Successful allotransplantation of microencapsulated parathyroids in rats.

Allotransplantation of parathyroid tissue in humans is desirable for treating long-term hypoparathyroidism (e.g., after inadvertent removal of parathyroid glands during thyroid surgery). Until now, parathyroid allotransplantation was not used clinically because its advantages were outweighted by the need of immunosuppression. To overcome the immunogenicity of the tissue to be transplanted, we employed the method of microencapsulation; first tried in islet cell transplantation for experimental allotransplantation of parathyroid tissue. We have been able to achieve long-term success in a rat model. After isolation and tissue culture, tissue pieces from parathyroid glands of 280 Lewis rats were encapsulated in barium alginate and grafted into hypocalcemic DA rats. From the 7th to the 90th day after transplantation the recipient rats (DA rats) showed a normal serum calcium concentration. This is the first report of successful long-term survival and function of microencapsulated allotransplanted parathyroid tissue.

Increased incidence of thyroid cancer in patients with primary hyperparathyroidism: a continuing dilemma.

A number of previous studies have reported a greater incidence of thyroid disease in patients with primary hyperparathyroidism (HPT) than in normal patients. However, few of these studies utilized controls, and most have dealt only with gross thyroid nodules and not with total histologic abnormalities. In order to clarify this problem, thyroid pathology was determined in each of 100 consecutive patients operated upon for HPT. Thyroid nodules were excised, but in addition, a random biopsy of the thyroid was performed in all cases. Patients in this group were matched by age, race, and sex with non-HPT autopsy controls. Histologic slides were reviewed by a single pathologist blinded to the patient's group. Data for the matched pairs were analyzed by the Sign test. There was no significant difference in the prevalence of colloid nodular disease between patients with HPT (45) and the autopsy control group (43, P = 0.2). There was also no significant difference in the prevalence of lymphocytic thyroiditis between HPT patients (24) and control (15, P = 0.07). There was likewise no significant difference in the prevalence of other benign thyroid gland diseases between the two groups. Only nonmedullary cancer of the thyroid was shown to be statistically more prevalent in HPT patients than in autopsy controls (7% vs 0%, respectively; P < 0.02). The major factor that accounts for the coexistence of benign thyroid lesions and HPT is that both are prevalent in middle-aged women.(ABSTRACT TRUNCATED AT 250 WORDS)

The value of measurement of ras oncogenes and nuclear DNA analysis in the diagnosis of Hürthle cell tumors of the thyroid.

Hürthle cell tumors (HCT) remain difficult to treat because some which appear non-malignant on light microscopy later metastasize. In order to improve diagnostic accuracy, the value of ras mutations and nuclear DNA analysis was determined in 65 patients with HCT. Rapid nuclear DNA cytometry (MicroTICAS system) was performed. Mutations of H-ras, K-ras, and N-ras genes were analyzed by oligonucleotide probe hybridizations to polymerase chain reaction (PCR) amplified DNA. HCT were classified by light microscopy as benign (n = 22), intermediate (n = 30), and malignant (n = 13). After a mean follow-up of 7 years, 1 (4.5%) of 22 benign tumors and 4 (13%) of 30 intermediate tumors had metastasized, leading to tumor death in 3 of these 5 patients. Six of the 13 cancers diagnosed by light microscopy also resulted in tumor-related deaths. Aneuploidy was found in 83% of all Hürthle cell cancers, including 3 (60%) of the 5 cancers not diagnosed microscopically. However, 49% of non-malignant HCT also demonstrated aneuploidy. A nuclear area of less than 55 square microns was found in 83% of all Hürthle cell cancers and in 100% of those cancers not diagnosed by light microscopy. However, 47% of non-malignant HCT also demonstrated a "small" nuclear area. Aneuploidy correctly identified 8 of 9 cancers that resulted in tumor death and each of 3 other tumors that developed metastases. However, 1 patient with a diploid tumor died of metastatic cancer. A nuclear area of less than 55 square microns identified each cancer that resulted in a tumor death.(ABSTRACT TRUNCATED AT 250 WORDS)

Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation in secondary hyperparathyroidism: a randomized trial.

In a randomized study subtotal parathyroidectomy (sPTX) was compared with total parathyroidectomy and autotransplantation of fresh tissue (PTX + AT) in 40 patients with severe secondary hyperparathyroidism (HPT). After surgery both groups were followed at 19 +/- 6 months (PTX + AT) and 19 +/- 7 months (sPTX) and at 43 +/- 9 months (PTX + AT) and 40 +/- 7 months (sPTX). There were 17 patients alive in each group at the time of the second follow-up. After sPTX, 2 patients required re-operation because of recurrent disease originating from the remaining parathyroid gland in the neck and another 2 patients were hypercalcemic at follow-up. After PTX + AT both serum calcium and alkaline phosphatase normalized significantly more often (p less than 0.03) than after sPTX. Re-operations were not required in this group. Radiological signs also improved significantly more after PTX + AT, as did clinical signs like pruritus (p less than 0.005) and muscle weakness (p less than 0.04). These results and the fact that in recurrent disease a re-operation at the autograft in the forearm is simpler than a re-operation in the neck, lead to the recommendation that PTX + AT should be considered as the method of choice in the surgical treatment of secondary HPT.

N-ras 61 oncogene mutations in Hürthle cell tumors.

Mutations of ras oncogenes are believed to play an important role in the initiation or progression of human tumors. In thyroid tumors the incidence of ras activation by specific point mutations has been reported to range from 33% in follicular adenomas up to 60% in anaplastic carcinomas. Because of our long-standing interest in Hürthle cell tumors, we began a study of 70 such cases to determine the incidence of ras mutations and their clinical correlates. Analysis of N-ras sequences at codon position 61, with the polymerase chain reaction method and oligonucleotide probe hybridization, showed point mutations of the normal codon CAA* in eight tumor samples. One was a mutation from CAA to AAA, one from CAA to CTA,* and six from CAA to CGA. These mutations would result in amino acid substitutions of lysine, leucine, or arginine for the normal glutamine at position 61 in the N-ras protein. Identical ras mutations in two tumors and some of their surrounding thyroid tissue may indicate that activating ras point mutations are an early event in carcinogenesis. The incidence of mutations was 1 of 24 (4%) of the histologically benign tumors, 5 of 34 (15%) of the intermediate tumors (with vascular or capsular permeation), and 2 of 12 (17%) in the malignant group. Four of these eight patients died of metastatic thyroid disease and four are alive without evidence of recurrence.

Gastrinomas: a 42-year experience.

In 1947, a patient with metastatic islet cell tumor was treated for intractable ulcer disease at the University of Chicago Medical Center. Eight years later, in retrospect, it was recognized that he and another patient had the Zollinger-Ellison syndrome (ZE). From 1947 until the present, 30 patients with the ZE syndrome have been treated at this institution. Twenty-one (70%) were male and 9 (30%) were female. Their ages ranged from 24 to 76 years. Most (79%) had abdominal pain, however, melena (42%), hematemesis (33%), and severe diarrhea (35%) were prominent as well. Symptoms were present for a mean of 5.8 years before diagnosis. Over their entire clinical course, duodenal ulcers occurred in 96% of patients, gastric ulcers in 24%, jejunal ulcers in 29%, esophageal ulcers in 6%, and stomal ulcerations in 58%. Eleven (38%) of all gastrinomas were proved to occur in the duodenum; 10 (34%) were pancreatic in origin, including 3 with the MEN I syndrome; 3 (10%) were extrapancreatic and extraduodenal in origin, and no tumor was found in 5 (17%). Each of the 3 patients with MEN I developed a proven pancreatic islet cell carcinoma with metastases as well as hyperparathyroidism and a pituitary lesion. Of 27 patients who were explored for gastrinoma, tumor was found in 20 (74%). Excluding patients with MEN who had multiple lesions throughout the pancreas, all tumors were found in the "gastrinoma triangle." Total gastrectomy was performed in 10 (37%) of 27 of all patients who were explored, in 5 (71%) of 7 when no tumor was found, and in only 5 (25%) of 20 when tumor was present. Operative mortality was 15% (4 of 27) but no death has occurred since 1974. Long-term survival has followed both tumor resection or total gastrectomy in selected individuals (including 1 patient with known multiple liver metastases who is alive 18 years after liver biopsy and total gastrectomy); however, since malignant gastrinomas were present in 46% of all patients (or 57% in whom tumor was found) and since local metastases can sometimes be removed, we favor an aggressive approach to localization and resection when liver metastases or other distant metastases are not found. Duodenal gastrinomas are particularly favorable for resection for cure. They were malignant in only 36% and their metastases were nodal in each of 4 cases. The major problem is finding them since they are often small and "occult."(ABSTRACT TRUNCATED AT 400 WORDS)

Left ventricular contractile state after surgical correction of tetralogy of Fallot: risk factors for late left ventricular dysfunction.

The purpose of this study was to analyze potential "risk-factors" for late left ventricular dysfunction after surgical correction of Fallot's tetralogy (FT). As the ejection-phase indices cannot distinguish abnormalities of contractility from altered loading conditions, the slope values of the end-systolic pressure-length and stress-shortening relationships were analyzed by increasing afterload. Thirty-two patients were studied after surgical correction of FT in infancy. The age at investigation was 19.2 +/- 5.6 years, total correction had been performed at the age of 7.7 +/- 3.3 years. In 20 patients a one-stage operation was performed, and in 12 patients a two-stage correction. The control group consisted of 30 healthy volunteers, aged 18-30 years. The following potential risk factors for left ventricular dysfunction were evaluated: one-stage vs. two-stage correction, age at total correction, preoperative systemic oxygen saturation, preoperative hematocrit, occurrence of hypoxic spells, preoperative ratio of left-to-right ventricular peak systolic pressure, and preoperative ratio of left-to-right ventricular end-diastolic volume. In most patients the baseline data for end-systolic wall stress lay outside the normal range, indicating abnormal loading conditions. Thus, analysis of load-independent indices of the contractile state seems to be mandatory in these patients. Our data show that the severity of preoperative hypoxemia is an important risk factor for late dysfunction of the left ventricle (p less than 0.01). Additionally, the relation of left and right ventricular peak systolic pressures and end-diastolic volumes were related to the contractile state (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Difficulties of parathyroidectomy after previous thyroidectomy.

Although the risks of reoperative thyroidectomy and parathyroidectomy have been well studied, the problems associated with parathyroidectomy after prior thyroidectomy have not been emphasized. Among a group of 282 patients who were treated for primary hyperparathyroidism in recent years at the University of Chicago Medical Center, 14 (4.8%) had undergone one or more previous thyroidectomies, and 6 others (2.1%) had undergone thyroid ablation with radioactive iodine as therapy for Graves' disease. Numerous difficulties were encountered during surgery in the postthyroidectomy group of patients as a result of scarring and fibrosis, prior recurrent laryngeal nerve injuries in 13%, the inability to known with certainty how many viable, normal parathyroid glands remained after previous operations, and the need for additional thyroid resection, mostly for associated malignant lesions. Preoperative vocal cord assessment, evaluation of prior operative and pathology reports, and localization studies with thallium-technetium scanning and ultrasonographic techniques were especially helpful. A "lateral approach" was used frequently during surgery. Each of these 14 patients was cured of the hyperparathyroidism. The postthyroid ablation group presented fewer intraoperative challenges, although in some patients the thyroid gland was virtually absent, which obscured the normal landmarks of the surgical field. Five of these six patients were cured of hyperparathyroidism. Parathyroidectomy after thyroidectomy presents many operative challenges to the surgeon and should be approached with the same care and concern that one reserves for a reoperative parathyroid operation.