The prognostic significance of neuroendocrine markers and carcinoembryonic antigen in patients with resected stage I and II non-small cell lung cancer.

Non-small cell lung cancer with neuroendocrine differentiation may represent a subset of patients with a more aggressive (like small cell lung cancer) or less aggressive (like carcinoid) biological behavior. To investigate their prognostic significance, immunohistochemical stains for 4 neuroendocrine markers (neuron-specific enolase, chromogranin A, Leu-7, and synaptophysin) and carcinoembryonic antigen (CEA) were studied in 260 patients with surgically resected stage I and II non-small cell lung cancer. The following percentages of cases were positive for each marker: neuron-specific enolase, 70.0%; chromogranin A, 14.2%; Leu-7, 7.7%; synaptophysin, 11.2%; and CEA, 68.5%. Sixty-one (23.5%) were positive for > or = 2 neuroendocrine markers. When compared to adenocarcinoma, squamous cell carcinoma displayed lower positivity for CEA and > or = 2 neuroendocrine markers. There was no significant difference in stage, site of relapse (distant versus local), disease-free, or overall survival for each marker individually or for those with > or = 2 neuroendocrine markers. Multivariate analysis showed that higher nodal stage (N1 versus N0), tumor stage (T2 versus T1), older age, and the presence of mucin predicted for poorer overall survival. Neuroendocrine markers and CEA were not of prognostic significance in this group of patients with resected stage I and II non-small cell lung cancer.

Recovery of hypoxic neonatal hearts after cardioplegic arrest.

OBJECTIVES: Surgery for repair of congenital heart defects in the infant may be affected by hypoxia associated with the defect. The effects of chronic hypoxia on systemic ventricular function are not well characterised and few studies have considered myocardial preservation in the hypoxic neonatal heart. The aim was to determine how chronic hypoxia would affect left ventricular function in neonatal rabbit hearts subjected to global ischaemia. METHODS: Hearts from rabbits one, four, and six weeks of age and raised at 9% O2 were compared with hearts from rabbits raised in ambient air. Haemodynamic variables were measured with an isolated heart preparation before and after cardioplegic arrest. Creatine kinase was measured during reperfusion and myocardial oxygen consumption (MVO2) during ischaemia. RESULTS: At all ages, hypoxic hearts had significantly lower peak dP/dt and contractility index (dP/dt/left ventricular pressure (LVP)) than normoxic controls. After ischaemia and reperfusion, one week hypoxic hearts did not differ significantly in recovery from controls. Four week hypoxic hearts had significantly higher stroke volume and aortic flow, and six week hearts had significantly higher coronary flow than age matched controls. Contractility index did not show significant differences between hypoxic and control animals at any age. Hypoxic hearts released less creatine kinase in the coronary effluent during reperfusion than did control hearts of similar age. Six week hypoxic hearts had significantly higher MVO2 measured during the second administration of cardioplegia compared with six week control hearts but MVO2 did not differ significantly at one and four weeks of age. CONCLUSIONS: Despite reduced baseline function, chronically hypoxic immature rabbit hearts can recover from an ischaemic insult as well as age matched controls, with less evidence of myocardial necrosis. This parallels clinical findings in cyanotic infants.

The relationship of iron and glycogen to the in vitro, ultraweak chemiluminescent analysis of lipid peroxidation in rabbit hearts of varying ages.

Oxidative stress, which occurs when prooxidants overwhelm antioxidants, has been implicated as a cause of tissue damage related to ischemia and reperfusion. Neonatal animal and human hearts have been shown to differ in their response to oxidative stress, but the mechanism for this difference is unclear. To study this phenomena, crude homogenates of hearts from 4-day, 4-week, and adult (> 6 months) New Zealand rabbits were studied by chemiluminescence after exposure to O2/CO2 (95/5) or tert-butyl hydroperoxide (TBHP). Loosely bound iron and glycogen concentrations were also determined. The 4-day hearts exhibited more chemiluminescence after both oxygen and TBHP-driven stress. When exposed to O2, they reached a maximum rate of chemiluminescence in one-third less time and exhibited a 22% higher count rate. Likewise, when stimulated by TBHP, their rate was 44% higher than the hearts of both older groups. The 4-day hearts also had a 40% greater content of loosely bound iron that may, in part, explain their greater susceptibility to oxidative stress. Although the youngest hearts had the highest glycogen content, that did not offer protection against oxidative stress, as has been previously reported for liver.

Single-dose versus multidose cardioplegia in neonatal hearts.

We designed an experiment to compare single-dose versus multidose cardioplegia (calcium 0.3 mmol/L) in neonatal rabbit hearts 1, 4 and 6 weeks of age at 25 degrees C and 32 degrees C. Isolated hearts had a stabilization period of retrograde perfusion, a working period, a period of ischemia with single or multidose cardioplegia, reperfusion, and a final working period. We measured hemodynamic recovery, creatine kinase during reperfusion, and coronary vascular resistance during administration of the cardioplegic solution. One-week and 4-week-old hearts exhibited better recovery with single-dose than with multidose cardioplegia. Six-week-old hearts, on the other hand, showed better recovery with multidose cardioplegia. Four-week-old hearts at 25 degrees C showed increased creatine kinase release with multidose cardioplegia. The 6-week-old hearts tended toward lower creatine kinase release with multidose cardioplegia. Coronary vascular resistance rose with subsequent administrations in 1-week and 4-week-old hearts at 25 degrees C but did not rise in 1- and 4-week-old hearts at 32 degrees C or in 6-week-old hearts at either temperature. On the basis of hemodynamic recovery, single-dose cardioplegia appears to provide better protection than multidose cardioplegia to 1- and 4-week-old isolated rabbit hearts. Once the rabbit has reached 6 weeks of age, multidose cardioplegia has some advantage over single-dose cardioplegia, similar to the findings in adult hearts. Creatine kinase release and coronary vascular resistance data corroborate the hemodynamic findings.

Preoperative evaluation of stage I and stage II non-small cell lung cancer.

The appropriate preoperative evaluation for occult metastasis in patients with potentially resectable lung cancer remains controversial. The records of 265 patients with stage I and II non-small cell lung cancers who underwent resection with curative intent were reviewed to determine if there was a survival benefit of negative preoperative scanning to detect metastases. A minimum of 5 years of follow-up was possible for all long-term survivors. Patients having preoperative bone scans, brain imaging, and abdominal imaging had no increased survival over those without such evaluation (using Kaplan-Meier survival curves). Additionally, no difference was found in the time to first recurrence between these groups, and the site of recurrence was independent of a negative preoperative scan for that location. These data, using patient outcome as the basis of our conclusion, support a policy of reserving expensive preoperative metastatic evaluations only for those patients with clinical evidence of metastatic disease.

Neonatal myocardium resists reperfusion injury.

The response of neonatal myocardium to ischemia and reperfusion was observed in an isolated working heart model using neonatal rabbits and compared to that of the adult rabbit heart. Lipid peroxidation occurring during ischemia and that occurring during reperfusion were evaluated separately. Malondialdehyde (MDA) in heart tissue was measured as an index of lipid peroxidation, and the occurrence of oxygen free radical damage was assessed by the effects of the scavengers, superoxide dismutase and catalase, on MDA production. Baseline MDA levels were similar in neonatal and adult hearts, were changed little by treatment with normoxic cardioplegia, and were elevated in both groups by treatment with hyperoxic cardioplegia. Thus, the degree of lipid peroxidation during ischemia is similar in neonatal and adult hearts. After 10 min of retrograde reperfusion subsequent to treatment with anoxic cardioplegia, the MDA content of adult hearts was significantly greater than that of similarly treated neonatal hearts. Addition of free radical scavengers to the reperfusion medium lowered the MDA content of adult hearts significantly, but not to the level of neonatal hearts. After 60 min of reperfusion subsequent to hyperoxic cardioplegia, adult hearts had higher MDA than neonates; addition of scavengers to the cardioplegia did not lower the MDA significantly in either group. Only 5 of 12 adult hearts recovered function after hyperoxic cardioplegia, while all 12 neonatal hearts recovered. Our results indicate that neonatal myocardium suffers less damage from oxygen-centered free radicals during reperfusion than does adult myocardium.

Effect of prolonged postischemic perfusion on neonatal hearts.

Recent research on myocardial preservation has emphasized the importance of events occurring early in the reperfusion period, which may be of less importance to myocardial outcome in the neonate. We therefore wished to study the contribution of prolonged postischemic perfusion. This situation may occur during repair of congenital heart defects when in an attempt to reduce the period of aortic cross-clamp, the surgeon completes right-sided repairs on a beating empty heart. We used an isolated working rabbit heart model to compare recovery after various periods of ischemia and postischemic perfusion. After 30 min in the working heart mode, hemodynamic measurements were made. The hearts were then rendered globally ischemic, with the exception of cardioplegia. At the conclusion of the ischemic period, the hearts were returned to the 37 degrees C chamber, and reperfused with buffer. After 30 or 60 min retrograde perfusion, the hearts were converted to the working mode again. The working heart period continued until the heart was no longer able to overcome its afterload ("pump failure"). We recorded the time to this point as survival time. Hearts were divided into four groups: Group I (n = 12), 60 min ischemia, 30 min nonworking perfusion; Group II (n = 11), 90 min ischemia, 30 min nonworking perfusion; Group III (n = 8), 60 min ischemia, 60 min nonworking perfusion; and Group IV (n = 11), 0 min ischemia, 130 min nonworking perfusion. Multivariate analysis showed that four factors influenced survival time: aortic flow, age, left ventricular end-diastolic pressure, and mean aortic pressure. Group II did not vary significantly from Group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of early versus delayed hypoxic environment on neonatal rabbits.

We developed a low-cost, nonsurgical small animal model simulating the condition of cyanotic heart disease. Six groups of New Zealand white rabbits were studied: Group (1-C), 1-week-old control rabbits (n = 9) reared in room air; Group (1-H), 1-week-old rabbits placed in a hypoxic environment (10% O2) at birth (n = 5); Group (1-H-3), 1-week-old rabbits (n = 11) reared in room air for 3 days and then placed under hypoxic conditions identical to those for Group (1-C); Group (4-C), 4-week-old control rabbits (n = 12); Group (4-H), 4-week-old rabbits placed in hypoxia since birth (n = 11); Group (4-H-3), 4-week-old rabbits kept in room air after birth for 3 days (n = 7) before being exposed to hypoxia. Animals were anesthetized, heparinized, and instrumented for measurement of hemodynamic parameters. Right ventricular (RV) hypertrophy and hematocrit were assessed. Lung tissue was analyzed using quantitative morphometric techniques to assess arterial size, number, and muscularity. Group (1-H) and Group (4-H) developed RV hypertrophy, pulmonary hypertension, and erythrocytosis. The RV hypertrophy developed rapidly, as early as 1 week of age and became so pronounced by 4 weeks as to result in high mortality rate (35%). None of the animals in Groups (1-H-3) or (4-H-3) died while chronic changes of hypoxemia still developed. Placing rabbits after birth in room air for 3 days before exposing them to hypoxia appeared to play a protective role, moderating the development of pulmonary hypertension and severe RV hypertrophy. The effects of hypoxia appear to be at least partially dependent on the time of exposure. Utilizing our low-cost model will allow future work, including study of the effects of chronic hypoxemia on systemic ventricle exposed to an ischemic insult.