Does neoadjuvant therapy for esophageal cancer increase postoperative morbidity or mortality?

Neoadjuvant therapy has proven to be effective in the reduction of locoregional recurrence and mortality for esophageal cancer. However, induction treatment has been reported to be associated with increased risk of postoperative complications. We therefore compared outcomes after esophagectomy for esophageal cancer for patients who underwent neoadjuvant therapy and patients treated with surgery alone. Using the American College of Surgeons National Surgical Quality Improvement Program database (2005-2011), we identified 1939 patients who underwent esophagectomy for esophageal cancer. Seven hundred and eight (36.5%) received neoadjuvant therapy, while 1231 (63.5%) received no neoadjuvant therapy within 90 days prior to surgery. Primary outcome was 30-day mortality, and secondary outcomes included overall and serious morbidity, length of stay, and operative time. Patients who underwent neoadjuvant treatment were younger (62.3 vs. 64.7, P < 0.001), were more likely to have experienced recent weight loss (29.4% vs. 15.9%, P < 0.001), and had worse preoperative hematological cell counts (white blood cells <4.5 or >11 × 10(9) /L: 29.3% vs. 15.0%, P < 0.001; hematocrit <36%: 49.7% vs. 30.0%, P < 0.001). On unadjusted analysis, 30-day mortality, overall, and serious morbidity were comparable between the two groups, with the exception of the individual complications of venous thromboembolic events and bleeding transfusion, which were significantly lower in the surgery-only patients (5.71% vs. 8.27%, P = 0.027; 6.89% vs. 10.57%, P = 0.004; respectively). Multivariable and matched analysis confirmed that 30-day mortality, overall, and serious morbidity, as well as prolonged length of stay, were comparable between the two groups of patients. An increasing trend of preoperative neoadjuvant therapy for esophageal cancer was observed through the study years (from 29.0% in 2005-2006 to 44.0% in 2011, P < 0.001). According to our analysis, preoperative neoadjuvant therapy for esophageal cancer does not increase 30-day mortality or the overall risk of postoperative complications after esophagectomy.

Age and sex differences in the incidence of esophageal adenocarcinoma: results from the Surveillance, Epidemiology, and End Results (SEER) Registry (1973-2008).

Risk factors driving sex disparity in esophageal cancer are unclear. Recent molecular evidence suggests hormonal factors. We conducted a national descriptive epidemiological study to assess the hypothesis that estrogen exposure could explain the male predominance in observed esophageal adenocarcinoma incidence. We analyzed the esophageal cancer incidence trends by histology and sex from 1973 to 2008 in nine population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) 9 Registry Database. We used age as a proxy for estrogen exposure in females. The collective age groups annual percentage change in esophageal adenocarcinoma for females is positive (0.03%; 95% confidence interval: 0.02, 0.03%) during the study period. Interestingly, the esophageal adenocarcinoma annual percentage change in incidence rates for females during the same time period is significantly negative from ages 50-54 to ages 60-64. Even though the incidence of esophageal adenocarcinoma rises in both males and females, the male-to-female ratio across age peaks in the 50-54 years then decreases. Furthermore, the esophageal adenocarcinoma age-adjusted incidence rate in postmenopausal females age 80 and above increases with age unlike their male counterparts. Taken together, these data support the hypothesis that the endocrine milieu in pre- and perimenopausal females serves as a protective factor against esophageal adenocarcinoma, and with loss of estrogen or because of the increasing time period away from estrogen exposure, the rate of esophageal adenocarcinoma incidence increases in the older postmenopausal female. Because females comprise the largest portion of the elderly population with esophageal adenocarcinoma, these findings are significant.

Induction therapy in lung transplantation: a prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab.

BACKGROUND: Because acute rejection is associated with inferior outcomes in lung transplantation, we have routinely employed OKT3, anti-thymocyte globulin (ATG), or daclizumab as adjuncts to reduce rejection. METHOD: We performed a 4-year prospective, controlled clinical trial of these 3 therapies to determine differences in post-operative infection, rejection, survival, and bronchiolitis obliterans syndrome (BOS). Eighty-seven consecutive lung transplant patients received OKT3 (n = 30), ATG (n = 34), and daclizumab (n = 23) as induction agents. The groups had similar demographics and immunosuppression protocols differing only in induction agents used. RESULTS: No differences were observed in immediate post-operative outcomes such as length of hospitalization, ICU stay, or time on ventilators. Twelve months post-transplant, OKT3 had more infections per patient than the other agents, a difference that only became significant 2 months post-operatively (p = 0.009). The most common infection was bacterial and OKT3 had more bacterial infections than any other agent. Daclizumab had more patients remain infection free in the first year (p = 0.02), having no fungal infections and a low rate of viral infections. No patient receiving daclizumab developed drug specific side-effects. Only those patients with episodes of acute rejection developed BOS. There were no significant differences in the freedom from acute rejection or BOS between the groups. The 2-year survival for the entire cohort was 68%, with no differences observed in patient survival. CONCLUSIONS: This study again reveals the importance of acute rejection in the subsequent development of BOS. Although daclizumab offers a low risk of post-transplant infection and drug specific side-effects, no drug is superior in delaying rejection or BOS or in prolonging long-term survival.

The changing profile of the cardiac donor.

BACKGROUND: Expansion of traditional donor criteria has become standard in most centers. To determine how this has affected donor profiles, at our institution, we reviewed all adult (age > or = 16) cardiac donors of the past 15 years. METHODS: We separated 261 cardiac donors into 2 groups based on time periods: Group I, 1983 to 1991 (n = 131), and Group II, 1991 to 1998 (n = 130). RESULTS: The groups differed significantly in mean donor age (26.2 years vs 30.9; p < 0.001), percent older than 40 years (6% vs 27%; p < 0.001), percent female (23% vs 35%; p = 0.04), percent distant procurement (54% vs 22%; p < 0.001), and percent minority donors (14% vs 29%; p < 0.001). We found an increase in non-traumatic deaths (24% vs 40%; p = 0.008). Older donors had significantly more non-traumatic deaths than younger donors (79% vs 13%; p < 0.001). Overall 5-year survival of recipients was 64% and was not significantly different between our early and late experiences (60% vs 68%; p = not significant [NS]). Recipients with hearts from older donors had a 5-year survival similar to recipients with younger donor hearts (61% vs 64%; p = NS). Traumatic and non-traumatic donors had similar 5-year survivals (64% vs 63%, p = NS). A stepwise multivariate analysis of the entire cohort identified donor age, donor weight, recipient United Network for Organ Sharing status, and cardiopulmonary bypass time as significant independent risk factors for recipient survival. Recipients of hearts from donors < 90 kg had significantly better 5-year survivals than recipients from donors > or = 90 kg (66% vs 48%; p = 0.01). CONCLUSIONS: Our evolving cardiac donor pool now has more minorities, women, and older donors whose deaths are often non-traumatic. At our institution, donor pool expansion has had no adverse effect on the long-term survival of recipients.

Percutaneous replacement jejunostomy after esophagogastrectomy.

A surgically placed jejunostomy tube is a safe and effective means of delivering nutritional support for the postesophagogastrectomy patient. We have previously described a method that permits percutaneous replacement of surgically placed jejunostomy feeding tubes, and now present our results with the use of this technique in 350 consecutive esophagogastrectomy patients. Replacement jejunostomy as required in 17 patients (4.9%). All patients had successful percutaneous jejunostomy replacement. There were no procedural complications or deaths. The timing of feeding tube replacement following esophagogastrectomy was predictive of the indication. Before 16 weeks, the indication for feeding tube replacement was intubation and inability to eat (1 patient) or anorexia with weight loss and dehydration (7 patients). At or after 16 weeks, the indications for feeding tube replacement were all related to symptoms resulting from recurrent carcinoma. We conclude that the technique of percutaneous jejunostomy allows the surgeon tremendous flexibility in the management of the postesophagogastrectomy patient as it preserves the advantages of an adjuvant surgically placed feeding tube over the lifetime of the patient. The technique is safe, and the success rate is excellent.

Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury?

BACKGROUND: Central nervous system dysfunction continues to produce significant morbidity and associated mortality in patients undergoing cardiac surgery. Using a closed-chest canine cardiopulmonary bypass model, dogs underwent 2 h of hypothermic circulatory arrest (HCA) at 18 degrees C, followed by resuscitation and recovery for 3 days. Animals were assessed functionally by a species-specific behavioral scale, histologically for patterns of selective neuronal necrosis, biochemically by analysis of microdialysis effluent, and by receptor autoradiography for N-methyl-D-aspartate (NMDA) glutamate receptor subtype expression. RESULTS: Using a selective NMDA (glutamate) receptor antagonist (MK801) and an AMPA antagonist (NBQX), glutamate excitotoxicity in the development of HCA-induced brain injury was documented and validated. A microdialysis technique was employed to evaluate the role of nitric oxide (NO) in neuronal cell death. Arginine plus oxygen is converted to NO plus citrulline (CIT) by the action of NO synthase (nNOS). CIT recovery in the cerebrospinal fluid and from canine cortical homogenates increased during HCA and reperfusion. These studies demonstrated that neurotoxicity after HCA involves a significant and early induction of nNOS expression, and neuronal processes leading to widespread augmentation of NO production in the brain. To further investigate the production of excitatory amino acids in the brain, we hypothesized the following scenario: HCA--> increased glutamate, increased aspartate, increased glycine--> increased intracellular Ca2+--> increased NO + CIT. Using the same animal preparation, we demonstrated that HCA caused increased intracerebral glutamate and aspartate that persists up to 20 h post-HCA. HCA also resulted in CIT (NO) production, causing a continued and delayed neurologic injury. Confirmatory evidence of the role of NO was demonstrated by a further experiment using a specific nNOS inhibitor, 7-nitroindazole. Animals underwent 2 h of HCA, and then were evaluated both physiologically and for NO production. 7-Nitroindazole reduced CIT (NO) production by 58.4 +/- 28.3%. In addition, dogs treated with this drug had superior neurologic function compared with untreated HCA controls. CONCLUSIONS: These experiments have documented the role of glutamate excitotoxicity in neurologic injury and have implicated NO as a significant neurotoxin causing necrosis and apoptosis. Continued research into the pathophysiologic mechanisms involved in cerebral injury will eventually yield a safe and reliable neuroprotectant strategy. Specific interventional agents will include glutamate receptor antagonists and specific neuronal NO synthase inhibitors.

Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest.

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline. METHODS: Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18 degrees C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury). RESULTS: Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 +/- 5.67 at 8 hours and 30.63 +/- 14.96 at 20 hours after HCA. CONCLUSIONS: Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.

Nitric oxide mediates neurologic injury after hypothermic circulatory arrest.

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) causes neurologic injury. However, the mechanism of this injury is unknown. We hypothesized that HCA causes nitric oxide production to result in neuronal necrosis. This study was undertaken to determine whether the neuronal nitric oxide synthase inhibitor 17477AR reduces necrosis after HCA. METHODS: Thirty-two dogs underwent 2 hours of HCA at 18 degrees C. Nitric oxide synthase catalytic assay and intracerebral microdialysis for nitric oxide production were performed in acute nonsurvival experiments (n = 16). Sixteen animals survived for 72 hours after HCA: Group 1 (n = 9) was treated with 17477AR (Astra Arcus), and group 2 (n = 7) received vehicle only. Animals were scored from 0 (normal) to 500 (coma) for neurologic function and from 0 (normal) to 100 (severe) for neuronal necrosis. RESULTS: Administration of 17477AR reduced nitric oxide production in the striatum by 94% (HCA alone), 3.65+/-2.42 micromol/L; HCA and 17477AR, 0.20+/-0.14 micromol/L citrulline). Dogs treated with 17477AR after HCA had superior neurologic function (62.22+/-29.82 for group 1 versus 141.86+/-61.53 for group 2, p = 0.019) and significantly reduced neuronal necrosis (9.33+/-4.67 for group 1 versus 38.14+/-2.23 for group 2, p<0.00001) compared with untreated HCA dogs. CONCLUSIONS: Our results provide evidence that neuronal nitric oxide synthase mediates neuronal necrosis after HCA and plays a significant role in HCA-induced neurotoxicity. Pharmacologic strategies to inhibit neuronal nitric oxide synthase after the ischemic period of HCA may be clinically beneficial.

Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest.

BACKGROUND: Prolonged hypothermic circulatory arrest (HCA) causes clinical neurologic injury. This injury involves neuronal apoptosis, or programmed cell death. We have previously demonstrated that HCA causes glutamate excitotoxicity, increased nitric oxide (NO) production, and NO-mediated apoptosis. We hypothesized that monosialoganglioside GM1 inhibits NO synthase. The purpose of this study was to determine whether GM1 inhibits NO production and neuronal apoptosis after HCA. METHODS: Fourteen dogs underwent intracerebral microdialysis to measure excitatory amino acids, glutamate, aspartate, and citrulline, an equal coproduct of NO. They underwent 2 hours of HCA at 18 degrees C and were sacrificed 8 hours after HCA. Group 1 (n = 6) was pretreated with GM1, 30 mg/kg intravenously every day for 3 days, as well as before and after HCA. Group 2 control dogs (n = 8) received vehicle only. Apoptosis was scored from 0 (normal) to 100 (severe injury). RESULTS: Excitatory amino acids, aspartate and glutamate, coagonist glycine, and citrulline levels increased significantly over baseline during HCA and after HCA. GM1 pretreatment did not appreciably alter levels of glutamate, aspartate, and glycine; however, it substantially decreased citrulline and therefore NO production throughout the experiment. GM1 significantly inhibited apoptosis (group 1 vs group 2: 15.56 +/- 13.60 vs 62.92 +/- 6.17; P < .001). CONCLUSIONS: Our results provide the first direct evidence that GM1 inhibits NO synthase to reduce NO production and HCA-induced neuronal apoptosis. GM1 did not affect excitatory glutamate or aspartate levels. GM1 has been used in clinical trials of spinal cord injury and may be efficacious in reducing neurologic injury after HCA.

The role of the monosialoganglioside, GM1 as a neuroprotectant in an experimental model of cardiopulmonary bypass and hypothermic circulatory arrest.

Twelve male dogs were placed on closed-chest cardiopulmonary bypass, subjected to 2 h of HCA at 18 degrees C, and rewarmed to 37 degrees C on closed-chest cardiopulmonary bypass. All animals were mechanically ventilated and monitored for 20 h before extubation and survived for 3 days. Group 1 dogs (n = 6) were pretreated with GM1, 30 mg/kg/24 h for 3 days before HCA, and received continuous infusion of GM1 during the procedure and 30 mg/kg/24 h for 3 days after HCA. Group 2 dogs (n = 6) received vehicle only. With a species-specific behavior scale that yielded a neurodeficit score ranging from 0% (normal) to 100% (brain dead), all animals were neurologically assessed every 12 h by two observers. After death at 72 h, brains were examined by glutamate receptor autoradiography and by histologic examination for patterns of selective neuronal necrosis and were scored blindly from 0 (normal) to 100 (severe injury). These results provide evidence of a role for GE in the development of HCA-induced brain injury and suggest that monosialogangliosides may have a neuroprotective effect in prolonged periods of HCA.

Clinical markers in CSF for determining neurologic deficits after thoracoabdominal aortic aneurysm repairs.

BACKGROUND: Spinal cord ischemia is a major cause of morbidity and mortality after thoracoabdominal aortic aneurysm operations. The incidence of paraplegia is high even in experienced institutions. METHODS: We investigated whether neurotransmitter excitotoxicity is associated with neurologic deficits after thoracoabdominal aortic aneurysm operations. We hypothesized that patients with spinal cord injury would manifest elevated levels of excitatory amino acids in their cerebrospinal fluid. Sixteen patients undergoing thoracoabdominal aortic aneurysm operations had cerebrospinal fluid drawn through lumbar spinal drains preoperatively, intraoperatively, and postoperatively. Excitatory amino acid levels (glutamate, aspartate, glycine) were measured using high-performance liquid chromatography. Excitatory amino acid levels were compared in patients who exhibited no neurologic deficits postoperatively (group I; n = 12) with patients who had clinically evident lower extremity and cerebral neurologic deficits (group II; n = 4). RESULTS: Significant elevations in glutamate and aspartate levels from baseline (p < 0.05) were limited to group II. Excitatory amino acid levels in group II were significantly elevated (p < 0.05) compared with those observed in group I. Glutamate levels were especially increased during aortic cross-clamping and late reperfusion, whereas aspartate levels were increased only during late reperfusion. CONCLUSIONS: These data suggest that neurotransmitter excitotoxicity plays a significant role in central nervous system injury.

Neuronal nitric oxide synthase inhibition reduces neuronal apoptosis after hypothermic circulatory arrest.

BACKGROUND: Neurologic injury, including choreoathetosis and learning and memory deficits, occurs after prolonged hypothermic circulatory arrest (HCA). Apoptosis, or programmed cell death, is a possible cause of the neurologic injury seen after HCA. However, the mechanism of apoptosis is unknown. Hypothermic circulatory arrest causes glutamate excitotoxicity, resulting in increased nitric oxide production. We therefore hypothesized that nitric oxide mediates apoptosis. The purpose of this study was to determine if neuronal nitric oxide synthase inhibition reduces neuronal apoptosis in an established canine model of HCA. METHODS: Fourteen male hound dogs (weight, 20 to 27 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of HCA at 18 degrees C, rewarmed to normothermia, and sacrificed 8 hours after HCA. Group 1 (n = 7) dogs were treated with the neuronal nitric oxide inhibitor 7-nitroindazole, 25 mg/kg intraperitoneally, before arrest and every 2 hours until sacrifice. Group 2 (n = 7) dogs received vehicle only. The brains were analyzed histopathologically. Apoptosis, identified by hematoxylin-eosin staining, was confirmed by DNA terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling assay and electron microscopy. Apoptosis was scored by a blinded neuropathologist from 0 (normal) to 100 (severe injury). RESULTS: Apoptosis occurred early after HCA in select neuronal populations, including the hippocampus, stria terminalis, neocortex, and entorhinal cortex. Apoptotic neurons showed a characteristic shrunken cytoplasm and nuclear chromatin condensation. 7-Nitroindazole significantly inhibited apoptosis (group 1 versus 2: 19.17 +/- 14.39 versus 61.11 +/- 5.41; p < .001). CONCLUSIONS: Our results provide evidence that apoptosis is associated with the neurologic injury that occurs after HCA and that nitric oxide mediates the apoptosis that occurs after HCA. Strategies for cerebral protection during HCA may include the inhibition of neuronal nitric oxide synthase.

Induction of neuronal nitric oxide after hypothermic circulatory arrest.

BACKGROUND: Although hypothermic circulatory arrest (HCA) has become routine practice in cardiac surgery, it is associated with substantial neurotoxicity. We tested the hypothesis that increased nitric oxide production during HCA participates in neuronal death. We previously described a canine survival model of HCA that produces a consistent neurologic deficit and histopathologic pattern of selective neuronal death. METHODS: Adult male hound dogs (n = 17) were subjected to 2 hours of HCA at a brain temperature of 18 degrees C and reperfused to normothermia; they were sacrificed at various intervals up to 74 hours. Using in vivo cerebral microdialysis, dogs (n = 5) were given a simultaneous infusion of artificial cerebrospinal fluid containing L-[14C]arginine or L-[14C]arginine and L-nitroarginine methyl ester (a nitric oxide synthase inhibitor) in contralateral hemispheres while undergoing 2 hours of HCA and reperfusion to normothermia. RESULTS: L-[14C]citrulline recovery, a coproduct of nitric oxide, significantly increased during HCA in the hemisphere without the inhibitor (at 300 minutes: control, 236 +/- 94 fmol/min versus L-nitroarginine methyl ester, 6 +/- 6 fmol/min; p < 0.05). Citrulline production in vitro from canine cortical homogenates in the presence of calcium (n = 12) was significantly greater 8 and 20 hours after reperfusion (5.11 +/- 0.54 x 10(-7) mmol.mg-1.min-1 and 7.52 +/- 0.59 x 10(-7) mmol.mg-1.min-1, respectively) than before HCA (1.51 +/- 0.09 x 10(-7) mmol.mg-1.min-1; p < 0.05). Nitric oxide metabolites in the serum were also increased significantly early after reperfusion (baseline, 6.72 +/- 0.95 mmol/L; at 4 hours, 17.58 +/- 1.46 mmol/L; p < 0.05). Immunocytochemical staining of the cortex with neuronal nitric oxide synthase-specific monoclonal antibodies (Transduction Labs) revealed increased neuronal nitric oxide synthase expression 6 to 18 hours after HCA. Darkfield analysis demonstrated neuronal nitric oxide synthase localization to neuronal processes with widespread formation of dense plexi of nitric oxide synthase fibers. CONCLUSIONS: We conclude that neurotoxicity after HCA involves a significant, early induction in neuronal nitric oxide synthase expression in neuronal processes leading to widespread augmented nitric oxide production in the brain.