Comitogenic effects of very late activation antigens on CD3-stimulated human thymocytes. Involvement of various tyrosine kinase pathways.

Thymocytes display several integrins that are involved in cell-extracellular matrix interactions and differentiation processes. We have examined the role of very late activation Ag (VLA) on human thymocyte stimulation. VLA-4, VLA-5, and VLA-6 activated with either mAbs or their natural ligands (fibronectin, laminin, and vascular cell adhesion molecule-1) are able to transduce costimulatory signals in thymocytes activated via the CD3 pathway, i.e., enhancement of thymocyte proliferation, CD25 and CD69 expression, and IL-2 secretion. In contrast, activation of thymocytes with a mitogenic pair of CD2 mAb was not modified by VLA molecules. Cross-linking of both beta 1- and alpha 5-chains induced tyrosine phosphorylation of several proteins, whereas the cross-linking of the alpha 4- and alpha 6-chains did not. Moreover, a different pattern of tyrosine phosphorylation was observed when thymocytes were activated via either beta 1- or alpha 5-chains. These results suggest that VLA molecules activate tyrosine kinase pathways in thymocytes, and that different pathways would be implicated during thymocyte interactions with extracellular matrix or accessory cells, which are likely to play a role in thymocyte differentiation.

Heart and lung grafts harvested en bloc: operative technique, utilization, and results.

Combined heart and lung transplantation has been shown to provide successful therapy for patients with end-stage heart and lung disease. The improved success of lung transplantation has resulted in increasing number of potential recipients and longer waiting times. Maximal utilization of all three thoracic organs is no longer a casual goal but of utmost necessity. We devised a new technique that improves operative visualization, decreases dissection time, and ensures excellent preservation of all three thoracic organs. Bench dissection after extraction of this heart-lung block allows the thoracic and cardiac surgeons to agree on precise dissection of the left atrium and adequate pulmonary venous and atrial cuff. This technique has been used in 48 of our last 50 harvests with excellent results. Utilization of heart and lungs has been 93% and 74%, respectively.

Nonthoracotomy lead system for implantable defibrillator.

Over a 2-year period, 110 patients underwent attempted implantation of an automatic cardioverter-defibrillator using the nonthoracotomy lead system. Indications included sustained monomorphic ventricular (n = 62), nonsustained with poor ventricular function (n = 7), ventricular fibrillation (n = 21), ventricular tachycardia/fibrillation (n = 18), and familial long QT syndrome (n = 2). There were 90 male and 20 female patients. Mean age was 57 +/- 15 years. Sixty percent had previous coronary bypass or valve operations, or both. Mean left ventricular ejection fraction was 30% +/- 14%, cardiac index was 2.4 +/- 0.9 L/m2, and systolic pulmonary artery pressure was 41 +/- 14 mm Hg. Under general anesthesia, the nonthoracotomy lead was introduced through the left subclavian vein. The subcutaneous patch and generator were placed posteriorly on the serratus muscle and left upper quadrant, respectively. The length of the procedure was 116 +/- 44 minutes and the mean number of defibrillation shocks for a successful implant was 8 +/- 4. Eighty-five patients (77%) had successful implantations. Failures were due to high defibrillation threshold (n = 23) and inability to place a right ventricular lead (n = 2). Predictors of failure included preoperative antiarrhythmic drugs and cardiac index of 1.8 +/- 4 L/m2 or less (p = 0.004). Three patients (2.7%) died after the operation of heart failure (n = 2) and chronic heart transplant rejection (n = 1). Complications included lead migration or dislodgment (n = 8), infection (n = 1), and hematoma (n = 3). In summary, the nonthoracotomy lead system may provide an alternative in patients undergoing cardioverter-defibrillator implantation.

Successful use of the total artificial heart as a bridge to transplantation with no mediastinitis.

UNLABELLED: High rates of infection, especially mediastinitis, have been reported with the use of the total artificial heart (TAH), thereby limiting its usefulness. We have used the TAH as a bridge to transplantation with only minor infectious complications and a zero incidence of mediastinitis. Between February 1988 and August 1990, the TAH was inserted at Loyola University Medical Center in 19 patients, ages 16 to 64 years (mean, 44 years). Seventeen patients (89%) underwent transplantation within 1 to 34 days (mean, 9.8 days). Of the patients who did not undergo transplantation, one was brain dead and the other died of bleeding diathesis. Early (30-day) deaths occurred in two patients (11.7%): acute rejection at 18 days and multiple cerebral infarcts at 14 days. Three late deaths (17.6%) occurred: one patient, cytomegalovirus and pneumocystis pneumonia at 4 months; one patient, bronchopneumonia and multisystem failure at 9 months; and one patient, chronic rejection at 14 months. Minor infectious complications during the TAH implantation included Enterobacter pneumonia treated with antibiotics and positive sputum cultures (Escherichia coli; Candida), with no clinical evidence of infection in two patients. No cases of mediastinitis occurred either while the TAH was implanted or after transplantation. All patients were on antibiotics while the device was in place. CONCLUSION: Our experience with the TAH shows this to be an excellent device for successful bridging of patients for heart transplantation. We have had minimal infectious complications and none directly attributed to the use of this device. This device should continue to be used safely as a bridge to transplantation.

Repeat median sternotomy for the automatic implantable cardioverter and defibrillator.

Forty-four patients with a repeat sternotomy for the implantation of the automatic implantable cardioverter and defibrillator are presented. Thirty-three of the patients had placement of the device only and 11 had a concomitant open heart procedure--nine for aorto-coronary bypass (mean of 1.6) and two for mitral valve replacement. Twenty-two complications occurred in 17 patients. Arrhythmia was the most common problem. Two deaths occurred perioperatively in the group (mortality rate of 4.5 per cent) and were caused by gram-negative pneumonia and pulmonary embolus. There were no specific complications related to the sternotomy. It is, therefore, concluded that the repeated sternotomy is an excellent method to insert the automatic cardioverter and defibrillator.

Use of the total artificial heart and ventricular assist device as a bridge to transplantation.

The proliferation of transplant programs has not been paralleled by a similar increase in the availability of organ donors. This has significantly prolonged the waiting period and consequently has resulted in increased mortality of the patients with end-stage heart disease who are awaiting transplantation. Between 1984 and 1987, 104 orthotopic heart transplants were performed at Loyola University Medical Center. During the same period, 25 patients died while waiting for a suitable donor. To reduce the mortality of our patients waiting for transplantation, we began using the total artificial heart and a ventricular assist device as a bridge to transplantation in 1988. Of 29 patients who underwent transplant procedures in 1988, 18 required either a total artificial heart (15) or a ventricular assist device (3) as a bridge to transplantation. The underlying heart conditions were ischemic cardiomyopathy (11), dilated cardiomyopathy (5), giant cell myocarditis (1), and allograft failure (1). The average duration of mechanical support was 10 days (range, 1 to 35 days). Seventeen of the supported patients had successful transplants. One patient had brain death and did not receive a heart transplant. Of the 17 patients who survived surgery, two died within 30 days: one at 17 days because of acute rejection, the other at 14 days because of a cerebral vascular event. Fifteen patients (83%) were long-term survivors. Nine of the supported patients required reoperation because of bleeding after device implantation. There was no mediastinal or incisional infection. While the mechanical device was in place, the activated clotting time was maintained between 170 and 200 seconds with the administration of heparin (400 to 1000 units per hour).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of opening the pericardium on right ventricular hemodynamics during cardiac surgery.

The impact of the pericardium on right ventricular performance in the presence of normal filling pressures was evaluated using a rapid response RVEF thermodilution pulmonary artery catheter and TEE. In eight patients with normal right coronary arteries undergoing coronary artery bypass surgery, hemodynamic measurements revealed increased right ventricular end-diastolic and end-systolic volumes with diminished RVEF after opening the pericardium. In eight additional patients with right coronary artery disease, directionally similar changes in right ventricular volume were seen. Ejection fraction, however, was unchanged possibly due to altered right ventricular compliance. Echocardiogram evaluation of right ventricular area changes in patients with compromised right coronary systems corresponded to ejection fraction determinations obtained with thermodilution technique.

Thyroid neoplasia following radiation therapy for Hodgkin's lymphoma.

The question of thyroid neoplasia following high-dose radiation treatment to the neck and mediastinum for malignant neoplasms such as Hodgkin's lymphoma in children and young adults has been raised recently. Five patients, 19 to 39 years old, were operated on for thyroid neoplasms that developed following cervical and mediastinal radiation therapy for Hodgkin's lymphoma. Three patients had papillary carcinomas and two had follicular adenomas. The latency period between radiation exposure and the diagnosis of thyroid neoplasm ranged from eight to 16 years. This limited series provided strong support for the recommendation that children and young adults who are to receive high-dose radiation therapy to the head, neck, and mediastinum should receive suppressive doses of thyroxine prior to radiation therapy in order to suppress thyrotropin (thyroid-stimulating hormone) and then be maintained on a regimen of suppression permanently.

Parathyroid autotransplantation in forty-four patients with primary hyperparathyroidism: the role of thallium scanning.

Forty-four patients with primary hyperparathyroidism were followed for 18 to 126 months after subtotal or total parathyroidectomy and parathyroid autotransplantation. Indications for autotransplantation included the devascularization of parathyroid glands during concomitant thyroid lobectomy or total thyroidectomy and the excision of the only remaining parathyroid tissue in patients with persistent hyperparathyroidism after previous unsuccessful parathyroidectomies. Before implantation, all parathyroid tissue was histologically evaluated by frozen-section light microscopy with hematoxylin and eosin stain. Fifteen patients had histologically normal implants; to date none of these patients have developed recurrent hyperparathyroidism. Twenty-nine patients had either adenomatous or hyperplastic parathyroid tissue used for implants; two of these patients developed graft-dependent recurrent hyperparathyroidism 4 and 7 years later. In both patients the grafts were preoperatively localized by thallium scanning and their resection restored eucalcemia. One hundred thirty-one patients from 11 series in the current literature had a cumulative incidence of 17.5% for presumed graft-dependent recurrence and a 9.2% incidence of graft excision followed by eucalcemia. In comparison, in the present series the incidence of graft-dependent recurrent hyperparathyroidism in patients with either adenomatous or hyperplastic implants stands at 6.9%. In contrast, in 15 patients with normal parathyroid tissue implants, the incidence was zero.

Thyroid carcinoma in Graves' disease.

The prevailing hypothesis of thyroid carcinogenesis is that thyroid-stimulating hormone (TSH) is a prime factor in the growth and possibly the genesis of thyroid carcinoma. On the other hand, Graves' disease is a hyperthyroid state caused presumably by human thyroid-stimulating immunoglobulin (HTSI), not TSH. However, the literature does contain scattered reports of an association between Graves' disease and thyroid carcinoma. With this background, we retrospectively reviewed our series of 117 consecutive patients operated on for Graves' disease from 1961 through 1984. The series contains 23 male and 94 female patients, with a mean age of 26.3 years at operation (median 26 years; range 8 to 58 years). Of these patients, six (two males and four females) were found to have carcinoma, four papillary and two follicular, for an incidence of 5.1%. Four of the 117 patients had a history of head and neck irradiation; two (50%) subsequently developed carcinoma. For the six patients with carcinoma, mean follow-up has been 8.1 years (median 8 years; range 1 to 14 years). To date there have been no recurrences of carcinoma, and all six are alive and well. Thus our series shows a carcinoma rate of 5.1% in patients with Graves' disease, which is markedly higher than the 0.1% to 0.2% incidence in random autopsy series of all patients. This raises the question of a possible carcinogenic role for HTSI, similar to that hypothesized for TSH, in patients with presumably suppressed TSH.

The incidence of thyroid carcinoma in patients with Hashimoto's thyroiditis and solitary cold nodules.

The reported incidence of thyroid carcinoma in Hashimoto's thyroiditis varies widely. For this reason the specific subpopulation of patients with Hashimoto's thyroiditis and a solitary cold nodule was analyzed. Between 1972 and 1984 we operated on 146 consecutive patients with solitary cold nodules and Hashimoto's thyroiditis. There were 47 carcinomas, for an incidence of 32%. The mean age of the 146 patients was 43 1/2 years (median 44 years), with 126 females and 20 males. There was a history of prior head and neck radiation exposure in 54 patients, with a 33% incidence of thyroid carcinoma. The 92 patients without a history of radiation exposure had a 31.5% incidence of carcinoma. The frequency of multicentricity (bilateralism) was 33% in the group that underwent radiation and 24% in the group that did not. To date, with a mean follow-up of 4.7 years, there have been no deaths and no evidence of recurrence. In conclusion, we report a 32% incidence of thyroid carcinoma in patients with Hashimoto's thyroiditis and a solitary cold nodule, with no apparent difference between the patients with or without a history of radiation exposure, although there was a higher incidence of bilateralism (33% versus 24%) in the carcinomas of the patients with a history of head and neck irradiation. We suggest that the operative management of these patients is total thyroidectomy for those with a history of head and neck radiation and thyroid lobectomy for patients with no history of radiation, followed by contralateral lobectomy if a carcinoma is demonstrated.

Hürthle cell tumors of the thyroid gland.

The recent controversy concerning the prognosis of Hürthle cell tumors instigated the review of our experience with 34 patients treated between 1972 and 1984. On the basis of strict histopathologic criteria, 14 patients with Hürthle cell hyperplasia, 10 with Hürthle cell adenoma, and 10 with Hürthle cell carcinoma were identified. There was a 40% incidence of bilateralism in Hürthle cell carcinoma, whereas we documented bilateral disease in only one of 10 patients with Hürthle cell adenoma. Lobectomies were performed in patients with tumors considered histopathologically benign and total thyroidectomy in patients with histologically malignant lesions as well as in most patients with a history of radiation exposure. Follow-up ranges from 4 months to 12 years (mean 3.1 years). To the present time there has been no evidence of recurrence and no deaths from Hürthle cell tumors. Consequently, in our experience, Hürthle cell tumors seem to behave in a rather benign manner. Therefore it seems that the appropriate treatment for Hürthle cell adenoma and nodular hyperplasia is a lobectomy. Total thyroidectomy is reserved for patients with Hürthle cell carcinoma primarily because of the high incidence of bilateralism.

Total thyroidectomy in irradiated patients. A twenty-year experience in 206 patients.

During a period of 20 years (1965-1985), 206 consecutive patients were operated on for radiation-associated nodular thyroids. The ages ranged between 8 and 76 years (mean 38.7). there were 136 women and 70 men. The average duration between radiation exposure and operation was 27 years. The operations performed were total thyroidectomy (192) or, in patients who had undergone a previous lobectomy in another institution, another lobectomy (14). In addition, 25 patients required a neck dissection for nodal metastases and 27 underwent simultaneous subtotal parathyroidectomy for coexistent hyperparathyroidism. The pathologic findings were: 87 (42.2%) carcinoma (73 papillary, 13 follicular, 1 undifferentiated); 92 (44.7%) follicular adenomas; and 27 (13.1%) thyroiditis. To date, with an average follow-up of 6 years (0.5-31 years), only two patients have expired from recurrent disease. A third died of unrelated cause. A comparison of the first 100 patients (12 years) with the last 106 patients (8 years) demonstrated that the incidence of carcinoma has dropped from 48 to 37%, the incidence of lymph node metastases has decreased from 35 to 26%, and the incidence of bilaterality has fallen from 75 to 54%. On the basis of this series, it was concluded that total thyroidectomy is still indicated for radiation-associated nodular thyroids. However, if the trend of decreasing incidence, bilaterality, and metastatic disease persists, this approach may have to be reevaluated in the near future.

Parathyroid carcinoma. A report of five cases.

Parathyroid carcinoma, although rare, represents 0.5-4.0 per cent of the cases of hyperparathyroidism. The authors have encountered five cases of parathyroid carcinoma in their experience treating 445 patients with primary hyperparathyroidism (1.1%) since 1965. All five patients were women, ranging in age fro 29 to 60 years, and had marked hypercalcemia at the time of presentation, with values up to 26 mg/dl in one case. All the tumors were locally adherent to surrounding structures at the time of parathyroidectomy. Pathologically they were characteristic with a dense sclerotic reaction and fibrous bands criss-crossing islands of parathyroid cells. Three patients with local as well as distant metastases have died as a result of recurrent parathyroid carcinoma (follow-up: 2, 3, and 6 years). The remaining two patients became normocalcemic following resection, and have been asymptomatic for 1 and 7 years, respectively. The overall survival and clinical course, in our limited experience with five parathyroid carcinoma cases demonstrates that the morbidity and mortality in these patients is mainly due to local recurrence with the resultant metabolic disturbances, as has been previously noted in the literature.

Localization of ectopic parathyroid adenomas by the technetium-thallium subtraction scan.

Among numerous methods utilized for preoperative localization of hyperfunctioning ectopic parathyroid tissue, the technetium-thallium scan appears to be a major advance. Eight patients are presented where this method located ectopic parathyroid tissue in the neck, in the mediastinum, within the pericardium, and within the thyroid gland. To date, these findings have been confirmed operatively in five of the eight patients. On the basis of our limited experience, the authors believe that this is a valuable method in the preoperative localization of ectopic parathyroid tissue, especially in patients with persistent or recurrent hyperparathyroidism following a thorough neck exploration.

Hyperparathyroidism unmasked by the treatment of hypothyroidism secondary to Hashimoto's thyroiditis.

Primary hyperparathyroidism masked by untreated hypothyroidism was first noted by Kissin and Bakst in 1947; since then there has been only a single case reported. As a result, it has been thought to be a rare complex of parathyroid disease. During the past 17 years we observed 17 patients who developed primary hyperparathyroidism after their treatment for hypothyroidism (secondary to Hashimoto's thyroiditis) with thyroxine had been well underway. The patients were all women whose ages ranged between 16 and 76 years. The clinical and biochemical manifestations of hyperparathyroidism were noted 2 months to 30 years after thyroxine therapy. All patients underwent standard subtotal parathyroidectomy. Fourteen patients had a single parathyroid adenoma and three had multiglandular adenomatous hyperplasia. It is of interest that all 17 patients were found to have Hashimoto's thyroiditis, based on antimicrosomal antibody titers or histopathologic criteria. Thus we present a series of patients who developed primary hyperparathyroidism in a background of Hashimoto's thyroiditis and hypothyroidism treated with thyroxine. We are intrigued by the association of hyperparathyroidism and Hashimoto's chronic thyroiditis. From this experience it seems appropriate to evaluate parathyroid function in patients with hypothyroidism secondary to Hashimoto's thyroiditis before the initiation of treatment with thyroxine and at intervals thereafter.

Successful adrenal autotransplantation in Cushing's disease.

Since Cushing's disease was delineated as a distinct entity, a wide array of therapeutic modalities has been employed to treat its symptoms, which are primarily the result of hypercortisolism. With the advent of pituitary polytomography and the concept of microadenomas, a wave of enthusiasm has developed in recent years in favor of transsphenoidal microdissection. In a recent national survey, however, one third of 30 endocrinologists reported cure rates below 60% and, according to several respondents, recurrence was a serious problem at 50% or greater incidence. We report on four patients treated by bilateral adrenalectomy and autotransplantation. They were weaned off all corticosteroid medication for up to 6 years. Two of the four patients have demonstrable iodocholesterol uptake at the site of autotransplantation. We also report on three additional patients who are taking reduced doses of cortisone. All seven patients have no demonstrable iodocholesterol uptake in the adrenal fossae or other possible ectopic sites. We believe that bilateral adrenalectomy with autotransplantation is a worthy alternative in the long-term treatment of Cushing's disease.

Parathyroid carcinoma: biochemical and pathologic response to DTIC.

Parathyroid carcinoma is a rare cause of hyperparathyroidism. Cure results from successful en bloc resection. However, because of its rarity, the malignant nature may not be appreciated at the initial operative procedure and as a result, definitive resection may not be accomplished. However, even with extensive en bloc resections, local recurrences do occur and patients die of metabolic derangements associated with hypercalcemia. Thus in addition to operative intervention, palliative chemotherapy may be required to control the hypercalcemia. Radiotherapy has been unsuccessful. A single case of nonfunctioning parathyroid carcinoma responding to treatment with methotrexate, Adriamycin, cyclophosphamide, and CCNU has been reported. We report a case of recurrent functioning parathyroid carcinoma treated with dacarbazine (DTIC) in which biochemical and pathologic evidence of at least a partial response was seen. The patient, a 33-year-old woman, had undergone five previous neck explorations during a 26-month period for aggressive locally recurrent disease. Before DTIC therapy the intact parathyroid hormone (PTH) level was 1032 pg Eq/ml (normal 163 to 347 pg Eq/ml) and the serum calcium level was 16.8 mg/dl (normal 8.8 to 10.0 mg/dl). After a course of DTIC there was a marked improvement in her clinical status and biochemical parameters (intact PTH 545 pg Eq/ml; serum calcium 11.8 mg/dl). For 2 months her condition stabilized, with PTH levels between 700 and 760 pg Eq/ml and serum calcium levels between 10.2 and 16.0 mg/dl. With a slowly progressive rise in biochemical parameters a second course of DTIC was initiated and a marked drop in serum calcium levels (5.7 mg/dl) occurred, but PTH levels remained unchanged. A progressive course of septicemia, malnutrition, and disseminated intravascular clotting ultimately lead to her death 4 weeks later. At autopsy examination the tumor was confined to the neck. Grossly and microscopically there was extensive central as well as peripheral necrosis of the tumor, which was thought to be the result of the cytotoxic effect of DTIC. From this experience and because of the grim prognosis in patients with recurring parathyroid carcinoma, it may be that aggressive use of chemotherapy with DTIC early in the course of treatment should be considered.

Factors influencing morbidity of carotid endarterectomy without a shunt.

A retrospective analysis of 156 unshunted carotid endarterectomies in 124 patients indicates that at least three factors may influence the surgeon to consider using an indwelling shunt. Contralateral internal carotid artery occlusion, prolonged cross-clamp time, and possibly stump pressures less than 25 mm Hg torr were associated with increased rate of permanent neurologic deficit. Selective shunting would not be based on stump pressures less than 50 mm Hg torr, previous ipsilateral stroke, or abnormal intraoperative electroencephalogram.