George S. Leight

Transplantation in miniature swine. I. Fixation of the major histocompatibility complex.

Three strains of miniature swine, each homozygous for a different allele of the major histocompatibility locus (MHC), have been developed by a selective breeding scheme based on tissue typing of the offspring of each generation. Prior to breeding, the original parents were reciprocally immunized by skin grafts and lymphocyte injections to produce lymphocytotoxic antisera. These antisera were then used to assess the MHC genotype of the offspring by an analysis based on selective absorption of cytotoxicity. Offspring inheriting the same serologically determined genotype were then bred sequentially. Subsequent mixed lymphocyte cultures showed a pattern of reactivity consistent with the serological genotyping, further confirming the homology between the MHC of these miniature swine and those of man and mouse. In addition to their usefulness as a model for large animal surgical transplantation, these animals provide an abundant homozygous source of histocompatibility antigens and of antihistocompatibility antisera for use in chemical characterization of products of the MHC.

Local failure and margin status in early-stage breast carcinoma treated with conservation surgery and radiation therapy.

ObjectiveThe authors determined whether microscopically positive surgical margins are detrimental to the outcome of early stage breast cancer patients treated with conservation surgery and radiation therapy. Summary Background DataThe optimal extent of breast surgery required for patients treated with conservation surgery and radiation therapy has not been established. To achieve breast preservation with good cosmesis, it is desirable to resect as little normal tissue as possible. However, it is critical that the resection does not leave behind a tumor burden that cannot be adequately managed by moderate doses of radiation. It is not known whether microscopically positive surgical margins are detrimental to patient outcome. MethodsThe records of 259 consecutive women (262 breasts) treated with local excision (complete removal of gross tumor with a margin) and axillary dissection followed by radiation therapy for clinical stage I and II infiltrating ductal breast cancer at Duke University Medical Center and the University of North Carolina between 1983 and 1988 were reviewed. Surgical margins were considered positive if tumor extended to the inked margins; otherwise the margins were considered negative. Margins that could not be determined, either because the original pathology report did not comment on margins, or because the original specimen had not been inked were called indeterminate. ResultsOf the 262 tumors, 32 (12%) had positive margins, 132 (50%) had negative margins, and the remaining 98 (38%) had indeterminate margins. There were 11 (4%) local failures; 3/32 (9%) from the positive margin group, 2/132 (1.5%) from the negative margin group, and 6/98 (6%) from the indeterminate group. The actuarial local failure rates at 5 years were 10%, 2%, and 10% respectively, p = 0.014 positive vs. negative, p = 0.08 positive vs. indeterminate (log rank test). Margin Status had no impact on survival or freedom from distant metastasis; 63 patients who originally had positive or indeterminate margins were re-excised, Two or 7 with positive margins after re-excision versus 1/56 rendered margin negative had a local recurrence. ConclusionsThe authors recommend re-excision for patients with positive margins because of Improvd local control of those rendered margin negative and identification of those patients at high risk for local failure (those who remain positive after re-excision). Because margin status impacts on local control, tumor margins after conservation surgery should be accurately determined in all patients.

Use of paravertebral block anesthesia in the surgical management of breast cancer: experience in 156 cases.

OBJECTIVE To assess safety and efficacy of the regional anesthetic technique paravertebral block for operative treatment of breast cancer, and to compare postoperative pain, nausea, vomiting, and length of hospital stay in patients undergoing breast surgery using paravertebral block and general anesthesia. BACKGROUND General anesthesia is currently the standard technique used for surgical treatment of breast cancer. Increasing hospital costs have focused attention on reducing the length of hospital stay for these patients. However, the side effects and complications of general anesthesia preclude ambulatory surgery for most patients undergoing breast surgery. In April 1994, the authors initiated the use of paravertebral block anesthesia for patients undergoing primary breast cancer surgery. A review of our early experience revealed that this regional anesthetic technique enables effective anesthesia for operative procedures of the breast and axilla, reduces postoperative nausea and vomiting, and provides prolonged postoperative sensory block that minimizes narcotic requirements. METHODS A retrospective analysis of 145 consecutive patients undergoing 156 breast cancer operations using paravertebral block and 100 patients undergoing general anesthesia during a 2-year period was performed. Anesthetic effectiveness and complications, inpatient experience with postoperative pain, nausea, vomiting, and length of stay were measured. RESULTS Surgery was successfully completed in 85% of the cases attempted by using paravertebral block alone, and in 91% of the cases, surgery was completed by using paravertebral block supplemented with local anesthetic. There was a 2.6% incidence of complications associated with block placement. Twenty percent of patients in the paravertebral group required medication for nausea and vomiting during their hospital stay compared with 39% in the general anesthesia group. Narcotic analgesia was required in 98% of general anesthesia patients, as opposed to 25% of patients undergoing paravertebral block. Ninety-six percent of patients having paravertebral block anesthesia were discharged within the day of surgery, compared with 76% of patients who had a general anesthetic. CONCLUSIONS Paravertebral block can be used to perform major operations for breast cancer with minimal complications and a low rate of conversion to general anesthesia. Paravertebral block markedly improves the quality of recovery after breast cancer surgery and provides the patient with the option of ambulatory discharge.

Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation.

Since 1973, we have performed total parathyroidectomy and forearm parathyroid autotransplantation in 36 patients with generalized (four gland) primary parathyroid hyperplasia. Twenty (56%) patients had nonfamilial parathyroid hyperplasia (NFPH) and 16 (44%) patients had familial parathyroid hyperplasia (FPH). Twenty-one patients (Group A) were undergoing operation for the first time and 15 (Group B) were having either second, third or fourth re-explorations for persistent hyperparathyroidism. All patients in Group A and nine patients in Group B had parathyroid resection and immediate autotransplantation as a single procedure. Six Group B patients had hyperfunctioning parathyroid tissue resected, cryopreserved, and subsequently grafted when it was evident that they had been rendered aparathyroid. A sustained differential elevation (13.7 fold ± 2.7) of parathyroid hormone was detected in the antecubital vein of the grafted compared to the nongrafted arm in 35 (97%) patients. Two (5.6%) of the 36 patients (both with FPH; one Group A and one Group B) required permanent oral calcium and vitamin D replacement therapy and one (3%) patient (NFPH: Group A) had persistent hypercalcemia postoperatively, presumably due to a supernumerary gland. The remaining 33 (92%) patients became normocalcemic after surgery and 23 (70%) of them remained so. Ten (30%) of the 33 patients developed recurrent graft dependent hyperparathyroidism. Eight patients were from the group with FPH (8/14, 57%) and two were from the group with NFPH (2/19, 11%) (FPH vs. NFPH, p < 0.005). Because of symptoms of hypercalcemia or a serum calcium concentration exceeding 11 mg/dl, partial graft resection was performed in five patients and four became normocalcemic. Patients with generalized primary parathyroid hyperplasia may be difficult to cure, especially if the disease is familial. The technique of total parathyroidectomy and heterotopic autotransplantation of fresh or cryopreserved parathyroid tissue offers distinct advantages over alternative techniques.

Progress in the operative management of sporadic primary hyperparathyroidism over 34 years.

Background:Progress in the diagnosis, localization of abnormal parathyroids, and intraoperative management of primary hyperparathyroidism has been observed over the past 34 years. The goal of this study is to report the outcome of patients undergoing 2 different operative approaches in a single institution, showing the evolution of surgical management of sporadic primary hyperparathyroidism (SPHPT). Methods:Parathyroidectomy was performed in 890 (827 initial, 63 reoperative) patients with SPHPT using 2 different approaches: traditional bilateral neck exploration (BNE, n = 396) or limited parathyroidectomy guided by parathormone dynamics (LPX, n = 494). Seven hundred eighteen patients (335 BNE, 383 LPX) followed ≥ 6 months or identified as operative failures were studied. Operative failure is defined as hypercalcemia and high intact (1–84) parathyroid hormone molecule (iPTH) within 6 months after operation. Successful parathyroidectomy is normocalcemia for 6 months; hypercalcemia and elevated iPTH after this time is recurrent hyperparathyroidism. Results:There were 20 (6%) of 335 operative failures in the BNE group and 11 (3%) of 383 failures in the LPX group (P = 0.04). The incidence of multiglandular disease (MGD) determined by gland size (10%) versus hormone hypersecretion (3%) was statistically different (P < 0.001). Since most of the recurrences occurred later than 30 months, the incidence of recurrent hyperparathyroidism in patients followed for longer than 2.5 years was 4% (11/287) in the BNE group (average, 11.5 years) and 3% (5/183) in the LPX group (average, 4.2 years). Conclusion:LPX, with its reported advantages of minimal dissection, shorter operative time, and use in ambulatory settings, compares favorably with the traditional BNE. Parathyroidectomy guided by parathormone dynamics has an improved success rate and should be considered as a standard operative approach in SPHPT.

Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma☆

INTRODUCTION Iodine 131-meta-iodobenzylguanidine ((131)I-MIBG) has been applied to the palliative treatment of metastatic pheochromocytoma in small studies. We report our institutional experience for the treatment of metastatic pheochromocytoma and paraganglioma. METHODS We performed a retrospective review of 33 patients with metastatic pheochromocytoma (n=22) and paraganglioma (n=11) treated at our institution with (131)I-MIBG over a 10-year period. RESULTS Patients received a mean dose of 388+/-131 mCi (131)I-MIBG. Median survival after treatment was 4.7 years. Most patients experienced a symptomatic response leading to an improved survival (4.7 years vs 1.8 years, P<.01). Patients with a measurable hormone response demonstrated an increased survival in comparison to those with no response (4.7 years vs 2.6 years, P=.01). Patients who received a high dose (>500 mCi) as their initial therapy also had improved survival (3.8 years vs 2.8 years, P=.02). CONCLUSION These data support (131)I-MIBG treatment for select patients with metastatic pheochromocytoma. In our experience, prolonged survival was best predicted by symptomatic and hormone response to (131)I-MIBG treatment. An initial dose of 500 mCi may be optimal. The benefit of (131)I-MIBG treatment for metastatic pheochromocytoma must also be weighed against its side effects.

The importance of early diagnosis in patients with hereditary medullary thyroid carcinoma.

Ninety-two patients from 12 kindreds with hereditary medullary thyroid carcinoma (MTC) were evaluated. We sought to determine if the stimulated plasma calcitonin (CT) level at the time of diagnosis was of prognostic significance. The patients were divided into four groups according to their preoperative stimulated plasma CT levels (1) 250–1,000 pg/ml (n = 25); (2) 1,000–5,000 pg/ml (n = 36); (3) 5,000–10,000 pg/ml (n = 8); (4) > 10,000 pg/ml (n = 23). Compared between the four groups were several parameters, including incidence of regional lymph node metastases, incidence of residual MTC post-thyroidectomy (as indicated by increased (>300 pg/ml) plasma CT levels after operation), incidence of distant metastases, and incidence of death. Also compared were the incidences of microscopic or gross MTC in thyroidectomy specimens. The incidence of regional lymph node involvement ranged from a minimum of one (4%) of 25 patients in Group 1 to 13 (57%) of 23 patients in Group 4. Similarly, plasma CT levels were elevated in only one (4%) of 25 patients in Group 1 compared to 14 (61%) of 23 patients in Group 4. There was no evidence of distant metastases or death in the patients in Groups 1, 2, or 3. In the 23 patients in Group 4, however, four (17.4%) had distant metastases and two (8.7%) died of disease during the period of observation. Of the 25 patients in Group 1, MTC was evident only by microscopic examination in 14 (56%). Eleven (44%) of the patients in Group 1 had macroscopically evident medullary thyroid carcinoma. This is in contrast with patients in Group 4 where all 23 had grossly evident MTC. These data indicate that the stimulated plasma CT level at the time of diagnosis is an excellent prognostic indicator of the extent of a disease in patients with hereditary MTC. Aggressive screening of kindred members at risk is of critical importance for establishing the diagnosis and instituting therapy at a time when the neoplasm is confined to the thyroid gland.

Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND The surgical management of secondary hyperparathyroidism by experienced surgeons is associated with excellent results. The presence of supernumerary glands and inadequate initial parathyroidectomy can lead to reoperations for recurrence. Intraoperative parathyroid hormone monitoring (qPTH), which has been described during parathyroidectomy for primary hyperparathyroidism, may be helpful in preventing or predicting the need for reoperation. This report describes the use of qPTH assays during parathyroidectomy in patients with secondary hyperparathyroidism. METHODS Intraoperative parathyroid hormone (PTH) levels were determined in 13 patients with secondary hyperparathyroidism undergoing total parathyroidectomy with autotransplantation (n = 3) or subtotal parathyroidectomy (n = 10). Levels were determined using a modified immunochemiluminometric assay (qPTH). RESULTS The average PTH levels before and after parathyroidectomy were 1599 pg/ml (620 to 2486 pg/ml) and 230.3 pg/ml (129 to 345 pg/ml), respectively. All patients had significant decreases in PTH levels after parathyroidectomy (mean, 84.6%). Symptoms were improved in all patients after operation. PTH levels at early follow-up were consistently below intraoperative levels. CONCLUSIONS Intraoperative PTH monitoring reproducibly demonstrates the clinically relevant decrease in PTH levels after parathyroidectomy for secondary hyperparathyroidism similar to those previously documented in patients with primary hyperparathyroidism. Long-term follow-up and increasing numbers of patients are crucial in defining the role of qPTH monitoring during parathyroidectomy for secondary hyperparathyroidism.

Relationship of age and menopausal status to estrogen receptor content in primary carcinoma of the breast.

The cytosolic estrogen receptor (CER) content of 1037 primary breast carcinomas was evaluated by sucrose density gradient analysis. Tumor specimens from premenopausal patients had significantly lower levels of CER (14.6 ±1.5 (mean ± SEM) 8S binding fmole/mg protein) compared with carcinomas from postmenopausal patients (57.5 ± 3.9 fmole/mg protein; p < 0.001). The proportion of specimens with CER levels above threshold values of 3, 7, or 10 fmoles/mg protein were significantly higher for postmenopausal patients (72%, 63%, 59%, respectively) than for premenopausal patients (56%, 42%, 36%, p < 0.001). When compared within half-decades, no statistically significant differences between premenopausal and postmenopausal patients were observed for mean, median, or rank sums of CER levels (p > 0.3). When patients were compared by half-decades, both mean and ranked sums of CER levels were significantly different (p < 0.001). The proportion of specimens that demonstrated CER levels above a threshold value of 10 fmole/mg protein increased sequentially from a low of 13/51 (26%) for patients <35 years to a high of 60/81 (74%) for patients >75 years.

Cystosarcoma phyllodes. Effective therapy with cisplatin and etoposide chemotherapy

Cystosarcoma phyllodes is an unusual breast neoplasm that rarely metastasizes. Most series report chemotherapy, radiation, and hormonal therapy to be ineffective. Three patients were treated with cisplatin and etoposide combination chemotherapy with effective palliation in two patients. Radiation therapy was effective in controlling symptomatic metastasis in all three patients. Hormonal therapy was ineffective in two patients despite the presence of positive hormone receptors. Chemotherapy and radiotherapy may be more effective in the treatment of this tumor than has been reported, although there is no apparent role for hormonal therapy. Functional hormone receptors are probably not present.