The outcome of fundoplication in patients with GERD based on abnormal impedance testing.

INTRODUCTION: The role of impedance testing in selecting patients for antireflux surgery is poorly understood. The aim of this study was to compare the outcomes of patients that underwent antireflux surgery for GERD based on an abnormal pH/abnormal impedance test versus a normal pH/abnormal impedance test. METHODS: Records of patients who had an abnormal off-medication impedance test (≥ 48 total reflux events) who underwent antireflux surgery were reviewed and divided into two groups: normal [pH-] or abnormal [pH+] esophageal acid exposure (DeMeester score > 14.7). Symptom resolution was compared: scale 1 (no resolution) to 5 (complete resolution). RESULTS: Eighty-two patients met criteria: 44 [pH+] and 38 [pH-]. There were no differences in the demographics or indications for surgery. The frequencies of heartburn and regurgitation symptoms were significantly reduced by fundoplication in both groups. Complete resolution of heartburn was more common in the [pH+] group (90%) compared to the [pH-] group (67%) [p = 0.02]. Resolution of regurgitation was similar in both groups (90% in the [pH+] group vs 79% in the [pH-] group, p = 0.20). The mean dysphagia frequency score decreased for the [pH+] group, but increased in the [pH-] group. New-onset dysphagia was more common in [pH-] patients (23%) compared to [pH+] patients (5%), (p = 0.02). Continued use of PPI medications was significantly more likely in [pH-] group (42%) compared to the [pH+] group (21%). There was no difference in surgical satisfaction rates between groups. DISCUSSION: Patients with abnormal impedance and increased esophageal acid exposure had significantly better symptom resolution, less dysphagia, and less frequent PPI use with antireflux surgery versus those with normal pH. These findings urge caution in the use of abnormal impedance values with normal esophageal acid exposure for the selection of patients for an antireflux operation.

Volumetric laser endomicroscopy and its application to Barrett's esophagus: results from a 1,000 patient registry.

Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett's esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.

Home self-dilatation for esophageal strictures.

Esophageal strictures secondary to caustic ingestion, head and neck radiation and at the anastomosis post-esophagectomy tend to be refractory to one or several dilatations. One option for these strictures is home self-dilatation. The aim of this study was to assess the efficacy and safety of home self-dilatation for a refractory esophageal stricture. A retrospective chart review was performed of all patients from 1997 to 2009 that performed home self-dilatation for an esophageal stricture. Patients with proximal strictures without tortuosity or a shelf proximal to the stricture were selected for self-dilatation. The patients were taught self-dilatation by the surgeon and an experienced nurse, and an appropriate sized Maloney dilator was provided to the patient and returned when no longer needed. There were 16 patients (11 male and 5 female) with a median age of 60 years (range 38-78). The stricture was related to the anastomosis after esophagectomy in 12 patients, caustic injury in 3 patients and cervical chemoradiotherapy in 1 patient. Prior to initiation of self-dilatation patients had a median of four endoscopic dilatations. Self-dilatation was done with a Maloney dilator ranging in size from 45 to 60 French. The median duration of self-dilatation was 16 weeks. No patient had a perforation or complication related to self-dilatation. No patient required stenting or repetitive endoscopic dilatations because of failure of self-dilatation. Strictures recurred in two patients after cessation of self-dilatation and both responded to endoscopic dilatation followed by additional self-dilatation. Self-dilatation effectively resolves refractory esophageal strictures. It was well tolerated, and there were no complications in this series. Home self-dilatation should be considered the treatment of choice in appropriate patients with refractory esophageal strictures in the cervical esophagus.

Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients.

In first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA(+) , GADA(+) , IA-2A(+) and/or ZnT8A(+) relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19 and 20-39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A(+) and/or ZnT8A(+) relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10-39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for ≥ 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.

Circular stapled pyloroplasty: a fast and effective technique for pyloric disruption during esophagectomy with gastric pull-up.

The necessity of pyloroplasty after esophagectomy and gastric pull-up is debated. Disadvantages of a standard pyloroplasty include the potential for leak, shortening of the length of the graft, and complexity when done during a minimally invasive procedure. The aim of this study is to report our experience with a novel internal pyloroplasty technique using a circular stapler (CS pyloroplasty), which is applicable for both laparoscopic and open esophagectomy. The records of all patients who underwent an esophagectomy with gastric pull-up and pyloroplasty between 2002 and 2007 were reviewed. The CS pyloroplasty was performed through a lesser curve gastrotomy with a 21-mm CS, while the standard pyloroplasty entailed a longitudinal full thickness incision through the pylorus with mucosal closure in the same direction and a Graham patch. A CS pyloroplasty was performed in 144 and a standard pyloroplasty in 133 patients. The median patient age was 66years, and the median follow-up was 17months, and was similar for both types of pyloroplasty. Routine postoperative videoesophagram was significantly more likely to show a delay in contrast transit through the pylorus after standard pyloroplasty (16% standard vs. 8% CS pyloroplasty, P= 0.03). Significantly more patients had postoperative endoscopy after standard pyloroplasty (40% standard vs. 24% CS pyloroplasty, P= 0.004), but the frequency of pyloric dilatation was similar. There were no leaks with either technique. A circular stapled pyloroplasty is as efficacious as a standard pyloroplasty after esophagectomy with gastric pull-up. Potential advantages include the ease and simplicity of the procedure along with virtually no risk of a leak and no graft shortening. The technique is amenable to both open and minimally invasive procedures.

The gene expression profile of cardia intestinal metaplasia is similar to that of Barrett's esophagus, not gastric intestinal metaplasia.

The etiology and significance of cardia intestinal metaplasia (CIM) is disputed. CIM may represent a form of Barrett's esophagus due to reflux or could reflect generalized gastric intestinal metaplasia due to Helicobacter pylori. The aim of this study was to utilize gene expression data to compare CIM to Barrett's and gastric intestinal metaplasia. Endoscopic biopsies were classified by endoscopic and histologic criteria as CIM (n= 33), Barrett's (n= 25), or gastric intestinal metaplasia of the antrum or body (n= 18). The squamocolumnar and gastroesophageal junctions were aligned in CIM patients and patients with diffuse gastric intestinal metaplasia were excluded. H. pylori was tested for in the biopsies of all patients. After laser-capture microdissection, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression of a panel of nine genes that has been shown to differentiate Barrett's from other foregut mucosa. Cluster analysis with linear discriminant analysis of the expression data was used to classify each sample into groups based solely on similarity of gene expression. Cluster analysis was performed for three groups (CIM vs. Barrett's vs. gastric intestinal metaplasia) and two groups (CIM + Barrett's vs. gastric intestinal metaplasia). There was no difference in H. pylori infection among groups (P= 0.66). Clustering into three groups resulted in frequent misclassification between CIM and Barrett's while misclassification of gastric intestinal metaplasia was uncommon. The CIM and Barrett's groups were then combined for two group clustering and linear discriminant analysis correctly predicted 95% of CIM and Barrett's samples and 83% of gastric intestinal metaplasia samples based on gene expression alone. In conclusion, the gene expression profiles of CIM and Barrett's esophagus were similar in 95% of biopsies and differed significantly from that of gastric intestinal metaplasia. The indistinguishable gene expression profile of CIM and BE suggests that they may share a common etiology in the majority of patients with a similar biology, and calls into question the perception that CIM is an innocuous process.

A multicenter study of survival after neoadjuvant radiotherapy/chemotherapy and esophagectomy for ypT0N0M0R0 esophageal cancer.

OBJECTIVE: To evaluate 5-year survival of patients with locally advanced esophageal cancer (LAEC) who have undergone multimodality treatment with complete histopathologic response. BACKGROUND: Patients with LAEC may obtain excellent local-regional response to multimodality therapy. The overall benefit of a complete histopathologic response, when no viable tumor is present in the surgical specimen, is incompletely understood and existing data are limited to single-center studies with relatively few patients. The aim of this multicenter study was to define the outcome of patients with complete histopathologic response after multimodality therapy for LAEC. METHODS: The study population included 299 patients (229 male, 70 female; median age: 60 years) with LAEC (cT2N1M0, T3-4N0-1M0; 181 adenocarcinomas, 118 squamous carcinomas) who underwent either neoadjuvant radiochemotherapy (n = 284) or chemotherapy (n = 15) followed by esophagectomy at 6 specialized centers: Europe (3) and United States (3). All patients in the study had stage ypT0N0M0R0 after resection. RESULTS: Esophagectomy with thoracotomy (n = 255) was more frequent than with a transhiatal approach (n = 44). The median number of analyzed lymph nodes in the surgical specimens was 20 (minimum-maximum: 1-77). Thirty-day mortality rate was 2.4% and 90-day mortality rate was 5.7%. Overall 5-year survival rate was 55%. The disease-specific 5-year survival rate was 68%, with a recurrence rate of 23.4% (n = 70; local vs distant recurrence: 3.3% vs 20.1%). Cox regression analysis identified age as the only independent predictor of survival, whereas gender, histology, type of esophagectomy, type of neoadjuvant therapy, and the number of resected lymph nodes had no prognostic impact. CONCLUSION: Patients with histopathologic complete response at the time of resection of LAEC achieve excellent survival.

Esophagectomy for cancer in octogenarians.

Because of changes in life expectancy, there is an increasing number of elderly patients with esophageal cancer. The aim of this study was to assess the outcome of esophagectomy for cancer in patients 80 years or older. A retrospective review was performed of the records of all patients who underwent esophagectomy for cancer from 1992 to 2007. A cardiac and pulmonary evaluation was obtained on an individual basis in the younger patients and in all octogenarians. Among 560 patients with esophagectomy for cancer, 47 patients (8%) were octogenarians. The median age of the younger group (n= 513) was 63 years (interquartile range 56-71). Octogenarians had significantly more stage III disease (49% vs 31%, P= 0.02) but received less neoadjuvant therapy than younger patients (2% vs 21%, P= 0.0004). In octogenarians, the transhiatal resection was more common than in the younger group (79% vs 36%, P < 0.0001). Weight loss prior to surgery was similar in both groups, but body mass index was significantly lower in octogenarians (25 vs 28 kg/m(2) , P= 0.0002). Major complications occurred in 26% in octogenarians and 31% in the younger group (P= 0.51). Hospital mortality was similar (9% for octogenarians vs 4% in the younger group, P= 0.13). The median postoperative hospital stay was similar at 16 days (P= 0.69). There was no difference in cancer-related survival (median survival 48.9 vs 59.3 months, P= 0.31 log-rank test). Esophagectomy can be performed safely in carefully selected octogenarians with good cardiac and pulmonary function. Patients should not be denied an esophagectomy based only on their age.

Recurrence of intramucosal esophageal adenocarcinoma arising in a former esophagostomy site: a unique case report.

A 75-year-old male with a long history of gastroesophageal reflux symptoms developed adenocarcinoma proximally within a long segment of Barrett's esophagus. He was taken for esophagectomy and gastric pull-up, but intraoperatively, he was found to have a marginal blood supply in the gastric tube. A temporary left-sided esophagostomy was created with the gastric tube sutured to the left sternocleidomastoid muscle in the neck. Pathology showed an intramucosal adenocarcinoma, limited to the muscularis mucosa with surrounding high-grade dysplasia and intestinal metaplasia. The proximal esophageal margin showed no tumor cells, but there was low-grade dysplasia within Barrett's esophagus. He was reconstructed after several months, and 2 years after reconstruction, the patient noticed a nodule at the former esophagostomy site. Biopsy revealed an implant metastasis of esophageal adenocarcinoma. Here, we review the literature and discuss the possible etiology.

Plasma DNA: a molecular marker of surgical insult and postoperative recovery in esophageal cancer.

AIM: To assess plasma DNA changes intraoperatively, to relate plasma DNA to the magnitude of the surgical insult and to monitor the changes during the postoperative recovery period. MATERIAL AND METHOD: Prospective study of 35 patients with esophageal cancer who had esophagectomy of different magnitudes: 19 esophagectomy without thoracotomy and 16 esophagectomy with thoracotomy. The plasma DNA was measured prior to surgery, throughout the course of the operation on four different intervals, and on postoperative days 1, 3, 5, and 7. RESULTS: A significant difference was seen in the median plasma DNA intraoperatively between the two groups: esophagectomy without thoracotomy, 507 ng/ml/min (range 211-2,708), esophagectomy with thoracotomy, median 1,098 ng/ml/min (range 295-22,284; p = 0.014). Postoperative complications were identified in 6 patients who demonstrated a significant elevation in plasma DNA on postoperative days 5 and 7. CONCLUSION: Plasma DNA increases during surgery as a result of cell damage and the rise correlates with the magnitude of surgery. The descent of plasma DNA postoperatively correlates with surgical recovery. Elevation of the plasma DNA during the postoperative period correlates with postoperative complications. Plasma DNA is an objective molecular marker of surgical insult and can be used to monitor postoperative recovery after esophagectomy.

Can clinical and endoscopic findings accurately predict early-stage adenocarcinoma?

BACKGROUND: The presentation and management of esophageal cancer are changing, as more patients are diagnosed at an earlier stage of the disease in which endoscopic treatment methods may be contemplated. Therefore, we conducted a study to determine whether symptomatic and endoscopic findings can accurately identify node-negative early-stage adenocarcinoma. METHODS: A total of 213 consecutive patients (171 men and 42 women) with resectable esophageal adenocarcinoma seen from 1992 to 2002 were evaluated. None of these patients received neoadjuvant chemotherapy or radiation therapy. Using a multivariable model, model-based probabilities of early-stage disease (T1 im/sm N0) were calculated for each combination of the following three features: no dysphagia as main symptom at presentation, tumor length

Predictive factors of coexisting cancer in Barrett's high-grade dysplasia.

BACKGROUND: Identification of high-grade dysplasia (HGD) in Barrett's esophagus has been considered an indication for esophagectomy because of the high risk for coexisting cancer. However, rigorous endoscopic surveillance programs recently have been recommended, reserving esophagectomy for patients whose cancer is identified on biopsy. This approach risks continued surveillance for patients who already have cancer unless reliable markers for the presence of occult cancer are identified. This study aimed to determine the endoscopic, histologic, and demographic features associated with the presence of occult cancer in patients with HGD. METHODS: Endoscopic, histologic, and demographic findings for 31 patients who underwent esophagectomy for HGD were reviewed. The presence of an ulcer, nodule, stricture, or raised area on preoperative endoscopy was noted. The results of endoscopic biopsies taken before resection every 1 to 2 cm along the Barrett's segment were reviewed. The HGD was categorized as unilevel if the dysplasia was limited to one level of biopsy and as multilevel if more than one level was involved. Patients were divided into two groups according to the presence or absence of cancer in the resected specimens, and these variables were compared. RESULTS: The prevalence of coexisting cancer in patients with HGD was 45% (14/31). Of the 31 patients in this study, 9 had a visible lesion. Cancer was found in the resected specimens from 7 (78%) of 9 patients with a visible lesion and 7 (32%) of 22 patients without a visible lesion (p = 0.019). Of 22 patients without a visible lesion, 10 had multilevel and 12 had unilevel HGD. The findings showed that 6 (60%) of 10 patients with multilevel HGD and 1 (8.3%) of 12 patients with unilevel HGD had cancer in the resected esophagus (p = 0.009). CONCLUSION: For patients with HGD, a lesion visible on endoscopy and/or HGD at multiple biopsy levels is associated with an increased risk for coexisting cancer. These patients should be considered for early esophagectomy.

Bravo capsule induction of esophageal hypercontractility and chest pain.

BACKGROUND: The Bravo catheter-free pH monitoring system uses a capsule attached to the esophageal mucosa to detect acid exposure. Placement of the Bravo capsule is associated with intermittent chest pain in 50% of normal volunteers. The authors hypothesized that chest pain in this setting may be attributable to hypertensive esophageal contractions induced by the Bravo capsule. METHODS: The study population consisted of 40 consecutive patients with reflux symptoms who had stationary esophageal manometry within 1 h after Bravo capsule placement. The control group consisted of 40 patients with symptomatic gastroesophageal reflux disease (GERD) from a population of patients with foregut symptoms who were computer matched to the study group for age, sex, lower esophageal sphincter (LES) pressure, LES length, and 24-h pH composite score. The patients in the control group had manometry before Bravo capsule placement. The occurrence of chest pain was assessed before and during the monitoring period by interview and review of the patient's diary. Mean contraction amplitudes in the distal third of the esophagus after 10 wet swallows were averaged. The prevalence of patients with esophageal contraction amplitudes in the distal third that exceeded the 95th percentile of normal (180 mmHg) and the mean amplitude of distal third esophageal contractions in the study and control populations were compared. In the study group, the incidence of chest pain among the patients with hypercontractility of the esophagus was compared with the incidence among those without hypercontractility. RESULTS: The mean contraction amplitude was higher in the study group (144.7 vs 105.5 mmHg; p = 0.002). The number of patients with a mean distal esophageal contraction amplitude exceeding the 95th percentile of normal also was significantly higher in the study group (13/40 vs 5/40; p = 0.03). A total of 10 patients experienced new onset of chest pain with the Bravo capsule in place, and 6 patients experienced hypertensive esophageal contractions. CONCLUSIONS: The intraesophageal Bravo capsule can cause hypertensive esophageal contractions, which may lead to chest pain.

Epigenetic patterns in the progression of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples]. This group could be further subdivided into three classes, according to the absence (CDKN2A, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progression.

The safety and usefulness of endoscopy for evaluation of the graft and anastomosis early after esophagectomy and reconstruction.

BACKGROUND: Although rare, graft ischemia and necrosis after esophagectomy is a devastating complication. The aim of this study was to review our experience with early endoscopy for evaluation of the graft and anastomosis after esophagectomy and reconstruction. METHODS: From a population of 479 patients who underwent esophagectomy during the years 1996-2003, we identified 102 patients who had endoscopy within 21 days of operation. RESULTS: Endoscopy was performed a median of 9 days after operation. Graft ischemia, anastomotic leak, or both were found in 63 of the 102 patients. Reoperation was necessary in 27% of these patients, including graft removal in nine patients. In 39 patients, endoscopy demonstrated a healthy graft; only one of these patients (2.6%) required reoperation. No patient with ischemia judged insufficient to warrant graft removal on initial endoscopy subsequently lost their graft. There were no complications or anastomotic injuries associated with early endoscopy. CONCLUSION: Endoscopy early after esophagectomy is safe and provides accurate and reliable identification of graft ischemia that can be used to guide the treatment of these patients.

Attenuation of rat lung isograft reperfusion injury with a combination of anti-ICAM-1 and anti-beta2 integrin monoclonal antibodies.

Four different combinations of monoclonal antibodies against rat ICAM-1, CD-11a, and CD-18 were utilized to determine the relative importance of LFA-1, Mac-1, and ICAM-1 in a rat model of severe lung allograft reperfusion injury. Negative control animals were given phosphate buffered saline (the carrier solution for the antibodies), while positive control animals were rendered neutropenic by the administration of a polyclonal mouse IgG. Antibodies were given with the donor lung flush, prior to left lung graft reperfusion, or both. Isolated graft function was determined 24 hr after implantation by arterial blood gas (ABG), and after sacrifice the native and transplanted lungs underwent bronchoalveolar lavage for alveolar protein quantitation, cell count and differential, and myeloperoxidase assay. Additionally, whole lung homogenates were assayed for myeloperoxidase activity. We found that the combination of anti-ICAM-1 (1 mg/kg) added to the donor lung flush, and anti-CD11a, anti-CD18, and anti-ICAM-1 (2 mg/kg i.v. of each) given to the recipient prior to reperfusion, resulted in significantly improved lung graft pAO2 by ABG, and decreased alveolar protein, cell count, and myeloperoxidase activity compared with control animals. Improvement was less than that seen in the neutropenic recipients, however. We conclude that LFA-1, Mac-1, and ICAM-1 are all important adhesion molecules in lung allograft reperfusion injury--yet even with antibody blockade of all three there are additional mechanisms allowing for neutrophil influx into the lungs.

Pyrrolidine dithiocarbamate activates the heat shock response and thereby induces apoptosis in primed endothelial cells.

Transcription factor NF-kappaB is an important regulator of the cellular response to diverse stresses. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB activity, was used to determine the role of this transcription factor in our model of stress-induced endothelial cell apoptosis. Porcine aortic endothelial cells were treated with an inducer of the acute phase response (LPS) followed by treatment with an inducer of the heat shock response (arsenite), a sequence that produces cell death by apoptosis. Treatment with PDTC attenuated LPS-induced NF-kappaB activity and endothelial cell death when added prior to LPS. However, PDTC unexpectedly increased cell death when given after LPS priming. This time-dependent effect of PDTC on endothelial cell death was similar to that which we had observed previously for inducers of the heat shock response. Therefore, we hypothesized that PDTC could induce the heat shock response in porcine and human endothelial cells. PDTC increased heat shock protein (HSP)-70 production and heat shock factor (HSF) activity. Thus, treatment of endothelial cells with PDTC, like other inducers of the heat shock response, increased HSP-70 levels and HSF activity and had time-dependent effects on cell death by apoptosis in primed endothelial cells. We conclude that PDTC induced the heat shock response, that induction of HSF activity may be linked with inhibition of NF-kappaB activity, and that interaction between acute phase and heat shock regulatory factors may be pivotal to determining cell fate (apoptosis).

Lobectomy combined with volume reduction for patients with lung cancer and advanced emphysema.

OBJECTIVE: Early-stage lung cancer is best treated by anatomic pulmonary resection. Patients with lung cancer and severe emphysema are often denied resection or are offered only limited, nonanatomic resections when established pulmonary function criteria for lobectomy are not met. Recently, with the introduction of the volume reduction operation, selected patients with disabling emphysema have undergone excision of approximately 30% of the most destroyed lung tissue and have subsequently demonstrated subjective and objective improvement in pulmonary function. Using these principles, we elected to combine anatomic lobectomy with volume reduction in a select group of patients with both emphysema and lung cancer who would not otherwise be candidates for pulmonary resection. METHODS: Five patients with severe emphysema and suspected or proven lung cancers, who were poor candidates for anatomic lobectomy by traditional criteria but were good candidates for volume reduction, underwent lobectomy combined with volume reduction of one or more additional lobes. RESULTS: All five patients having lung volume reduction and anatomic lobectomy for early-stage primary lung cancer did well postoperatively. Furthermore, each patient has demonstrated subjective and objective improvement in respiratory function on serial postoperative studies. CONCLUSIONS: Selected patients with disabling emphysema and suitable anatomy for volume reduction, who have a lung cancer situated in destroyed lung tissue, may benefit from combined lobectomy and volume reduction. The introduction of the volume reduction operation has added a new factor in the algorithm for the evaluation and treatment of lung cancer in selected patients with advanced emphysema.

Inhibition of inducible nitric oxide synthase ameliorates rat lung allograft rejection.

Recently, the inducible isoform of nitric oxide synthase has been shown to be an important immunomodulation molecule in allograft rejection. We have observed the production of nitric oxide during rejection and the effect of nitric oxide synthase inhibition on allograft rejection in a rat lung transplant model. Rat left lung allotransplants were performed in two strain combinations: brown Norway-to-F344 (major histocompatibility complex incompatible); and Lewis-to-F344 (minor loci incompatible) as severe and mild rejection models respectively. Syngeneic F344-to-F344 transplants were performed as a negative control. Nitric oxide production during rejection was determined by measuring the recipient's serum nitrite/nitrate levels as a stable end product of nitric oxide. The progression of rejection was evaluated radiographically and the grade of rejection was determined histologically. After operation, recipients of allotransplantation were randomly divided into two groups and received either aminoguanidine (200 mg/kg, intraperitoneal every 6 hours), a potent inducible nitric oxide synthase inhibitor, or normal saline treatment. The levels of serum nitrite and nitrate in recipients increased in the early phase of rejection in both allotransplant combinations. However, in the terminal phase of rejection, the serum nitrite/nitrate level decreased significantly compared with the peak level in the brown Norway-to-F344 recipients. The serum nitrite/nitrate levels in the syngeneic transplant recipients were normal during the entire observation period. In aminoguanidine-treated animals, serum nitrite/nitrate levels remained normal in both allograft combinations. Significant suppression of rejection in aminoguanidine-treated recipients was observed histologically and radiographically in comparison with untreated recipients in the brown Norway-to-F344 combinations. In the Lewis-to-F344 combination, aminoguanidine treatment significantly ameliorated histologic rejection but did not affect radiologic appearance. We therefore conclude nitric oxide is produced during early allograft rejection and may prove to be a marker and mediator of early rejection. The inhibition of inducible nitric oxide synthase results in significant reduction in rat lung allograft rejection.

Inhaled nitric oxide improves lung allograft function after prolonged storage.

Morbidity caused by early allograft dysfunction, manifested by a progressive increase in pulmonary vascular resistance and a decrease in oxygenation, remains a serious problem in lung transplantation. Inhalation of nitric oxide, an essential homeostatic molecule, has been shown to have beneficial effects on a variety of acute lung injuries. The purpose of the present study was to investigate the effect of inhaled nitric oxide on posttransplant function of canine left lung allografts. Fourteen dogs underwent left lung allotransplantation. Donors received systemic heparin and prostaglandin E1 followed by pulmonary artery flush with modified Euro-Collins solution. Donor left lungs were stored for 18 hours at 1 degree C and subsequently implanted. Immediately after reperfusion, the contralateral right main pulmonary artery and bronchus were ligated. The chest was closed and recipients turned to the supine position for the 6-hour assessment period. Hemodynamic and arterial and venous blood gas analyses were made at 15-minute intervals at an inspired oxygen fraction of 1.0 and 5 cm of water positive end-expiratory pressure. Animals were killed at the end of the assessment. Allograft myeloperoxidase activity assays and wet/dry weight ratios were done. In group I (n = 5), nitric oxide gas was administered continuously at concentrations of 60 to 70 ppm before reperfusion and throughout the 6-hour assessment period. In group II (n = 5), nitric oxide administration was initiated at the same concentration after reperfusion injury had developed. Group III animals (n = 4) received no nitric oxide. Significant improvement in gas exchange was apparent in group I. At the end of the 6-hour assessment period, mean arterial oxygen tension was 253.8 +/- 44.7 mm Hg and 114.9 +/- 25.5 mm Hg in groups I and III, respectively (p < 0.05). Group II animals had no improvement in oxygenation with nitric oxide. Systemic hemodynamics were unaffected by nitric oxide. However, an immediate decrease in pulmonary vascular resistance was noted. Group I myeloperoxidase activity was significantly lower than that in control group III (0.24 +/- 0.06 versus 0.36 +/- 0.04 units, respectively; p < 0.05).