Comparison of nuclear DNA content in primary and metastatic papillary thyroid carcinoma.

Nuclear DNA values were determined in 40 primary papillary thyroid carcinomas, as well as in 52 corresponding local recurrences and metastases were observed either at the time of diagnosis or up to 20 years later. The patient population consisted of 34 survivors and 6 nonsurvivors. In survivors, both the primary tumors and their recurrences and metastases exhibited a majority of cells with DNA values within the normal diploid region, whereas nonsurvivors showed increased and scattered DNA values. In all cases, the primary tumors and the corresponding recurrences and metastases showed similar DNA distribution patterns even if many years had passed between the detection of the primary tumor and the metastases. The results indicate that in papillary thyroid carcinomas, the DNA distribution patterns in the primary tumor and the corresponding recurrences or metastases are generally similar throughout the entire period of disease.

Determinants of prognosis of patients with aortic regurgitation who undergo aortic valve replacement.

Insidious and potentially irreversible left ventricular dysfunction may develop in patients with aortic regurgitation. To determine whether preoperative variables can predict postoperative outcome, 113 consecutive patients with aortic regurgitation who underwent surgical correction between 1962 and 1977 were studied and survivors were followed up for 4.6 +/- 3.3 years. Clinical and hemodynamic examinations were made in all patients before the operation. Echocardiograms were performed in 44 patients preoperatively and in 36 patients postoperatively. Perioperative or postoperative death due to congestive heart failure occurred in only eight patients (19%). No statistically significant predictors of total mortality or death due to cardiac failure were found based on preoperative clinical, hemodynamic or echocardiographic findings. Survivors of the operation showed significant functional improvement: preoperatively, 77% of all patients were in functional class III or IV; postoperatively, 84% of patients were in class I or II (p less than 0.0001). A weak statistical correlation of functional improvement was found with a preoperative presence of increased cardiac diameter on the chest radiograph (p less than 0.05) and the severity of left ventricular hypertrophy (p less than 0.05). Improvement of left ventricular function was also consistently found in survivors and correlated best with the degree of preoperative preservation of left ventricular function. Patients with an echocardiographic preoperative fractional shortening of the minor diameter greater than 26%, end-systolic dimension less than 55 mm and end-diastolic dimension less than 80 mm were most likely to have normal function after the operation. It is concluded that operative mortality and survival after surgical correction of aortic regurgitation cannot be accurately predicted from preoperative findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart failure. A proposed definition and classification.

Heart failure exists when either the systolic or diastolic operation of the ventricle is impaired to a degree that, despite compensatory mechanisms, the demands of the peripheral organs are not satisfied, the peripheral muscle shortens inadequately, and/or the pulmonary or systemic venous system becomes congested from high filling pressures. Since every pumping system has finite limits and can fail if excessive and prolonged demands are made on it, any definition of failure must take into consideration the degree of stress imposed and whether or not the cardiac response is appropriate or subnormal. When failure is present, it becomes essential to discern whether it involves the intrinsic pumping structures of the heart, the myocardial cells, or, rather, whether failure of one of the other components of the integrated cardiovascular system (for example, valvular dysfunction, ruptured ventricular septum) has occurred.

Evidence for tumor-host cooperation in regulating MMP-2 expression in human colon cancer.

Matrix metalloproteinase 2 (MMP-2) facilitates tumor growth and metastasis in colon cancer. Although tumor cells may produce MMP-2, stromal cells, such as macrophages and fibroblasts, contribute significantly to MMP-2 synthesis in human tumors. We characterized four human colon cancer cell lines with differing biological behavior for MMP-2 expression. While the parent tumors from which the cell lines were derived all expressed MMP-2 mRNA, MMP-2 transcripts were detected in only one cell line, TF-17C, which is nontumorigenic in a nude mouse tumor model. TF-43C, which is tumorigenic and metastatic in the same tumor model, did not produce MMP-2, yet the tumors which arose from it after injection into nude mice did contain MMP-2 mRNA, suggesting a contribution from stromal cells. Co-culturing TF-43C with fibroblasts resulted in an increase in MMP-2 protein, whereas co-culturing with the nontumorigenic cell line TF-13Cm did not alter constitutive fibroblast MMP-2 secretion. Conditioned medium from TF-43C cells also stimulated fibroblast MMP-2 production. These data suggest that a soluble factor from TF-43C cells can stimulate fibroblast MMP-2 production and support the hypothesis that colon cancer cell interactions with stromal fibroblasts may be important determinants of tumor behavior in vivo.

Enhanced rate of progression of coronary artery disease following aortocoronary saphenous vein bypass surgery.

To evaluate the fate of the boronary arteries after aortocoronary bypass, 40 patients underwent serial selective coronary angiographic studies 1 year apart, and the frequency of progression of coronary artery disease was estimated. Thirty-two had saphenous vein bypass surgery after the first procedure, six had Vineberg operations, and two had no interim operation. In each patient, the right, left, anterior descending and circumflex coronary arteries (including their branches) were separately evaluated. Progressive narrowing was evident in 31 of 50 (62 per cent) bypassed vessels and in only 11 to 113 (9.7 per cent) nonbypassed arteries (p less than 0.001). Coronary arteries with moderate to severe obstruction initially (50 to 99 per cent occluded) manifested progressive diseasee more frequently (33 of 70 arteries) than did arteries that were normal or mildly narrowed initially (4 of 71) (p less than 0.001. Considering only those vessels with 50 to 99 per cent obstruction initially, 27 of 35 (77 per cent) of the bypassed arteries and only 6 of 35 (17 per cent) of the nonbypassed arteries showed progression (p less than 0.001). We conclude that moderately or severely narrowed coronary arteries are more likely to show progressive narrowing than normal or mildly obstructed ones and that progression of coronary disease is greater in bypassed vessels than in nonbypassed vessels. In view of potential graft closure, the implications of these findings must be considered in selecting patients for aortocoronary bypass.

Asymptomatic coronary artery disease and coronary bypass surgery.

The actuarial survival curves of "medically treated" patients whose arteriographic studies demonstrated coronary arterial lesions of various degrees-- now used widt applicable to the asymptomatic patient. No information is available regarding the course or prognosis of the asymptomatic patient with demonstrated lesions in the coronary arteries. For the reasons explained one can propose a hypothesis that the overall prognosis of this type of patient is better than average, probably better than that shown in the best data collected on symptomatic patients. The prophylactic value of aortocoronary bypass operations in preventing myocardial infarction and death has not been established. One can therefore question the justification for the wide case-finding effort of subjecting asymptomatic persons to coronary arteriography, even in light of the low risk of this procedure, unless unusual findings suggest an especially poor prognosis (one example might be past myocardial infarction in a very young patient). Although there are exceptional instances when prophylactic surgery is indicated for asymptomatic patients, further investigation of this subject is needed before the procedure becomes generally accepted.

Inefficacy of "therapeutic" serum levels of digoxin in controlling the ventricular rate in atrial fibrillation.

Although therapeutic and toxic serum concentrations of digoxin have been established, there is sparse information permitting correlation of drug level with clinical effect. This study was undertaken to assess the radioimmunoassay serum digoxin levels in 30 patients with acute atrial fibrillation (38 determinations) and 30 patients with chronic atrial fibrillation (54 determinations). Those with chronic fibrillation were subdivided into those in clinically stable condition (14 patients), and those seriously ill and in clinically unstable condition (16 patients). Slowing of ventricular rate in patients with stable, chronic atrial fibrillation was accomplished in 10 of 16 instances by "therapeutic" and "subtherapeutic" levels of digoxin (less than 2 ng/ml). Ventricular rate was "controlled" (65 to 95 beats/min) with therapeutic levels of serum digoxin in only five instances of acute atrial fibrillation and seven of unstable chronic atrial fibrillation. In 43 studies (23 of acute atrial fibrillation, 20 of chronic atrial fibrillation), a rapid ventricular rate (95 to 140 beats/min) persisted in the presence of "therapeutic" or high levels of digoxin. Thirty-nine of these were in patients who were seriously ill with conditions such as infection, hypoxia or recent thoracotomy. Slowing of the ventricular rate required "toxic" concentrations of digoxin (2.5 to 6 ng/ml) in 15 instances. We conclude that sufficient amounts of digoxin to achieve "therapeutic" serum concentrations may fall to lower the ventricular rate in atrial fibrillation to less than 100 beats/min, especially when a serious, complicating illness coexists.

Variability of hemodynamic responses to acute digitalization in chronic cardiac failure due to cardiomyopathy and coronary artery disease.

Eight patients with chronic congestive heart failure (four with cardiomyopathy and four with ischemic heart disease) underwent hemodynamic studies during acute administration of digoxin, given intravenously in two 0-5 mg doses 2 hours apart. Observations were made before administration of digitalis (control period) and serially therafter for 4 hours after the first dose. Resting mean cardiac index and pulmonary arterial wedge pressure were as follows: 2.0 liters/min per m2 and 23 mm Hg (control period); 2.1 and 24 (at 1 hour); 2.0 and 23 (at 2 hours); 2.7 and 19 (at 3 hours); and 2.3 and 20 (at 4 hours). Exercise responses of mean cardiac index and pulmonary arterial wedge pressure in five patients were: 3.1 liters/min per m2 and 36 mm Hg (control period); 3.2 and 33 (at 1 hour); 3.2 and 28 (at 2 hours); 3.1 and 27 (at.3 hours); and 3.4 and 31 (at 4 hours). The pulmonary arterial wedge pressure remained elevated during exercise in all cases. Arrhythmias were seen in five patients after administration of 0.5 mg of digoxin. Hemodynamic improvement at 4 hours involving both reduced filling pressure and increased blood flow was observed in only two patients at rest and in one additional patient during exercise. Acute deterioration of cardiac function (elevated pulmonary arterial wedge pressure of decreased cardiac index) occurred 30 minutes after administration of digoxin in four patients, concomitantly with increased systemic resistance. In six patients, a peak hemodynamic effect appeared 1 to 1 1/2 hours after administration of digoxin, with partial or total loss of initial benefit by 2 and 4 hours. In previously performed studies observations have seldom exceeded 1 hour; the results of this 4 hour study suggest that, in patients with cardiomyopathy or coronary artery disease and chronic congestive heart failure, acute digitalization does not necessarily lead to consistent, marked or lasting hemodynamic improvement. Thus, current concepts of the use of digitalis is such patients may require revision.

Marked depth of ST-segment depression during treadmill exercise testing; indicator of severe coronary artery disease.

This study was designed to evaluate whether treadmill stress testing would facilitate selection of patients with advanced coronary artery disease and, specifically, whether markedly abnormal ischemic responses could be used as indicators of severity of disease. Among 59 consecutive patients with documented coronary artery disease having both maximal treadmill testing and coronary angiographic studies, 15 (group 1) had normal responses to exercise, 18 (group 2) showed 1 to 2.9 mm "ischemic" (flat or downward-sloping) ST-segment depression, and 26 (group 3) demonstrated marked (or equal to 3 mm) ischemic responses. Group 3 had statistically significant higher incidences of triple-vessel disease (18/26; 69 percent) and proximal lesions of the left anterior descending coronary artery (24/26; 92 percent), compared with group 1 (2/15 and 10/15, respectively) and group 2 (6/18 and 12/18, respectively). Group 3 also manifested more extensive disease than groups 1 and 2 (judged by scoring system of Friesinger et al), with a score of 11 or more in 18 of 26 patients. We conclude that marked depth of "ischemic" ST-segment depression aids in identifying that subgroup of the coronary population with severe coronary artery disease and, therefore, serves as a useful means of culling out patients with a potentially serious prognosis who might benefit from intensive diagnostic or therapeutic interventions.

Correlation of HLA types in premature coronary artery disease: an attempt to define independent genetic risk factors.

This study was designed to investigate whether isolated genetic factors, controlled by genes in the HLA chromosomal region, could be indicted as independent contributing influences in the genesis of premature coronary artery disease (CAD). Nineteen patients with fixed obstructive CAD documented by coronary angiography had no coronary risk factors with respect to age; levels of serum cholesterol, fasting triglycerides, and blood glucose; blood pressure; obesity; history of diabetes mellitus or hypertension; and cigarette-smoking history. Sixteen patients had a family history of CAD. HLA typing was restricted to antigens of the A and B loci. Control subjects (n = 1,157) were normal. At the A locus, no antigens demonstrated an observed frequency significantly higher than that expected from the control population. At the B locus, BW 38 had a statistically significant greater frequency (p less than 0.01) in the study group with CAD (21 percent) than in the control population (4 percent). The association between BW 38 and premature CAD lost its statistical significance when conservatively corrected for the number of HLA antigens tested by the Bonferroni adjustment. The relative risk for CAD if a patient had antigen BW 38 was 6.2. Our data suggest a statistically significant trend between the presence of HLA BW 38 and premature CAD. Whether the HLA tissue antigens are involved directly in the pathogenesis of CAD, act as markers for immune response genes, or serve as markers of other yet undefined genetic factors needs further study.

Adrenocortical carcinoma.

From 1962 to 1985, 47 patients with carcinoma of the adrenal cortex were treated at Memorial Sloan-Kettering Cancer Institute. There were 21 men and 26 women. Seventy-two percent of the tumors were functional and 28% were nonfunctional. Despite the advent of ultrasonography and computerized tomography, these tumors were infrequently diagnosed until they infiltrated adjacent organs or metastasized to distant sites. Only 30% of patients had tumors confined to the adrenal gland; their mean duration of survival was 5.0 years. Seventy percent of the patients had invasion of the kidney, lymph nodes, liver, diaphragm, and/or pancreas at the initial operation; their mean duration of survival was 2.3 years. Eight patients had reoperation for abdominal recurrences; three of the patients with abdominal recurrence and one additional patient underwent thoracotomy to resect localized lung metastases. The mean duration of survival of these nine patients was 3.5 years, not significantly different from the mean overall survival of 3.1 years. The duration of survival of all patients was not significantly correlated with age, sex, adjuvant therapy, or production of hormones by the tumor. Only two patients were deemed unresectable. Wide en-bloc dissection of the primary tumor, resection of contiguous organs for local invasion, and excision of resectable metastases in the liver and lungs remain the basis of therapy.

Parathyroid carcinoma: the Lahey Clinic experience.

From 1942 to 1984, 301 operations were performed for hyperparathyroidism; nine patients (3%) had carcinoma. The mean serum calcium level of the patients with carcinoma was 14.0 mg/dl, whereas the mean serum calcium level of patients with benign hyperparathyroidism was 12.0 mg/dl. With follow-up ranging from 2 to 16 years, there has been one death 9 years after the initial operation caused by primary lung cancer. At autopsy the patient also had a recurrence of parathyroid carcinoma in the neck. There were no additional recurrences or deaths. Prognosis was not correlated with any laboratory or pathologic findings. The importance of intraoperative recognition at the time of the initial operation is stressed. En bloc resection is recommended, including ipsilateral thyroid lobectomy and dissection of the tracheoesophageal groove. Radical neck dissection is performed only for extensive cervical node metastases or for reoperations where scarring prevents accurate delineation of the extent of the tumor.

Adenocarcinoma arising within a colonic diverticulum: report of two cases and review of the literature.

The first reported cases of colonic carcinoma arising within a diverticulum are documented. Although colonic diverticulitis and cancer are common diseases in patients over 60 years of age, cancer arising within a diverticulum is rare. Only close histopathologic scrutiny can differentiate inflammatory changes from neoplasia. Because colonic diverticula are characteristically thin-walled, cancers arising within diverticula may easily penetrate the serosa and first be diagnosed at an advanced stage despite their small size.

The effect of thyroid hormone administration upon survival in patients with differentiated thyroid carcinoma.

Seven hundred sixty-one patients with operable differentiated thyroid carcinoma were treated between 1931 and 1970. Median follow-up time was 18 years and ranged from 5 to 40 years. Sixty-three percent of the patients were followed more than 15 years, and 46% were followed more than 20 years. Because resections usually spared sufficient thyroid tissue for homeostasis, thyroid hormone was not routinely prescribed after operations performed before 1960. Altogether 244 patients with papillary carcinoma and 76 patients with follicular carcinoma received thyroid hormone, while 296 patients with papillary carcinoma and 45 patients with follicular carcinoma did not receive thyroid hormone after operation. With papillary carcinoma, 14% of men greater than 40 and women greater than 50 years of age (high risk) but only 2% of men less than or equal to 40 years of age and women less than or equal to 50 years of age (low risk) died of disease (P 0.0001). Twenty-six percent of high-risk but only 4% of patients with low-risk follicular cancer died (P 0.0001). However, there was no statistically significant improvement in survival times with use of thyroid hormone when patients were categorized by risk group and pathology. These data support the importance of age and sex in previously described risk groups; these factors supersede the effects of adjuvant treatment. This absence of effect on survival times calls into question current recommendations for routine use of thyroid hormone after surgical therapy. Conceptually, such absence of adjunctive hormone effect on survival time after operation is similar to hormonal effects in other endocrine cancers, which may nevertheless provide good palliation in some cases.

Biologic considerations and operative strategy in papillary thyroid carcinoma: arguments against the routine performance of total thyroidectomy.

Reasons cited for the routine performance of total thyroidectomy in patients with papillary thyroid carcinoma include: fear of multicentric neoplastic foci causing local recurrence and death; risk of anaplastic transformation of unresected multifocal microscopic carcinoma; toxicity of high-dose radioactive iodine to ablate normal thyroid remnants; and lack of reliable criteria for grading malignancy and identifying patients at high risk. However, autopsy studies have detected microscopic foci of papillary thyroid cancer as incidental findings in up to 24% of patients dead of other diseases. The prevalence of anaplastic transformation of papillary thyroid carcinoma as determined from reports in the literature is less than 1%. A retrospective investigation of 90 patients with papillary thyroid carcinoma derived from the Swedish National Cancer Registry showed no complications from radioiodine ablation of postoperative thyroid remnants in 45 patients. Retrospective analysis of the DNA content of tumors at the time of the initial operation showed a significant difference between a group of 10 patients who died of recurrent and metastatic papillary thyroid carcinoma and a group of 16 patients alive at least 10 years after operation despite distant metastases or recurrent cancer in the thyroid bed and/or cervical lymph nodes. The risk of permanent hypoparathyroidism is higher in patients after total thyroidectomy without apparent improvement in survival rates when compared with less extensive resections. Therefore it is proposed that the criteria for total thyroidectomy in patients with papillary thyroid carcinoma be limited to: tumors that clinically involve both lobes of the thyroid gland, extracapsular spread of cancer requiring enbloc resection, and reoperations where scarring prevents accurate delineation of the extent of the tumor. By differentiating patients at high risk for death from papillary thyroid carcinoma from patients at low risk, the measurement of DNA content may decrease the need for routine total thyroidectomy.

Localization of radioiodinated monoclonal antibody in colorectal cancer. Initial dosimetry results.

HT-29-15 is an IgG1 monoclonal antibody reacting with a neuraminidase-sensitive determinant on a cell-surface antigen (molecular weight, 200,000 daltons) present on the colon cancer cell line HT-29. HT-29-15 was selected for a tumor localization study because the antigen was shown to be present, by immunohistochemical staining, in a high percentage of primary and metastatic colorectal cancers. HT-29-15 labeled with iodine 131 was given intravenously over a dose range of 0.2 to 10.0 mg to 23 patients with colorectal cancer. No significant toxicity was seen. Imaging of hepatic metastases was successful from days 5 to 7. Analysis of tissue radioactivity by biopsy showed that the tumor-liver ratio increased from day 1 to day 7, suggesting more rapid clearance of antibody from normal tissue than from tumor. Thus, tissue biopsy specimens and scintigraphy have shown that imaging of metastatic colorectal cancer is possible with monoclonal antibody HT-29-15. Tissue biopsy specimens are essential for demonstrating specificity of localization. Scans alone provide insufficient evidence of specific localization by monoclonal antibodies. Simultaneous infusion of a nonreactive control antibody would be necessary for specific localization to be demonstrated unequivocally.

Moose-motor vehicle collisions. An increasing hazard in northern New England.

OBJECTIVE: To analyze the epidemiology and epizootiology of moose-motor vehicle collisions (MMVC) and outcomes in severely injured patients to identify variables that might be modified to reduce the impact of this mutually deleterious interspecies interaction. DESIGN: Wildlife and Traffic Safety databases permitted retrospective, population-based assessment of MMVC epidemiology. A case series compiled from hospital trauma registries characterized morbidity and mortality from MMVC. SETTING: New Hampshire and Maine area. PATIENTS: All victims of MMVC (1980 through 1991) were included in population-based analyses. Twenty-three patients hospitalized at three rural trauma centers (January 1990 through June 1994) were included in the case series. MAIN OUTCOME MEASURES: Location, time of day and seasonal occurrence of MMVC were determined. Injury patterns and Injury Severity Scores were analyzed in 23 representative patients. Maine's 1991 traffic and medical data were linked, and factors predictive of injury from MMVC were identified using multivariate logistics. RESULTS: Most MMVC occur from April through October after dark. Of 23 subjects, 70% sustained head and/or face injuries and 26%, cervical spine injuries. Mortality was 9%. Mean Injury Severity Score was 15.7 (SD=9.0). Safety belt use, rear seat location, and light truck occupancy were associated with reduced injury (p<.05). CONCLUSIONS: Moose-motor vehicle collisions are increasing in rural regions. Prevention programs should emphasize defensive driving and seat belt use, especially during high-risk periods. Injury patterns in MMVC suggest a need for automobile design modifications that better protect the passenger compartment form direct impact.

Lessons of parathyroid reoperations.

The case histories of the 23 patients in this series demonstrate the importance of a systematic approach to parathyroid surgery. Ligation of the superior thyroid vessels and mobilization of the upper pole of the thyroid are often necessary to find the superior parathyroid glands that are located on the posterior surface of the thyroid. Devascularization of the thyroid gland does not occur with this maneuver because of abundant collateral circulation from the inferior thyroid artery and tracheal vessels. Normal appearing parathyroid glands should not be resected because this procedure does not treat hypercalcemia and may leave the patient with insufficient parathyroid tissue if an adenoma is found at a later date. Bilateral cervical exploration [35,36] is performed before resection of any abnormal appearing parathyroid tissue. Patients may also have supernumerary parathyroid glands [16], especially in the inferior cervical and superior mediastinal areas that are associated with the thymus [37,38].

Sister-chromatid exchanges in lymphocytes of anatomy students exposed to formaldehyde-embalming solution.

Sister-chromatid exchanges measured in the peripheral lymphocytes of 8 non-smoking persons after exposure to formaldehyde-embalming solution during a 10-week anatomy class showed a small (P = 0.02) average increase when compared with samples obtained from the same individuals immediately before exposure began. Breathing-zone air samples collected during dissection procedures showed a mean concentration of 1.2 ppm (1.5 mg/m3) formaldehyde.

Thermal-energy dissipation: a laboratory study to assess patency in blood vessels.

Surgeons involved in the repair of small blood vessels could benefit from a postoperative monitoring system that would allow vessel-patency determination. These experiments have confirmed that thermal-energy dissipation, measured electrically by direct vascular thermocouple application, is a sensitive and accurate indicator of regional arterial perfusion. Occlusion of arteries 1 to 2 mm in diameter produced a significant temperature decrease in direct artery measurements in the rat and island-flap artery assessments in rats and rabbits. Early recognition of vessel occlusion could allow for rapid intervention and increase the likelihood of tissue salvage. While this technology need not replace existing methodology, it does alleviate many of the problems seen with other vessel- and tissue-monitoring methods and thus may deserve further investigation.