal motility and 24-hour pH monitoring. In 411 patients, cardiac-type mucosa was identified; in 147 patients, the cardiac-type mucosa showed intestinal metaplasia. They were divided into 3 groups based on the extent of intestinal metaplasia commonly seen clinically: long segments (>3 cm), short segments (<3 cm), and limited to the gastroesophageal junction. The duration of symptoms, the status of the lower esophageal sphincter, the degree of esophageal acid exposure, and the time to clear a reflux episode were assessed in each group. RESULTS The presence of intestinal metaplasia in cardiac-type mucosa was associated with the hallmarks of gastroesophageal reflux disease. The extent of intestinal metaplasia correlated strongly with the degree of esophageal acid exposure (r = 0.711; P <.001) and inversely with the lower esophageal sphincter pressure (r = 0.351; P <.001) and length (r = 0. 259; P =.002). Patients with a long segment of intestinal metaplasia (>3 cm) had longer duration of symptoms (16 years) than those patients with a segment of intestinal metaplasia less than 3 cm (10 years; P =.048) or those patients with intestinal metaplasia limited to the gastroesophageal junction (10 years; P =.01). CONCLUSION The extent of intestinal metaplasia, that is, Barretts esophagus, is related to the status of the lower esophageal sphincter and the degree of esophageal acid exposure.

Inability of an aggressive policy of thromboprophylaxis to prevent deep venous thrombosis (dvt) in critically injured patients: are current methods of dvt prophylaxis insufficient?

BACKGROUND Deep venous thrombosis (DVT) in severely injured patients is a life-threatening complication. Effective and safe thromboprophylaxis is highly desirable to prevent DVT. Low-dose heparin (LDH) and sequential compression device (SCDs) are the most frequently used methods. Inappropriate use of these methods because of the nature or site of critical injuries (eg, brain lesion, solid visceral or retroperitoneal hematoma, extremity fractures) may lead to failure of DVT prophylaxis. STUDY DESIGN A prospective study was performed to evaluate the efficacy of a policy of aggressive use of LDH and SCDs in patients who are at very high risk for DVT. From January 1996 to August 1997, 200 critically injured patients were followed by weekly Doppler examinations to detect DVT at the proximal lower extremities. Only 3 patients did not receive any thromboprophylaxis. SCDs were applied in 97.5% and LDH was administered to 46% of the patients; 45% had both. RESULTS DVT was found in 26 patients (13%). The majority (58%) developed DVT within the first 2 weeks, but new cases were found as late as 12 weeks after admission. The incidence of DVT was the same among patients who had SCDs only or a combination of LDH and SCDs. Mechanism of injury, type and number of operations, site of injury, Injury Severity Score, and the incidence of femoral lines were not different between patients with and without DVT. Differences were found in the severity of injury to the chest and the extremities and the need for high-level respiratory support. Patients with DVT had prolonged ICU and hospital stays (on average, 34 and 49 days, respectively) and a high mortality rate (31%). CONCLUSIONS The incidence of DVT remains high among severely injured patients despite aggressive thromboprophylaxis. A combination of LDH and an SCD showed no advantage over SCD alone in decreasing DVT rates. Risk factors in this group of patients who are already at very high risk are hard to detect; Doppler examinations are justified for surveillance in all critically injured patients. Current methods of thromboprophylaxis seem to offer limited efficacy, and the search for more effective methods should continue.

Prolonged use of dexmedetomidine in the paediatric cardiothoracic intensive care unit.

BACKGROUND Dexmedetomidine is an alpha2-adrenergic agonist that causes sleep-like sedation and mild analgesia without narcosis or respiratory depression, and has relative cardiovascular stability. Due to these properties, it may be an effective agent for prolonged use in the sedation of patients in the paediatric cardiothoracic intensive care unit. We reviewed our experience with the drug to detail its safety and efficacy. METHODS We conducted a retrospective chart review of all patients who received dexmedetomidine over a six month period in a dedicated paediatric cardiothoracic intensive care unit. Patients were identified from pharmacy records showing administration of drugs. We collected demographic data, information relating to doses of dexmedetomidine, physiologic parameters, and clinical outcomes. RESULTS We identified 54 patients who received the drug. The median age of recipients was 6 months, with a range from 1 day to 16 years. The mean duration of administration was 37.3 hours, with a range from 2 to 177 hours. The mean duration of continuation of administration after extubation was 16.7 hours, with a range from zero to 112.5 hours. Physiologically, there were no clinically significant changes in mean arterial pressure, heart rate, respiratory rate, or saturations of oxygen before, during, or after utilization of the drug. Use of dexmedetomidine significantly reduced the need to administer narcotics, and scores using the COMFORT system were not different between patients who received dexmedetomidine and those who did not. CONCLUSIONS In this limited and retrospective review, dexmedetomidine was found to be safe and efficacious. Its use as a sedative agent for extended periods of time in critically-ill children deserves investigation in a prospective and controlled manner.

A novel approach to neonatal management of tetralogy of Fallot, with pulmonary atresia, and multiple aortopulmonary collaterals.

Tetralogy of Fallot (TOF), pulmonary atresia (PA), and multiple aortopulmonary collateral arteries (MAPCAs) need complex interventions, and pre-natal diagnosis allows for appropriate peri-partum planning [(1)][1]. Traditionally the post-natal echocardiogram is followed by cardiac catheterization to

Genetic engineering of stent grafts with a highly efficient pseudotyped retroviral vector

PURPOSE The purpose of this study was first to compare the gene transfer efficiency of amphotrophic murine leukemia viral vector (ampho-MuLV) with the efficiency of MuLV pseudotyped with the vesicular stomatitis virus G glycoprotein (VSVG-MuLV) in tissue of vascular origin. The second purpose of this study was to determine cell retention after the implantation of genetically engineered stent grafts. METHODS Gene transfer efficiency was ascertained with the b-galactosidase assay. The target tissues included endothelial cells (ECs), smooth muscle cells (SMCs), and human saphenous veins (HSVs). Polyurethane stent grafts were suffused with lac Z-transduced ECs and SMCs that were harvested from porcine jugular vein. The grafts were implanted into the iliac artery of each pig whose jugular vein had been harvested. Cell retention was analyzed at 1 and 4 weeks with X-Gal staining. RESULTS VSVG-MuLV transduction efficiency exceeded that of ampho-MuLV in human ECs (VSVG-MuLV, n = 24, 89% +/- 6%; ampho-MuLV, n = 18, 14% +/- 6%; P <. 001), human SMCs (VSVG-MuLV, n = 5, 92% +/- 3%; ampho-MuLV, n = 4, 17% +/- 2%; P <.001), pig ECs (VSVG-MuLV, n = 4, 81% +/- 2%; ampho-MuLV, n = 4, 13% +/- 3%; P <.001), and pig SMCs (VSVG-MuLV, n = 5, 89% +/- 3%; ampho-MuLV, n = 4, 16% +/- 1%; P <.001). As much as a 10-fold higher transduction efficiency was observed with VSVG-MuLV in HSVs. After the stent graft implantation, the engineered cells were retained and proliferated on the stent membrane, with ingrowth into the underlying intima. CONCLUSION VSVG-MuLV significantly increased the gene transfer efficiency in vascular SMCs and ECs and in organ-cultured HSVs. The cells were retained and proliferated on stent grafts for the short term in the pig.

Total artificial heart in the pediatric patient with biventricular heart failure.

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m2, thus, limiting pediatric application of this device. This unique case report shares this pediatric institution’s first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m2) below the recommendation of 1.7m2. A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient.

Manometry of the lower esophageal sphincter: inter- and intraindividual variability of slow motorized pull-through versus station pull-through manometry.

The purpose of this study was to evaluate the interindividual and intraindividual variability of slow motorized pull-through lower esophageal sphincter (LES) manometry compared to standard station pull-through LES manometry to measure LES overall length, abdominal length, and pressure and to report normal values for the slow motorized pull-through method. The slow motorized pull-through had significantly smaller coefficient of variation, indicating closer agreement between different examiners in analyzing a given tracing. The correlation coefficients for each parameter in normal subjects and symptomatic patients was significantly higher when using slow motorized pull-through for both patients and normal subjects for all three parameters. The 5th percentile of normal values obtained from 41 volunteers for LES overall length, abdominal length, and pressure was 2.7 cm, 1.4 cm, 5.1 mm Hg, respectively. The results indicate that the slow motorized pull-through method is more reproducible than the standard station pull-through method both between different observers and when the same examiner measures the same tracing on two different occasions.