MONDAY AFTERNOON, April 25, 1983

2:00 p.m. Scientific Session - Grand Ballroom

9. Prevention of Local Recurrence and Survival in Surgically Treated Patients with Small Cell Carcinoma (SCC)

ROBERT J. GINSBERG, FRANCIS A. SHEPHERD*,

WILLIAM K. EVANS*, RONALD FELD*, JOEL COOPER,

RIIVO ILVES*, THOMAS R. TODD*,

F. GRIFFITH PEARSON and PAUL F. WATERS*

Toronto, Ontario

There is a resurgent interest in adjuvant surgery as part of multi-model therapy for SCC. In patients with limited disease (N₂M₀ or better) treated by chemotherapy and mediastinal irradiation, a high rate of local recurrence (50%) has been found. Surgery may be able to reduce the incidence of local recurrence if it is added to treatment planning for limited SCC. Hopefully, this will ultimately improve the curability of this disease.

To assess the role of surgery in treating and preventing local recurrence in limited SCC, we analyzed retrospectively patients undergoing surgical resection for SCC between 1976 and mid 1982. Thirty-seven selected patients of over 1000 treated for SCC in our institutions have had surgical treatment over this 5½ year period. Most patients underwent resection for presumed non-small cell histology. Six later patients had preoperative planned combined modality therapy. All patients had presumed N, or less disease prior to surgery. Twenty-seven patients have been treated and followed for a minimum of one year. Most received adjuvant postoperative chemotherapy and/ or radiotherapy. There were 12 stage I patients, 9 stage II and 6 stage III.

In 15 of 27 patients, relapse has occurred. The commonest site of first relapse was brain (7 of 15). Five of these patients had received prophylactic cranial irradiation. In only 2 patients, did relapse occur locally in the hemithorax and/or mediastinum - 1 in N₀ disease, 1 in N₁ disease. No local recurrence occurred in 6 patients with N₂ disease found at thoracotomy. Only 2 relapses have occurred beyond one year - both in brain. In those patients surviving greater than 2 years, no relapses have occurred.

In stage I surgically treated SCC, the estimated actuarial 5 year survival rate is 50%, in stages II and III, 23%. The median survival time for the whole group is 84 weeks. These survival times compare quite favorably to those for resected non-small cell carcinoma patients.

It appears that surgical excision may help in preventing local recurrence in SCC in N₁ and N₂ disease. In our small series, surgical treatment of limited SCC has yielded estimated actuarial five year survival rates similar to those seen in the surgical treatment of non-SCC patients.

The eventual role of surgery in preventing local recurrence and improving the overall treatment of limited SCC awaits prospective randomized trials.

*By Invitation

10. Occult Lung Cancer

DENIS A. CORTESE*, PETER C. PAIROLERO*,

ERIK J. BERGSTRAHL*, LWEIS WOOLNER*,

MARY ANN UHLENHOPP*, JEFFREY M. PIEHLER*,

DAVID R. SANDERSON*, PHILIP BERNATZ,

DAVID E. WILLIAMS*, WILLIAM F. TAYLOR*,

W. S. PAYNE and ROBERT S. FONTANA*

Rochester, Minnesota

During the past 10 years, 92 patients (all male) were found to have roentgenographically occult respiratory cancer. Upper airway cancer was found in 16 patients (17%)and lung cancer in 76. Sputum cytology in patients with lung cancer demonstrated marked cellular atypia in 16 patients and squamous cell carcinoma in 60. These latter 60 patients (positive sputum cytology, negative chest x-ray) form the basis of this report.

Ages ranged from 45 to 76 years (mean 62 years). The occult cancer was localized by bronchoscopy (range 1 to 5 times, mean 1.6 times) in 57 patients. One patient refused localization and is alive without treatment 6 years later. The remaining 2 patients were localized by chest roentgenogram and autopsy. Seventy-five percent of tumors were localized within 2.5 months following positive sputum cytology (range 1 day to 49 months). Six patients (10%) had 2 simultaneous occult neoplasms. All 65 localized tumors were squamous cell bronchogenic carcinoma. Nine patients did not undergo pulmonary resection; 6 had evidence of distant metastases, 1 refused operation, 1 had severe coronary artery disease precluding operation, and 1 died of an acute myocardial infarct prior to treatment. Curative pulmonary resections were performed in the remaining 50 patients (83%): lobectomy in 34, pneumonectomy in 11, bilobectomy in 4, and segmentectomy in 1. Forty-five patients were classified post-surgically as stage I (41, T1 NO MO; 3, T2 NO MO, 1, T1 N1 MO), 4 as stage II, and 1 as stage III.

Follow-up ranged from 16 to 115 months (mean 72 months). Overall five-year actuarial survival (lung cancer death only) for all 60 patients was 81% (Kaplan-Meier). Five-year survival for the 41 patients with T1 NO MO neoplasms was 91%. Currently 28 patients have died, but only 13 (22%) from lung cancer. Subsequent lung cancer developed in 20 patients (33%). Eleven of these patients had a second primary lung cancer, 4 of which were occult. We conclude that occult lung cancer has a strong likelihood of long-term survival. Close surveillance is indicated because of the high incidence of a second primary lung cancer.

*By Invitation

11. Prognostic Significance of N1 Disease in Carcinoma of the Lung

NAEL MARTINI, FUMIO NAGASAKI*,

and BETTY J. FLEHINGER*

New York and Yorktown Heights, New York; Chiba, Japan

From 1973 to 1981, 75 patients with T1N1M0 and T2N1M0 disease had a complete potentially curative resection with mediastinal lymph node dissection. There were 38 adenocarcinomas, 36 epidermoid cancers and 1 large cell carcinoma. Surgical treatment consisted of lobectomy in 54, sleeve lobectomy in 3 and pneumonectomy in 18. Two patients died postoperatively.

Of 17 patients with T1N1 disease, 13 had no further treatment and 4 received postoperative radiation and/or chemotherapy. There was no local or regional recurrence, but 8 patients had distant metastases and 1 developed another cancer. Eight are now alive and well and one is alive with recurrence. The 5-year cumulative survival of these patients was 51%.

There were 58 patients with T2N1 disease. Forty-two had no further treatment and 14 received postoperative radiation and/or chemotherapy. Twenty-six patients had no recurrence, 9 developed local and regional recurrence and 21 had distant metastases. The 5-year cumulative survival of these patients was 52%.

Factors influencing recurrence were the size of the tumor and proximity to the nilum. The specific location of nodal involvement, the number of nodes affected and the extent of involvement within the nodes had no observed effect on survival.

The incidence of local and regional recurrence was low. This we believe is due to the fact that systematic mediastinal lymph node evaluation reduced the margin of error in staging these patients. We conclude that patients with correctly staged N1 disease have a favorable prognosis.

*By Invitation

12. Modern Postoperative Mortality of Surgical Resections for Lung Cancer

F. GRIFFITH PEARSON, ROBERT J. GINSBERG,

LUCIUS D. HILL, ROBERT T. BAGAN*,

PAUL THOMAS, WILLARD FRY, RALPH BUTZ*,

PAUL F. WATERS*, MELVYN GOLDBERG*,

DONALD P. JONES* and THE LUNG CANCER STUDY GROUP

Toronto, Ontario; Seattle, Washington; Rochester,

Minnesota; Chicago, Evanston and Hines, Illinois

Modern postoperative mortality rates for resectional surgery for lung cancer is not readily available. In recent publications estimating the risk factors for surgical resection, mortality rates of 10 - 15% for pneumonectomy and 5-7% for lobectomy are frequently quoted.

In order to determine modern operative mortality rates (up to 30 days postoperative), the Lung Cancer Study Group analyzed the surgical mortality rates of the various participating centers during the years 1977 to 1982. Fourteen hundred and ten resections for lung cancer were available for analysis. Not all participating centers were able to report their data, nor could every contributing institution from the various centers. However, each reporting institution included all resections performed during their assessment period.

Of the 1410 resections performed, 75% were lobectomies, 20% were pneumonectomies and 5% were lesser resections (segmental or wedge). There was no major difference in these proportions among the contributing centers or institutions within these centers.

Fifty postoperative deaths occurred among the 1410 resections (3.6%). The mortality rate for pneumonectomy was 5.5% and lobectomy 2.6%. Lesser resections carried a 3.5% mortality rate, probably reflecting a higher risk group. There was no significant difference in any of these results among the centers and institutions.

In one institution, data was available for mortality rates adjusted for age (315 resections). Between ages of 50-59, the mortality rate was 0.9%, 60-69 - 3.3%, and 70-79 - 6.1%.

The striking similarity of postoperative mortality rates for resectional surgery for lung cancer among the various centers of the Lung Cancer Study Group and among the various institutions within these centers suggest that this data is a reasonably accurate analysis of modern surgical mortality in the treatment of lung cancer.

*By Invitation

13. Human Trials of the Automatic Implantable Defibrillator: A Two Year Program Report

LEVI WATKINS, JR.*, MARTINM. MOWER*,

M. MIROWSKI*, PHILIP R. REID*,

LAWRENCE S.C. GRIFFITH* and EDWARD PLATIA*

Baltimore, Maryland

Sponsored by: VINCENT L. GOTT, Baltimore, Maryland

Since February 1980, 53 survivors of multiple arrhythmic cardiac arrests unresponsive to therapy underwent implantation of the automatic defibrillator (AD). In 30 patients (pts) (Group I), AD implantation alone was performed by sub-xiphoid insertion (15 pts) and thoracotomy (15 pts). In 23 pts (Group II), implantation was combined with definitive open-heart procedures. Coronary artery bypass (CAB) was performed in 7 pts, CAB and mitral valve replacement in 4 pts and left ventricular aneurysmectomy with endocardial resection in 12 pts. There was no surgical mortality in Group I, three operative deaths occurred in Group II.

The longest follow-up was 31 months; the average is 14 months. Following hospital discharge, 20 episodes of automatic out-of-hospital resuscitations were observed in 10 Group I pts. Similarly 2 resuscitations were observed in 2 Group II pts. Kaplan-Meier survival curves based on the assumption that out-of-hospital resuscitations would otherwise have been lethal indicated a one-year mortality expected to be 45 percent in Group I. Eight late deaths were observed for an actual mortality of 25 percent. One late death was observed in Group II for an actual late mortality of 5 percent. In view of two successful automatic resuscitations, the expected late mortality was calculated to be 15 percent.

While surgery markedly reduced the number of automatic resuscitations, the automatic defibrillator appears to increase survival when implanted alone or in combination with open-heart surgery.

Invited Commentary - ALDEN H. HARKEN, Wynnewood, Pennsylvania

3:45 p.m. Intermission - Visit Exhibits - Lower Level

(Galleria) - Complimentary Coffee

*By Invitation

4:30 p.m. Forum Session - Grand Ballroom

14. Improved Myocardial Preservation During Global Ischemia by Continuous Retrograde Coronary Sinus Perfusion

STEVEN F. BOLLING*, JOHN T. FLAHERTY*,

VINCENT L. GOTT and TIMOTHY J. GARDNER

Baltimore, Maryland

In an attempt to avoid poor cardioplegia delivery and inadequate myocardial cooling in a model of regional coronary obstructions, continuous retrograde low pressure coronary sinus perfusion was studied during prolonged global ischemia. Forty-one isolated in situ, blood perfused canine heart preparations were divided into four study groups. All hearts had reversible occlusion of the proximal circumflex coronary artery at the onset of 90 min of global ischemia. Group I hearts (n = 11) then received 250 ml of a crystalloid hyperkalemic (25mM) cardioplegic solution at 4°C via aortic root perfusion. Group II (n = 10) received the same initial cardioplegic infusion and in addition had uniform topical myocardial cooling with cold saline to maintain myocardial temperature at or below 16°C. Using a balloon tipped catheter, Group III hearts (n= 10) received continuous retrograde coronary sinus perfusion of a crystalloid hyperkalemic (10 mM) solution at 15 mm Hg pressure and 15°C throughout the ischemic period, while Group IV (n= 10) had continuous coronary sinus perfusion with a similarly cooled (15 °C), oxygenated and hyperkalemic (10 mM) perfluorocarbon solution at 15 mm Hg perfusion pressure. Following 90 min of ischemia, the circumflex obstruction was released and all hearts were reperfused at 80 mm Hg for 60 min at 37 °C. Left ventricular (LV) developed pressure (DP, maximum positive dP/dt and end diastolic pressure (EDP) were measured isovolumically before ischemia and every 15 min during reflow. Intramyocardial gas tensions (PmO₂ and PmCO₂) were measured continuously during ischemia and reperfusion both in the obstructed circumflex and unobstructed left anterior descending regions. Myocardial water content (%H₂O) was determined in all hearts after reperfusion. Results below are expressed as mean ± SEM (*p < 0.05).

	Mean Myocardial	Circumflex Area	DP	EDP
GROUP	Temp During	PmO2 At End	After 60 min Reperf		% H2O
	Ischemia (°C)	Ischemia (mmHg)	(% control)	(mmHg)
I	22.9 ± .6*	13 ± 3	36 ± 4	16 ± 3	80.0 ± 0.6
II	15.7 ± .5	18 + 4	41 ± 5	17 ± 2	80.4 ± 0.3
III	17.4 ± .4	39 ± 6*	78 ± 5*	12 ± 2*	81.1 ± 1.0
IV	16.0 ± .4	49 ± 6*	73 ± 5*	13 ± 1*	80.3 ± 0.4

Not only did intramyocardial oxygen and carbon dioxide tensions remain at or near normal levels throughout ischemis, even in the area of the obstructed coronary artery, but LV functional recovery was significantly better in the two groups receiving retrograde coronary sinus perfusion. In addition, LVEDP remained low and there was no increase in myocardial edema formation in these same hearts. These results clearly demonstrate enhanced myocardial protection with low pressure coronary sinus perfusion during prolonged ischemia in hearts with severe coronary arterial obstructions.

*By Invitation

15. Prevention of Reperfusion Injury by Verapamil After Hypothermic Cardioplegia

W.R. ERIC JAMIESON*, HARTMUT HENNING*,

HILTON LING*, CHERYL A. DA VIES*,

BRENDA UHRYNUK* and DONALD M. LYSTER*

Vancouver, British Columbia

Sponsored by: G. FRANK O. TYERS,

Vancouver, British Columbia

The effect of Verapamil (V) on myocardial protection was assessed in two techniques of administration and compared to hypothermic cardioplegia (HC). Three groups of seven canine experiments were compared-Group I (HC-370m Osm/L; K 25 meq/L; Ca 2 meq/L; Mg 3 meq/L; Group II HC with V (HC-V Img/L as intermittent infusion); and Group III-HC with single dose V (HC-SDV 0.5 mg in 500 cc infusion 20 mins prior to reperfusion). Myocardial temperatures were maintained between 15-19°C for two hours of ischemia during cardiopulmonary bypass (CPB). Left ventricular global function was measured by ultrasound as LV internal diameter shortening (AL) and velocity of fiber shortening (Vcf), and regional function as LV wall thickening (%Ah). At 30 min after CPB AL declined by 14 ± 8% in I (HC) and increased by 23 ± 21% in II (HC-V) and by 15 ± 14% in III (HC-SDV), (I vs II and III p<0.01, analysis of variance, II vs III pNS). The mean Vcf declined by 14.7 ± 12<% in I, but increased by 25.7 ± 26 in II and by 21 ± 16 in III (I vs II and III p<0.001; II vs III pNS). The mean Ah decreased by 41 ± 6% (I), 11 ± 6% (II), and 15 ± 8% (III) (I vs II and III p<0.001; II vs III pNS). Systemic vascular resistances were not significantly changed after CPB and after V and not different between groups (pNS). We conclude that Verapamil combined with HC provides protection of LV function in the early postop period, both by intermittent infusion during CPB and single bolus infusion at the end of CPB. Our data indicate that LV function impairment is caused by reperfusion after HC rather than during HC. The three methods of protection do not change myocardial perfusion and energy contents during CPB.

*By Invitation

16. Warm-Glutamate Blood Cardioplegic Induction in Inotrope, Intraaortic Balloon Dependent Coronary Patients in Cardiogenic Shock: Initial Experience.

ELIOT R. ROSENKRANZ*, GERALD D. BUCKBERG,

HILLEL LAKS and DONALD G. MULDER

Los Angeles, California

This report reviews the initial clinical application of our experimental studies of warm (37°C)-glutamate blood cardioplegic induction in ischemically damaged hearts. Over the past 14 months, 23 consecutive coronary patients requiring pre-operative intraaortic balloon and inotropic drug support for cardiogenic shock underwent emergency operation. Twelve patients received warm-glutamate blood cardioplegic induction during the first 5 minutes of aortic clamping before multidose cold (4°C) glutamate blood cardioplegia; 11 patients received standard multidose cold blood cardioplegia without glutamate.

All patients had comparably depressed preoperative LV performance despite maximal inotropic and balloon support and showed evidence of extending myocardial infarction. They did not differ in the number of grafts placed (3.7 ± 0.2), associated valve and aneurysm procedures (7 patients) or cross-clamp time (89 ± 6 min). All patients received warm blood cardioplegic reperfusion before aortic unclamping.

The overall mortality was 9%(2/23); both patients who died received cold blood cardioplegia without glutamate. In addition to lower mortality, patients receiving warm glutamate blood cardioplegia exhibited better hemodynamics, allowing earlier discontinuation of inotropic and balloon support.

Blood Cardioplegic	CI**	LAP	IABP	Inotrope	Deaths
Induction	(1/min/m2)	(mmHg)	(days)	(days)	(%)
Warm Glutamate	2.6 ± 0.1	16 ± 1*	1.2 ± 0.2*	1.3 ± 0.5	0
(n = 12)
Cold	2.4 ± 0.2	22 ± 1	3.6 ± 0.5	2.7 ± 0.8	18
(n = 11)
*p<0.05 SEM, **Recovery Room

Management principles evolving from this early experience include 1) warm blood cardioplegic induction; 2) glutamate enrichment; 3) meticulous attention to cardioplegic distribution and grafting sequence and 4) warm cardioplegic reperfusion before unclamping. Hopefully, further application of these techniques will improve results in these extremely high risk coronary patients requiring operation.

*By Invitation

17. Creatine Phosphate: An Additive Myocardial Protective Agent in Cardioplegia

LARY A. ROBINSON*, DAVID J. HEARSE*

and MARK V. BRAIMBRIDGE*

Durham, North Carolina; London, England

Sponsored by: ROBERT H. JONES, Durham, North Carolina

The potential for enhanced myocardial protection by the addition of high energy phosphates to cardioplegic solutions was investigated using the isolated working rat heart model of cardiopulmonary bypass and ischemic cardiac arrest. Creatine phosphate (CP) was chosen for evaluation as an additional protective agent in the St. Thomas' Cardioplegic Solution (NaCl 110 mM/l, KCl 16 mM/l, CaCl₂ 1.2 mM/l, MgCl₂ 16 mM/l, NaHCO₃ 10 mM/l, pH 7.8). Dose response studies (CP 0-50 mM/l) revealed 10 mM/1 as the optimal additive concentration, such that its inclusion in the St. Thomas' Cardioplegic Solution during a 3 min period of pre-ischemic cardioplegic infusion improved the recovery of aortic flow (AF) and cardiac output (CO) upon reperfusion after a 40 min period of normothermic (37°C) ischemic arrest from 21.1 ± 5.4% and 32.8 ± 4.6% in the CP-free control group to 82.5 ± 3.7% and 82.6 ± 4.2% (p<0.001) respectively. Creatine kinase (CK) leakage was reduced by 68.7% (p<0.001) in the CP group. With hypothermic (20°C) ischemia (240 min) and multidose (every 30 min) car-dioplegia, recoveries of AF and CO were improved from 33.1 ± 8.3% and 42.2 ± 7.7% in the CP-free control group to 77.9 ± 4.2% and 79.6 ± 4.3% (p<0.001) respectively in the drug group. In addition to improving various indices of function and decreasing CK release, CP reduced reperfusion arrhythmias. The drug significantly decreased the time between cross clamp removal and the return of regular rhythm and also completely obviated the need for electrical defibrillation. In studies with ⁵¹Cr-EDTA (extracellular space marker), disappearance of CP from the cardioplegic solution during its stasis in the heart was assessed. Upon reperfusion, two thirds of the infused dose appeared unchanged in the coronary effluent; the remainder was either degraded or accumulated by the myocardium. In conclusion, despite its alleged inability to enter the myocardial cell, exogenous CP exerts potent protective and antiarrhythmic effects when added to St. Thomas' Cardioplegic Solution. Although the mechanism of action remains to be elucidated, it may involve binding or uptake of the drug.

*By Invitation

18. First Report of On-Line Monitoring of Intramyocardial pH in Man

SHUKRI F. KHURI*, MIGUEL JOSE*,

NINA S. BRAUNWALD and ERNEST M. BARSAMIAN

Boston, Massachusetts

Except for myocardial temperature (T) measurement, there has not been an on-line intraoperative technique to monitor adequacy of myocardial preservation in man. This report comprises the first 20 patients undergoing cardiopulmonary bypass (CPB) in whom a new glass electrode system was utilized intraoperatively to measure septal intramyocardial pH (MpH) and T before and throughout CPB. All patients had LAD disease and underwent bypass grafting of the LAD amongst other procedures. Periods of aortic clamping (AC) ranged from 32-130 minutes. The myocardium was protected with a cold K+ cardioplegic solution (CKCP) having a pH of 7.8. There were no operative deaths. Intraoperative need for inotropic support or intraaortic balloon, and postoperative ECG, enzymatic or radionuclide evidence of septal ischemic injury, constituted the criteria according to which the patients were divided into Group I (n = 14) with optimal protection, and Group II (n = 6) with suboptimal protection. Results are listed below as means ±SEM.

					Integrated Mean
	Before CPB		On CPB Prior to AC		Values During AC		At End of CPB
	MpH	T	MpH	T	MpH	T	MpH	T
Group I	6.84 ± 0.3	35.4 ± 0.6	7.04 ± 0.2	25.7 ± 0.7	7.29 ± 0.07	16.4 ± 0.6	7.01 ± 0.03	37.5 ± 3.3
Group II	6.81 ± 0.2	36.2 ± 1	24.2 ± 0.1	24.2 ± 1.5	6.85 ± 0.1	14.5 ± 1.6	6.89 ± 0.1	38.3 ± 1.0
p*	N.S.	N.S.	<0.02	N.S.	<0.005	N.S.	N.S.	N.S.
*Group I vs. Group II

Changes in T were not significantly different in both groups. A significant rise in MpH occurred with the administration of CKCP in every patient (P<0.0001), but it was significantly more marked in Group I than Group II (P<0.005). All 9 patients with an integrated mean MpH during AC>7.2 belonged to Group I, while 6 of 11 patients (54%) with an integrated mean MpH<7.2 belonged to Group II (P<0.001). These data confirm our recent animal experiments and prompt us to conclude that: (1) On-line intraoperative monitoring of MpH in patients is feasible, practical, and reproducible. (2) Cold K + cardioplegia results in a marked rise in MpH, suggesting that a hallmark of intraoperative myocardial preservation may be the avoidance of tissue acidosis. (3) Monitoring both MpH and T is a significantly more sensitive indicator of the adequacy of myocardial preservation than monitoring T alone.

*By Invitation