Utility of endoscopic therapy in the management of Boerhaave syndrome.

Background/aims: The optimal intervention for Boerhaave perforation has not been determined. Options include surgical repair with/without a pedicled muscle flap, T tube placement, esophageal resection or diversion, or an endoscopic approach. All management strategies require adequate drainage and nutritional support. Our aim was to evaluate outcomes following Boerhaave perforation treated with surgery, endoscopic therapy, or both. Patients and methods: We performed a 10-year review of our prospectively maintained databases of adult patients with Boerhaave perforations. We documented clinical presentation, extent of injury, primary intervention, "salvage" treatment (any treatment for persistent leak), and outcome. Results were analyzed using the Fisher's exact and Kruskal - Wallis tests. Results: Between October 2004 and October 2014, 235 patients presented with esophageal leak/fistula with 17 Boerhaave perforations. Median age was 68 years. Median length of perforation was 1.25 cm (range 0.8 - 5 cm). Four patients presented with systemic sepsis (two treated with palliative stent and two surgically). Primary endotherapy was performed for eight (50 %) and primary surgery for eight (50 %) patients. Two endotherapy patients required multiple stents. Median stent duration was 61 days (range 56 - 76). "Salvage" intervention was required in 2/8 (25 %) endotherapy patients and 1/8 (13 %) surgery patient (stent). All patients healed without resection/reconstruction. There were no deaths in the surgically treated group and two in the endotherapy group (stented with palliative intent due to poor systemic condition). Readmission within 30 days occurred in 3/6 of alive endotherapy patients (50 %) and 0/8 surgery patients. Re-intervention within 30 days was required for one endotherapy patient. Conclusion: Endoscopic repair of Boerhaave perforations can be useful in carefully selected patients without evidence of systemic sepsis. Endoscopic therapy such as stenting is particularly valuable as a "salvage" intervention. The benefits of endoscopic therapy and esophageal preservation are offset against an increased risk of readmission in patients primarily treated endoscopically.

Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%. PATIENTS AND METHODS: From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0. RESULTS: Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%). CONCLUSIONS: Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended. CLINICALTRIALSGOV IDENTIFIER: NCT00757172.

Patterns of operative mortality following esophagectomy.

Esophagectomy has one of the highest mortality rates among all surgical procedures. We investigated the type and frequency of complications associated with perioperative mortality after esophagectomy. We performed a retrospective review of all perioperative deaths following esophagectomy for esophageal cancer at the Mayo Clinic, Rochester from 1993 through 2009. Of 1522 esophagectomies, perioperative mortality occurred in 45 (3.0%). The majority who died were male (82%); median age was 72 years (range 46-92). The median age-adjusted Charlson comorbidity score was 6. Twenty-three (51%) underwent neoadjuvant chemoradiotherapy. The type of esophagectomy was transthoracic in 27 patients (60%), transhiatal in eight (18%), tri-incisional in seven (16%), left thoracoabdominal in one (2%), and transabdominal in one (2%). A mean of 3.2 major complications occurred prior to death (median 2.5, range 1-8), with the most common being pulmonary complications occurring in 30 patients (67%) and anastomotic complications in 20 (44%). The primary underlying cause of death was pulmonary complications and anastomotic complications in 18 patients (40%) each, respectively, abdominal sepsis in three (7%), fatal hemorrhage in three (7%), and pulmonary embolism, stroke and multisystem organ failure in one each (2%), respectively. Patients died a median of 19 days (range 3-98) following esophagectomy. Most patients who died following esophagectomy experienced multiple serious complications rather than a single causative event. Major pulmonary and anastomotic complications were implicated in the vast majority of perioperative mortality, and should remain the focus of efforts to improve clinical outcomes.

Impact of endoscopic ultrasonography and physician specialty on the management of patients with esophagus cancer.

While endoscopic ultrasonography (EUS) and EUS-guided fine-needle aspiration (EUS-FNA) are the most accurate techniques for locoregional staging of esophageal cancer, little evidence exists that these innovations impact on clinical care. The objective on this study was to determine the frequency with which EUS and EUS-FNA alter the management of patients with localized esophageal cancer, and assess practice variation among specialists at a tertiary care center. Three gastroenterologists, three medical oncologists, three radiation oncologists and four thoracic surgeons were asked to independently report their management recommendations as the anonymized staging information of 50 prospectively enrolled patients from another study were sequentially disclosed on-line. Compared to initial management recommendations, that were based upon history, physical examination, upper endoscopy and CT scan results, EUS prompted a change in management 24% (95% CI: 12-36%) of the time; usually to a more resource-intensive approach (71%), for example from recommending palliation to recommending neoadjuvant chemoradiation therapy. EUS-FNA plus cytology results altered management an additional 8% (95% CI: 6-15%) of the time. Agreement between specialists ranged from fair (intraclass correlation [ICC=0.32) to substantial (ICC=0.65); improving with additional information. Among specialists, agreement was greatest for patients with stage I disease. EUS and EUS-FNA changed patient management the most for patients with stages IIA, IIB or III disease. EUS, with or without FNA, significantly impacts the management of patients with localized esophageal cancer. With respect to the optimal treatment for each patient, agreement among physicians incrementally increases with endoscopic ultrasound results. Specialty training appears to influence therapeutic decision-making behavior.

Curing patients with locally advanced esophageal cancer: an update on multimodality therapy.

Combining different treatment modalities--such as surgery, radiation, and chemotherapy--is often utilized to treat patients with locally advanced esophageal cancer. However, it remains controversial how best to combine these modalities to provide patients with the greatest chance of cure. This review discusses recent studies in this field and outlines promising versus less promising therapeutic strategies.

Percutaneous endoscopic gastrostomy risks rendering the gastric conduit unusable for esophagectomy.

Surgical treatment for cancer of the esophagus most often involves replacement of the esophagus with a gastric conduit. This gastric tube relies upon the continuity of the gastroepiploic artery for its blood supply. This case report involves a patient whose gastroepiploic artery became thrombosed by a percutaneous endoscopic gastrostomy, rendering his gastric conduit unusable.

Flaccid quadriplegia due to necrotizing myopathy following lung transplantation.

Critical illness myopathy (CIM) which is common after sepsis and multiorgan failure also has been described after organ transplantation. Prior reports of CIM after lung transplantation have not recorded a necrotizing myopathy. We present a 42-year-old man who developed a necrotizing critical illness myopathy following bilateral orthotopic lung transplantation. In addition we provide pathological confirmation that the ventral roots, spinal cord and the rest of the neuraxis are preserved in this condition. Extensive muscle necrosis is documented.

Massive intrapericardial herniation of stomach following pericardial window.

Herniation of intra-abdominal contents into the pericardial cavity is rare. We describe one such case occurring after creation of a pericardioperitoneal window for drainage of a pericardial effusion. The diagnosis of an intrapericardial hernia should be considered in patients presenting with gastrointestinal and/or cardiorespiratory symptoms following surgical procedures involving the diaphragm.

Transplant immunosuppression increases and prolongs transgene expression following adenoviral-mediated transfection of rat lungs.

BACKGROUND: Gene therapy provides the potential to modify donor organs to better withstand transplantation, but this has yet to be realized. In vivo gene transfer using adenoviral vectors has had limited success because of host immune response that induces inflammation and limits the amount and duration of transgene expression. We hypothesize that transplantation immunosuppression can attenuate the post-transfection host-immune response to allow for improved gene transfer following adenoviral-mediated transfection. METHODS: We intratracheally transfected with adenovirus containing the beta-galactosidase gene and randomized the rats to either the immunosuppression group, receiving daily cyclosporine, azathioprine, and methylprednisolone, or the control group, receiving no immunosuppression. We evaluated transgene expression and post-transfection inflammation at time points ranging from 1 day to 5 weeks. RESULTS: Following transfection, control rats showed relatively low levels of transgene expression, which rapidly decreased to non-detectable levels. In contrast, immunosuppressed rats demonstrated significantly higher levels of transgene expression overall (p < 0.00005), peaking at almost 3 times that of the control group (p < 0.02), and showing prolonged and elevated transgene expression at 5 weeks (p < 0.02). On histologic sections of the lungs, immunosuppressed rats exhibited overall lesser grades of post-transfection inflammation. CONCLUSIONS: Transplant immunosuppression provides the means to attenuate the severe immune response to adenoviral-mediated gene transfection and thereby increase and prolong transgene expression.

A novel cell culture model for studying ischemia-reperfusion injury in lung transplantation.

Many cell culture models have been developed to study ischemia-reperfusion injury; however, none is specific to the conditions of lung preservation and transplantation. The objective of this study was to design a cell culture model that mimics clinical lung transplantation, in which preservation is aerobic and hypothermic. A549 cells, a human pulmonary epithelial cell line, were preserved in 100% O(2) at 4 degrees C for varying periods in low-potassium dextran glucose solution, simulating ischemia, followed by the introduction of warm (37 degrees C) DMEM plus 10% fetal bovine serum to simulate reperfusion. Cultures were assayed for cell attachment and viability. Sequential extension of ischemic times to 24 h showed a time-dependent loss of cells. There was a further decrease in cell number after simulated reperfusion. Cell detachment was due mainly to cell death, as determined by cell viability. The effects of chemical components such as dextran 40 and calcium in the preservation solution and various preservation gas mixtures were examined by use of this model system. With its design and validation, this model could be used to study mechanisms related to ischemia-reperfusion injury at the cellular and molecular level.

Alterations of nitric oxide synthase expression and activity during rat lung transplantation.

Decreased nitric oxide (NO) production has been reported during lung transplantation in patients. To study the effects of ischemia and reperfusion on endogenous NO synthase (NOS) expression, both an ex vivo and an in vivo lung injury model for transplantation were used. Donor rat lungs were flushed with cold low-potassium dextran solution and subjected to either cold (4 degrees C for 12 h) or warm (21 degrees C for 4 h) ischemic preservation followed by reperfusion with an ex vivo model. A significant increase in inducible NOS and a decrease in endothelial NOS mRNA was found after reperfusion. These results were confirmed in a rat single-lung transplant model after warm preservation. Interestingly, protein contents of both inducible NOS and endothelial NOS increased in the transplanted lung after 2 h of reperfusion. However, the total activity of NOS in the transplanted lungs remained at very low levels. We conclude that ischemic lung preservation and reperfusion result in altered NOS gene and protein expression with inhibited NOS activity, which may contribute to the injury of lung transplants.

Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation.

OBJECTIVE: To examine the presence and extent of apoptosis as well as the affected cell types in human lung tissue before, during, and after transplantation. SUMMARY BACKGROUND DATA: Apoptosis has been described in various human and animal models of ischemia-reperfusion injury, including heart, liver, and kidney, but not in lungs. Therefore, the presence of apoptosis and its role in human lungs after transplantation is not clear. METHODS: Lung tissue biopsies were obtained from 20 consecutive human lungs for transplantation after cold ischemic preservation (1-5 hours), after warm ischemia time (during implantation), and 30, 60, and 120 minutes after graft reperfusion. To detect and quantify apoptosis, fluorescent in situ end labeling of DNA fragments (TUNEL assay) was used. Electron microscopy was performed to verify the morphologic changes consistent with apoptosis and to identify the cell types, which were lost by apoptosis. RESULTS: Almost no evidence of apoptosis was found in specimens after immediate cold and warm ischemic periods. Significant increases in the numbers of cells undergoing apoptosis were observed after graft reperfusion in a time-dependent manner. The mean fraction of apoptotic cells at 30, 60, and 120 minutes after graft reperfusion were 16.6%, 22.1%, and 34.9% of total cells, respectively. Most of the apoptotic cells appeared to be alveolar type II pneumocytes, as confirmed by electron microscopy. CONCLUSIONS: Programmed cell death (apoptosis) appears to be a significant type of cell loss in human lungs after transplantation, and this may contribute to ischemia-reperfusion injury during the early phase of graft reperfusion. This cell loss might be responsible for severe organ dysfunction, which is seen in 20% of patients after lung transplantation. Therefore, this work is of importance to surgeons for the future development of interventions to prevent cell death in transplantation.

Transtracheal gene transfection of donor lungs prior to organ procurement increases transgene levels at reperfusion and following transplantation.

BACKGROUND: Gene therapy's potential to modify donor organs to better withstand the process of transplantation has yet to be realized. To determine whether gene transfection is feasible to treat the early post-transplant injury of ischemia-reperfusion, we compared transfection of lungs in the donor prior to organ procurement with transfection of harvested ex vivo lungs in a rat single lung transplant model. METHODS: Lewis rats (donor transfection [DT]; n = 4) underwent transtracheal adenoviral-mediated transfection with 10(9) plaque forming unit of the beta-galactosidase reporter gene. Donor lungs were harvested following 6 hours of in vivo post-transfection ventilation, and then preserved for 6 hours at 4 degrees C prior to left single-lung transplantation. Ex vivo transfection was performed following organ retrieval; lungs were then preserved at 4 degrees C for 6 hours (EVT6h; n = 6) and 12 hours (EVT12h; n = 6) prior to transplantation. Lung transgene expression was measured by chemiluminescence at reperfusion, and at 2 hours following lung transplantation. RESULTS: Donor transfection lungs showed significantly higher levels of transgene expression as compared with EVT lungs at the time of reperfusion (DT = 3,408+/-1,301 relative light units/mg protein; EVT6h = 218+/-7; EVT12h = 213+/-26; p < 0.02) and at 2 hours after lung transplantation (DT = 2900+/-870; EVT6h = 62+/-27; EVT12h = 123+/-21; p < 0.005). Transgene expression measured in the heart, liver, kidney, and serum from DT rats demonstrated virtually no evidence of collateral transfection at 12 hours post-transfection (all <5.0). CONCLUSIONS: Gene transfection of donor lungs produces significantly higher levels of transgene expression in lungs at the critical time of reperfusion and in the early period following lung transplantation as compared to ex vivo transfection of cold preserved lungs. Transtracheal donor-lung transfection does not appear to result in collateral transfection of other transplantable organs. Local adenoviral-mediated transfection of the lungs is possible in the multiorgan donor prior to organ procurement and may provide the optimal strategy for gene therapeutic manipulations to address post-transplant ischemia-reperfusion injury.

Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression.

OBJECTIVES: Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged. METHODS: Lewis rats underwent intratracheal adenovirus-mediated transfection with the beta-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection. RESULTS: After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P <.001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation. CONCLUSIONS: Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administration of gene therapy.

Effect of complement inhibition with soluble complement receptor 1 on pig allotransplant lung function.

BACKGROUND: Lung dysfunction after transplantation continues to be a significant clinical problem. Soluble complement receptor 1 (sCR1) is a potent inhibitor of complement activation. We evaluated the inhibitory effect of sCR1 on complement activation and reperfusion injury in pig lung allografts. METHODS: In a randomized and blinded study, left lung transplantation was performed in 13 pigs. Donor lungs were flushed and then stored for 30 hr at 4 degrees C. Control pigs (n=7) received saline, and the treatment group (n=6) received 15 mg/kg sCR1 1 hr before reperfusion. One hour after reperfusion, the right pulmonary artery was clamped for 10 min to assess the function of the transplanted lung. Pulmonary function was assessed again on day 3. RESULTS: Complement inhibition was 93% in the sCR1 group and returned to baseline (8% inhibition) after 3 days. There was a trend toward a higher partial pressure of oxygen at 1 hr in the sCR1 group compared with the control group (mean +/- SE: 408+/-42 mmHg vs. 288+/-69 mmHg, P = 0.19). Alveolar ventilation was better in the sCR1 group than in the control group (P = 0.01) at 1 hr. Mixed venous saturation was significantly lower in the control group at both 1 hr (P = 0.02) and 3 days (P = 0.001). The wet/dry weight of the lung tissue was lower in the sCR1 group compared with the control group on day 3 (P < 0.05). Chemiluminescence, an index of phagocyte priming, was lower in the sCR1 group when cells were stimulated with complement opsonized zymosan but not when stimulated with zymosan or phorbol myristate acetate. CONCLUSION: sCR1 improves ventilation, reduces pulmonary edema, and may be beneficial in improving posttransplant lung oxygenation.