Fine-needle aspiration biopsy of the thyroid. Diagnostic accuracy when performing a moderate number of such procedures.

The diagnostic accuracy of fine-needle aspiration biopsy of the thyroid was evaluated. Between June 1982 and July 1987, 354 fine-needle aspiration biopsies were performed on 289 patients with thyroid nodules. The ages of the patients ranged from 21 to 86 years (median, 45 years); 61 (21%) were men and 228 (79%) were women. Surgical confirmation of the cytologic diagnosis was obtained in 59 patients. Fine-needle aspiration biopsy identified 10% of the nodules as probably malignant and 10% as possibly malignant. Of these nodules, 30.5% were proved to be malignant by histologic examination. The accuracy of distinction between a benign (class I or II) or probably malignant (class IV) diagnosis was 95.2%. Patient acceptance of this procedure was good and complications were infrequent. These results indicate that fine-needle aspiration biopsy of the thyroid is accurate, safe, well tolerated, and easily applied, without its highly desirable features being compromised, even when a moderate number of such procedures are performed.

Megestrol acetate: first-line therapy for advanced breast cancer.

Megestrol acetate as initial hormonal therapy produced a 40% objective response rate in 53 patients with advanced breast cancer; another 26% achieved stable disease. For 19 patients with visceral-dominant disease, the response rate was 42%. To investigate the effect of the order of sequential hormonal therapy, records of 66 patients treated with tamoxifen before megestrol acetate or with megestrol acetate before tamoxifen were reviewed retrospectively. Of the 24 patients who were given megestrol acetate first, nine (38%) had objective response to primary therapy, and four (17%) to secondary therapy. Among the 42 patients treated with tamoxifen first, there were nine (21%) objective responses to primary therapy and eight (19%) responses to secondary therapy. Results show that megestrol acetate is effective first-line hormonal therapy for advanced breast cancer. Megestrol acetate can be used as primary hormonal therapy and tamoxifen as secondary hormonal therapy, as an alternative to the more usual reverse order. One may also consider megestrol acetate for some advanced breast cancer patients with visceral-dominant disease.

Sequential hormone therapy for advanced breast cancer.

Sequential hormone therapy for advanced breast cancer can offer significant and prolonged disease control with minimal morbidity. Predictors of response to sequential hormone therapy have not previously been identified. Sixty postmenopausal women with advanced or recurrent breast cancer treated with sequential megestrol acetate and tamoxifen were evaluated to identify factors which predict response to sequential therapy. The response rate to first-line therapy was 28% (17/60). Forty-seven percent of patients who responded to the first therapy responded to the second (8/17). Four of 16 patients (25%) who failed the first hormone therapy responded to the second. The response rate to a second hormone therapy was 25% (15/60). Chi-square tests were used to test the association between a response to sequential hormonal therapy and prior chemotherapy, age at first hormone trial, number of sites of disease, dominant site of disease, sequence of hormonal therapy, second response on the basis of first response, presence of soft tissue disease or bone disease alone, and receptor value. A one-tailed Fisher exact probability test revealed that a greater proportion of receptor-positive patients exhibited positive responses to sequential hormonal therapies than did receptor-negative patients. All of the patients who responded to a second hormonal therapy were estrogen receptor (ER)- and progestogen receptor (PgR)-positive. Fisher exact probability tests revealed a statistically significant association between response to initial hormone therapy and response to a subsequent hormone trial. This study suggests that patients who fail their initial hormone trial should be considered for a second hormonal trial if they are ER- and PR-positive.

Extension of survival of rat parathyroid allografts by depletion of Ia donor cells plus preoperative cyclosporine.

Methods that avoid chronic immunosuppression of transplant recipients must be developed to eliminate the various risk factors associated with such treatment (e.g., increased infections and malignancies). Pretransplant treatment of the graft with anti-Ia serum plus complement to eliminate "passenger cells" is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine (CsA). In this study, parathyroid glands from Lewis X Brown Norway rats were cultured for one week at 37 degrees C and treated with anti-Ia and complement. Treated glands were transplanted into parathyroidectomized, hypocalcemic Wistar-Furth recipients that had received 30 mg/kg of CsA once a day for the three days prior to transplant. At 1 year posttransplant, 67% of the recipients had functional parathyroid allografts. Control rats (no CsA; fresh, untreated glands) rejected their grafts within 28 days. Controls given three days of CsA and transplanted with fresh, untreated glands all had functional grafts for greater than 56 days (median survival: 80.5 days). Prolongation of allograft survival with short-term, preoperative CsA demonstrates the efficacy of immunosuppression given only at the time of antigen presentation. This course of CsA allowed for indefinite graft survival when the recipient received a graft previously cultured and treated with Ia antiserum. These results are encouraging and should be evaluated further to determine whether similar approaches will be useful in human transplants.

Indefinite survival of rat parathyroid allografts without postoperative immunosuppression.

Methods that avoid long-term immunosuppression must be developed for human parathyroid allotransplantation to be feasible. Pretransplant treatment of the graft to eliminate passenger cells is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine (CsA). In this study, parathyroid glands from Lewis X Brown Norway rats were cultured for 1 week and treated with antiserum directed against class II major histocompatibility complex antigens. Treated glands were transplanted into hypocalcemic Wistar-Furth recipients that previously received 30 mg/kg of CsA once a day for 3 days before transplantation. At 280 days after transplantation, 67% of the recipients had functional parathyroid allografts. Control rats (no CsA; fresh, untreated glands) rejected these grafts within 28 days. Control rats given 3 days of CsA and transplanted with fresh, untreated glands had functional grafts for greater than 56 days (median survival, 80.5 days). Prolongation of allograft survival with short-term, preoperative CsA demonstrates the efficacy of immunosuppression given at the time of antigen presentation. This course of CsA is even more effective when the recipient receives a graft whose passenger cells are eliminated.

Neuroendocrine carcinomas of the colon and rectum: a clinicopathologic evaluation.

Neuroendocrine carcinomas were diagnosed in 13 of 683 patients who had colon cancers removed from January 1980 to June 1987 for an incidence of 1.9%. The patients were 28 to 89 years of age (median, 72 years). There were seven male and six female patients. The treatment was as follows: right hemicolectomy, 5; transverse colectomy, 1; left hemicolectomy, 1; low anterior resection, 2; abdominal-perineal resection, 1; and in 3 patients with rectal tumors, biopsy examination only was performed. Microscopic stages were as follows: Dukes' stage B, 1; stage C, 6; stage D, 5; and stage indeterminate, 1. By light microscopy, the tumors showed solid clusters or ribbons of round to fusiform, small to intermediate-sized cells with variably abundant mitoses. Eight tumors had foci of glandular and/or squamous differentiation. By immunohistochemistry, all tumors showed one or more neuroendocrine markers, including neuron-specific enolase, chromogranin, synaptophysin, serotonin, and various neuropeptides. By electron microscopy, single membrane-bound neurosecretory granules were noted. The sites of metastases included regional nodes, 8; liver, 5; bone, 1. Four patients were treated with a combination of chemotherapy and radiation therapy. These tumors were, as a group, aggressive, with eight patients dead within 12 months of diagnosis. Median survival was 7 months, with three patients alive at 2, 38, and 68 months, respectively. Specifically, small- and intermediate-cell neuroendocrine carcinomas of the colon and rectum behaved very aggressively and displayed numerous structural and functional similarities with their bronchopulmonary counterparts.

Continuous epidural infusion for analgesia after major abdominal operations: a randomized, prospective, double-blind study.

We performed a prospective, randomized, double-blind study of continuous epidural analgesia for 72 hours after major abdominal procedures. Patients were randomly assigned to one of five treatment groups: epidural morphine, epidural bupivacaine, a combination of morphine and bupivacaine, epidural saline solution, and no epidural catheter. All patients received supplemental morphine sulfate or meperidine hydrochloride, intramuscularly or intravenously, as needed. Epidural infusion was begun at 2 to 4 ml/hr, depending on age and height, with two increments of 1 ml/hr allowed if pain relief was insufficient. All pain management decisions were made by nurses, who also monitored epidural function. Performance was measured four ways: pain as measured at regular intervals in the 72-hour period with a visual analog, pain as measured after 72 hours with the McGill Pain Questionnaire, amount of supplemental narcotics needed, and recovery of respiratory function and ambulation as percent of preoperative levels. The group that received the combination of morphine and bupivacaine did best on all measures; in most instances the difference between the results seen with the combination regimen and those seen with saline solution or no catheter were significant at the 0.05 level. With the exception of pruritus, complications were evenly distributed among all treatment groups, including noncatheterized controls. We conclude that epidural analgesia with the combination of morphine and bupivacaine is safe, is easily managed, and gives pain relief superior to that provided by traditional, systemic administration of narcotics.

Pheochromocytoma: operative strategy.

We studied 28 patients who had undergone 30 operations for pheochromocytoma since 1964. The tumor types included bilateral, extra-adrenal, malignant, recurrent, and multiple endocrine neoplasia, with 20 tumors confined to the adrenal gland. The preoperative studies used to localize the tumor included ultrasonography, intravenous urography, angiography, and computed tomography. Patients underwent exploratory operations via flank, subcostal, bilateral subcostal, midline, or thoracoabdominal approaches. In one case, that of a recurrence after bilateral adrenalectomy, surgical exploration discovered a tumor that had not been localized during the preoperative workup. Two patients underwent splenectomy because of injury incurred during operative exploration. Our experience suggests that preoperative localization is highly reliable, and therefore the benefits of extensive surgical exploration may be outweighed by its risks. We believe that with the exception of tumors that occur in association with childhood or pregnancy, multiple endocrine neoplastic syndromes, or recurrent disease, a direct approach to the tumor, possibly via the flank, is justified. Our results suggest that exploration of the contralateral adrenal or periaortic area is not so important as to be worth jeopardizing the spleen or other organs by a complex or extensive dissection.

Neck mass caused by thrombus in the external jugular vein.

Three cases of lateral neck tumors caused by thrombosis of the external jugular vein have been presented. Microscopic examination of the excised thrombosed veins revealed all of them to have a dilated architecture with somewhat degenerated vessel walls much like an aneurysm. Such a dilatation would cause some stasis and eddy currents and make the vessels more susceptible to thrombus formation. The final factor which induced these thrombi remains unknown. Indeed, when the interrelation of the factors discussed previously is considered, multiple etiologic factors appear most likely. Some form of minor trauma, although not documented, would still seem the most likely cause of thrombosis of a vein in a patient with no previous symptoms. In case III, trauma of inflammatory changes in a mass already noted to be present for some time could have induced thrombosis within the dilated vessel. Thrombosis of the external jugular vein is yet another lesion in the extensive differential diagnosis of a mass in the lateral neck.

Importance of repeat fine-needle biopsy in the management of thyroid nodules.

Fine-needle aspiration (FNA) biopsy of a thyroid nodule was performed in 797 patients. Ninety-six patients had resection of the thyroid nodule performed subsequent to a one-time FNA biopsy. The surgical pathology of these 96 cases demonstrated a 5.8% false-negative rate and a 9.9% false-positive rate. As a consequence, we prospectively evaluated the routine practice of repeat FNA of cytologically benign thyroid nodules. Repeat FNA confirmed the original benign cytology in 183 (93%) of 196 patients. Seventeen of these 183 patients with benign FNA on both biopsies had resection of the nodule performed because of the development of suspicious clinical signs or in response to the patient's choice; 1 recurrent cyst was found to be carcinomatous. Of the 13 patients demonstrating a change in cytology on repeat FNA biopsy, 9 had a nodule that was classified as possibly malignant (suspicious); 6 of these patients underwent resection, and 1 patient was found to have a carcinomatous nodule. Four patients had nodules that were classified as probably malignant on repeat FNA biopsy; all of their nodules were resected, and three of them were found to be carcinomatous. This study demonstrates that, although one-time FNA biopsy of thyroid nodules is highly accurate, with a relatively low false-negative rate, repeat fine-needle biopsy improves on this diagnostic accuracy, thereby decreasing the risk of misdiagnosing a thyroid nodule that is malignant.

Complications of laparoscopic cholecystectomy: a national survey of 4,292 hospitals and an analysis of 77,604 cases.

Complications of laparoscopic cholecystectomy were evaluated by a survey of surgical department chairpersons at 4,292 US hospitals. The 77,604 cases were reported by 1,750 respondents. Laparotomy was required for treatment of a complication in 1.2% of patients. The mean rate of bile duct injury (exclusive of cystic duct) was 0.6% and was significantly lower at institutions that had performed more than 100 cases. Bile duct injuries were recognized postoperatively in half of the cases and most frequently required anastomotic repair. Intraoperative cholangiography was practiced selectively by 52% of the respondents and routinely by 31%. Bowel and vascular injuries, which occurred in 0.14% and 0.25% of cases, respectively, were the most lethal complications. Postoperative bile leak was recognized in 0.3% of patients, most commonly originating from the cystic duct. Eighteen of 33 postoperative deaths resulted from operative injury. These data demonstrate that laparoscopic cholecystectomy is associated with low rates of morbidity and mortality but a significant rate of bile duct injury.

Neuroendocrine differentiation in "poorly differentiated" colon carcinomas.

The diagnosis of "poorly differentiated" carcinoma was made in 47 of 683 colon cancers on the basis of conventional light microscopy which showed poorly defined glands, solid architecture or variable admixtures thereof. Samples from 44 of these 47 tumors were assessed by immunohistochemical analysis for the presence of neuroendocrine (NE) antigens. Paraffin sections were immunostained with antibodies to NSE, chromogranin, serotonin, VIP, substance P and somatostatin. Additional sections were also stained with monoclonal antibody (Mab) A-80 that recognizes a glycoprotein related to exocrine (EX) differentiation. Based on our findings, the tumors were phenotypically reclassified as follows: I) pure EX (n = 8), II) pure NE (n = 4), III) mixed EX-NE carcinomas (n = 23), and IV) predominantly EX carcinomas with occasional NE cells (n = 9). Survival among groups II and III appeared to be less than group I and survival in group IV was significantly less than group I. Survival among the four pure NE (group II) and 11 predominantly NE mixed carcinomas (group III) taken together was significantly less than the pure EX carcinomas. This study indicates: 1) The incidence of NE differentiation in tumors of the colon and rectum is higher than previously believed. 2) The poorly differentiated colon carcinomas comprise four distinct groups: pure EX, pure NE, mixed EX-NE carcinomas, and predominantly EX carcinomas with a NE cell subpopulation. 3) The presence of NE differentiation or of a NE cell subpopulation in colon carcinoma appears to be associated with a poorer prognosis.

Identification of normal rat organs by two-dimensional protein electrophoresis.

Proteins from nine normal rat organs, including heart, lung thymus, liver, spleen, kidney, prostate, abdominal muscle, and brain, were solubilized, separated by electrophoresis according to their different isoelectric points and molecular weights, and stained with Coomassie blue. Patterns of major proteins unique to each organ were identified. Nine "unknown" samples, chosen from the same sources and submitted for analysis in a single blind study, were easily identified by comparing their protein profiles against the nine "reference" patterns. The ability to identify the origin of a tissue sample without recourse to microscopy, by comparing the pattern of its electrophoresed proteins with a "catalogue" of identified protein profiles, provides a prototype for the identification of histologically indeterminate normal and abnormal cells, tissues, and organs. Application of this technique to problems in human pathology and forensic medicine could prove to be very useful.

Two-dimensional protein electrophoresis and the identification of histologically indeterminate human cancers.

It is proposed to identify histologically indeterminate human cancers by comparing their qualitative content of stained proteins, separated by two-dimensional electrophoresis, with patterns of proteins from a series of identified human cancers of comparable or different stem cell origin. The hypothesis to be tested is that in cancer, biochemical ontogeny, reflected in the distribution of cellular and tissue proteins, will recapitulate phylogeny, albeit in a manner less organized than normal. Patterns of protein from cancer cells, whether histologically identified or not but originating from embryologically similar stem cells, are expected to exhibit greater homology, compared with protein profiles of cancer cells derived from stem cells of different embryologic origin. Normal or cancer cell proteins common or unique to one or more cell sources can be identified, and subsets of proteins that characterize cancer cells of specific stem cell origin identified. There are reasons to believe that cancer cells rarely, if ever express properties inconsistent with the basic cellular commitment of their stem cell of origin. Photo-optical scanning and computer-assisted analysis will greatly facilitate collating the many hundreds of discrete proteins, among which those used to characterize different cancer cells are to be found.

Chitosan: evaluation of a new hemostatic agent.

Topically applied chitosan fails to improve the control of bleeding in a liver laceration model when compared to pressure alone in both normal and heparinized rats, and both chitosan and pressure alone are significantly less effective in controlling bleeding than the application of thrombin. In addition, our histologic results suggest that there may be an increased inflammatory response by the healing liver following topical application of chitosan.

Bone scanning in pregnant patients with breast carcinoma.

Radionuclide scanning is usually contraindicated in pregnancy because of the danger of fetal radiation exposure. Radionuclide bone scanning with Tc-99m MDP is a sensitive indicator of early osseous metastases in breast cancer. Three cases of breast cancer during pregnancy are reported; modified bone scanning was utilized for staging and decision analysis. Modifications of bone scanning techniques to minimize fetal radiation exposure and fetal dosimetry calculations are described.