Clinical and pharmacokinetic effects of combined warfarin and 5-flourouracil in advanced colon cancer.

Twenty-five patients with advanced measurable adenocarcinoma of the colon were treated with 5-fluorouracil (FUra), 15 to 20 mg/kg/week i.v., plus warfarin p.o. at a dosage which maintains therapeutic levels of anticoagulation. Sixty-four % of patients achieved either objective response (20%) or stable disease (44%). Overall median survival was 19.2 months. Three patients (all with intraluminal lesions) developed gastrointestinal blood loss requiring transfusion and discontinuation of anticoagulation. The interaction between warfarin and FUra as measured by plasma levels was investigated in seven rabbits and three patients. Plasma samples were obtained for 2 hr after FUra administration, both before and after anticoagulation with warfarin. FUra was measured by gas chromatography, and warfarin was assayed using a thin-layer chromatographic fluorescence method. In rabbits, prolongation of FUra plasma t1/2 was seen with high (0.6 mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. In patients, FUra t1/2 was not changed by therapeutic warfarin anticoagulation. Thus, (a) plasma clearance interaction between FUra and warfarin does not occur in patients receiving therapeutic levels of anticoagulation; (b) FUra and warfarin anticoagulation can be safely given and frequently result in stable disease status for patients with advanced colon cancer. Further trials of this combination are warranted in adenocarcinoma of the colon.

Significance of relapse after adjuvant treatment with combination chemotherapy or 5-fluorouracil alone in high-risk breast cancer. A Western Cancer Study Group Project.

Beginning in 1974, patients undergoing mastectomy at high risk for recurrence (greater than or equal to 4 nodes positive; median, 9.4 positive; range, 4 to 28) were randomized after stratification for menopausal status and radiotherapy to receive either 5-fluorouracil (5-FU, 500 mg/sq m i.v. every week) or cyclophosphamide, 400 mg/sq m; methotrexate, 30 mg/sq m; and 5-FU, 500 mg/sq m (CMF; all given i.v. every 2 weeks) in a 12-month program. All 62 patients remain evaluable with median follow-up now exceeding 70 months (range, 60 to 80 months). CMF significantly prevented early disease recurrence (97% relapse free on CMF versus 75% on 5-FU at 12 months; p less than 0.05) and demonstrated survival advantage during the initial 40-month follow-up. This significance was subsequently lost, and the percentages of relapse free and overall survival after 70 months are: (formula, see text) The apparently paradoxical relationship between relapse and survival on the 5-FU arm was related to survival after recurrence. Survival after recurrence was significantly longer on the 5-FU compared to the CMF arm (median of greater than 38 versus 10 months, respectively; p less than 0.01). These results suggest (a) long-term survival in adjuvant trials cannot be accurately predicted by short-term differences in relapse frequency, (b) survival after relapse may be influenced by the antecedent adjuvant therapy received, and (c) disease relapse does not necessarily preclude long-term survival.

Pernicious anemia in Latin Americans is not a disease of the elderly.

Pernicious anemia is widely regarded as a disease of the elderly. However, it is expressed differently in black women, among the most striking differences being their younger age at presentation of the disease compared with whites. We now compared 92 Latin-American patients with 115 white and 100 black patients to see if similar age differences occur in other racial groups. Latin-American men and women were both significantly younger than white men and women, and were similar in age to blacks. Only 21% of Latin-American patients were 70 years of age or older, compared with 49% of whites. It is apparent that pernicious anemia is indeed predominantly a disease of the elderly in whites but that this is not the case in other racial groups.

Transfusion practice in medical patients.

OBJECTIVE: Blood transfusion raises serious issues of safety and economics. We therefore examined blood usage and its characteristics in medical inpatients, given the relative scarcity of existing data. DESIGN: During a 1-year period, transfusion episodes on two medical services were reviewed by five specialists for justifiability on the basis of generally agreed on guidelines. SETTING: The study was conducted at two institutions, a municipal teaching hospital where house staff deliver care and a community hospital where patients are under the direct care of private physicians. PATIENTS: Four hundred thirty-eight randomly selected transfusion episodes on the medical services of the two institutions were reviewed. MAIN OUTCOME MEASURES: The prevalence of unjustifiable transfusions based only on the information available to the managing physician at the time of transfusion. RESULTS: Eighteen percent of the 438 randomly selected transfusion episodes were viewed as not justifiable by at least four of five reviewers; another 17% were classified as equivocal because two or three reviewers judged them to be not justifiable. The most striking observation was the greater prevalence of nonjustifiable transfusion episodes at the community hospital (26% vs 16% at the teaching institution; P = .0121). Other observations included a tendency for physicians to prescribe transfusions by the numbers (at least 11% of nonjustifiable transfusions) and to overtransfuse. The routineness with which transfusion was viewed by managing physicians was also identifiable by the absence of written transfusion notes in 39% of all episodes reviewed, which incidentally raises questions about the adequacy of the medical chart's documentary functions today. CONCLUSIONS: The rate of nonjustifiable or equivocal transfusion on medical services may be as high as 35%. Reliance on numbers rather than clinical status seems to be a major problem. Education is obviously a critical issue and should also target private practitioners, who seemed to perform less well than physicians in training. Transfusion guidelines that use specific hematocrit values also need to be reexamined.

Persistence of myocardial injury following brief periods of coronary occlusion.

Transient (20 min) occlusion of the left anterior descending coronary artery in open-chest anaesthetized dogs caused immediate aneurysmal bulging of the ischaemic segment, which preceded epicardial ST-segment elevation. Reperfusion after 20 min restored epicardial electrograms to normal, wheras mechanical dysfunction persisted for a least 45 min therafter. The study shows that there is temporal disparity between electrical and mechanical events both at the inception of myocardial ischaemia and during recovery from transient myocardial ischaemia.

Free thyroxine estimates in nonthyroidal illness: comparison of eight methods.

Eight methods for estimating free serum T4 were compared for 26 patients with nonthyroidal illness (NTI) and 16 hypothyroid patients with comparable total T4 (TT4) concentrations. Free T4 values were determined by equilibrium dialysis, enzyme immunoassay (Abbott), antibody-coated tube (Clinical Assays), antibody-coated microfine silica (Corning Immunophase), microencapsulated antibody (Damon), and free T4 index using the T3 uptake ratio or thyroxine-binding globulin method. Equilibrium dialysis, Clinical Assays and Abbott methods usually provided free T4 estimates in the normal range in NTI patients with low TT4 values and differentiated them from hypothyroid patients with comparable TT4 levels. In contrast, the other methods gave decreased free T4 estimates in the low TT4-NTI groups and often did not distinguish them from hypothyroid patients. The normal free T4 estimates by equilibrium dialysis, Clinical Assays, and Abbott methods in the low TT4-NTI patients are consistent with the previous findings of normal T4 disposal rates in these patients. These three methods may assist the clinician in differentiating the low T4 state of NTI from overt thyroxine deficiency of hypothyroidism.

Auditory evoked potentials in coma after closed head injury: a clinical-neurophysiologic coma scale for predicting outcome.

We studied auditory evoked potentials in 45 head-injured patients. All but three were comatose or stuporous at the time of study. Preservation of brainstem auditory or long-latency auditory evoked potentials predicted good outcome. The Glasgow coma scale (GCS), the clinical subtotal of the neurophysiologic coma scale (NPCS), and the NPCS had predictive accuracies of 71%, 82%, and 82%. Although there were 22 falsely pessimistic predictions with the GCS and 9% with the clinical subtotal of the NPCS, there were no falsely pessimistic predictions with the NPCS.

CT criteria of hemisphere asymmetry fail to predict language laterality.

We compared CT measures of the left and right cerebral hemispheres for two groups of right-handed aphasic adults: those who were left-hemisphere language dominant (n = 89) and those who were right-hemisphere language dominant (n = 15). The distribution of linear CT measures of anterior and posterior widths and lengths did not differ significantly in the two groups. These findings fail to support the hypothesis that CT criteria of hemisphere asymmetry predict language laterality.

Left hemisphere pathways in reading: inferences from pure alexia without hemianopia.

In pure alexia, reading is impaired despite almost normal speech, spelling, and writing. We studied a right-handed man with pure alexia, but no hemianopia. He had more difficulty reading longer words (word-length effect), but had no selective reading impairment in phonologic or semantic analysis. Clinical-CT correlation suggests that (1) left hemisphere visual pathways crucial for reading arise from or pass close to the left occipitotemporal or inferior temporal gyrus, and (2) relevant transcallosal fibers from the right hemisphere course inferior to the posterior horn of the left lateral ventricle before ascending to left hemisphere language areas.

Arteriography of the carotid bifurcation: oblique projections.

Atherosclerotic plaques may not be demonstrated adequately by standard anteroposterior (AP)-lateral projections of carotid arteriography. We evaluated selective carotid arteriography in oblique projections for 60 individual carotid arteries. Two neuroradiologists evaluated arteriograms in four separate sessions devoted to AP-lateral views alone and in combination with oblique projections. The lumen surface was characterized as "smooth," "irregular," or "ulcerated." When oblique projections were added to AP-lateral views, there was a significant shift of radiologic diagnosis from smooth to irregular or ulcerated. Addition of oblique projections to standard AP-lateral views increases the radiographic diagnosis of carotid artery lesions that may be the source of emboli.

Metastatic and histologic presentations in unknown primary cancer.

The patient with metastatic adeno- or undifferentiated carcinoma who presents with a cryptic primary is subjected to an extensive diagnostic search. These efforts apparently stem from the following assumptions: 1). The ultimately proven primary sites in such patients will occur with the same frequency as the most commonly occurring carcinomas (i.e., lung, breast, colon, prostate, etc.); and 2). Metastatic patterns and histologies seen at diagnosis are the same as for patients presenting with these more common tumors. Our data contradict these assumptions. For example, the most commonly occurring unknown primary was pancreas. Rarely occurring primaries included breast and prostate. Lung cancer was observed frequently, but the presentation was atypical because of the large proportion of female patients. In addition, the metastatic patterns at diagnosis were unusual for many of the ultimately proven primary sites. In an attempt to deal with these contradictions, a method to search for new relationships between primary site and metastatic-histologic presentations was employed. This method succeeded in placing the location of the primary cancer to above or below the diaphragm in 80% of the patients studied retrospectively. Tested prospectively in a small group of patients, the method appears to be clincally useful. Finally, in this study we have made the diagnosis, antemortem, of the primary cancer site (PCS) in only 30 of 264 patients. The failure to find the primary site, dispite extensive radiologic work-up, was disappointing to the authors, and emphasizes the difficulty of finding PCS antemortem. In our study pancreas and lung appear to be most common cryptic primary sites.

Endoscopy or radiography?--The patient's choice. Prospective comparative survey of patient acceptability of upper gastrointestinal endoscopy and radiography.

Patient acceptability of endoscopy and the double-contrast barium meal test was compared in a prospective randomized fashion. Ninety-six inpatients were interviewed with a standardized questionnaire within 24 hours of completion of double-contrast barium meal test and endoscopy, after recovery from administered sedation. Twenty-five percent of patients reported moderate to severe discomfort with each procedure. The levels of discomfort reported were similar for both procedures. The majority of patients would readily undergo a repeated procedure, if requested. There was a tendency (p less than 0.1) for patients to prefer endoscopy overall. No specific patient group that preferred one procedure over the other could be identified, although older patients (more than 55 years) showed a tendency to prefer endoscopy. The choice of one procedure over the other should no longer be based on the presumed superior acceptability of the double-contrast barium meal test.

Lupus nephritis. Experience with 230 patients in a private practice from 1950 to 1980.

Nephritis developed in 230 of 609 private patients with systemic lupus erythematosus (SLE) (38 percent) followed up from 1950 to 1980. Eighty-seven percent of patients with nephritis were female; 71 percent were Caucasian. They were observed a mean of 10 years. Five- and 10-year survival rates were 80 percent and 65 percent, with improvement to 86 percent and 76 percent in the last decade. Normalization of urinary sediment and protein levels, blood pressure and serum albumin levels correlated with improved survival and tended to occur during the first year. Life-threatening complications of SLE were more common after the onset of nephritis but decreased as renal function worsened. Infection was the most frequent cause of death in the last decade. Forty-four patients received nitrogen mustard; 55 percent of the courses were followed by significant improvement in renal function and reduced steroid dosage. Control of the disease was associated with improved long-term survival of patients with SLE.

Experimental myocardial infarction. 14. Accelerated myocardial stiffening related to coronary reperfusion following ischemia.

In six dogs with surgically opened chests, segmental mechanical function was determined by measuring segment length using mercury-in-Silastic gauges attached to the epicardial surface of the left ventricular wall. Following coronary arterial occlusion the amplitude of the resulting paradoxical systolic bulge was quantitated in terms of "muscle lengths", defined as the ratio of the amplitude of the segment length over the end-diastolic segment length (EDSL). From an excursion of 0.176 +/- 0.029 muscle lengths at six hours of ischemia, the amplitude of the bulge decreased abruptly to 0.125 +/- 0.024 muscle lengths after 15 minutes of coronary reperfusion (P less than 0.05) but maintained paradoxical expansion in systole. Segmental "effective stiffness", calculated at the same periods of time from end-diastolic pressure-length relationships during transient pressure loading of the left ventricle, showed a reciprocal change, increasing from 1.416 +/- 0.161 to 2.051 +/- 0.238 mm Hg/% deltaEDSL (P less than 0.05). These data indicate that the degree of paradoxical bulging of an ischemic segment is affected by its pressure-length characteristics (distensibility) and that a rapid decrease both in the amplitude of the bulge and in distensibility occurs during reperfusion. The mechanism is uncertain but may relate to either myocardial edema or myofibrillar contracture.

Urinary steroids in the measurement of aging and of atherosclerosis.

Several studies conducted by the authors' group have shown that urinary steroid measurements are a valuable aid in differentiating the normal aging process, the pronounced aging associated with increased risk to coronary heart disease, and the deviations associated with myocardial infarction. Data are presented on 428 men in the age range of 30-70 years. The study design most effective in elucidating aging and disease patterns involves selection of subjects from a wide age range. Data on persons identified as clinically normal can be used to describe physiologic aging. Once this is determined, data on persons with disease can be used to identify abnormalities of aging associated with the clinical conditions studied. This approach offers a potential method for differentiating between aging effects and disease effects. The foregoing findings led to the development of an Index of Aging in males, based on combined serum lipid and urinary steroid values. This Index may be a means of differentiating between normal aging and the deviations seen in atherosclerosis and myocardial infarction. Current studies are directed toward extending these observations.

Juvenile fibrosarcoma of the orbit and eyelid. A study of five cases.

Five patients had juvenile fibrosarcoma of the orbit and eyelid. At initial surgical intervention, the patients ranged in age from newborn to 8 years (mean, 3 years 9 months). Three patients were male and two were female. Proptosis and/or painless swelling of the eyelid were the most common signs and symptoms. Four tumors grew within a few weeks or months, and all five were poorly circumscribed. They were composed of immature, spindle-shaped fibroblastic cells in a classic herringbone pattern or in interlacing fascicles. Hypercellularity and mitotic activity were present in all lesions. The differential diagnosis included rhabdomyosarcoma, fibromatosis, and fibrous histiocytoma. Electron microscopy confirmed the fibroblastic nature of the tumor cells in three cases. Follow-up ranged from one to 32 years (median, seven years). Two of five tumors recurred locally but none metastasized. Apparently surgical excision is the treatment of choice and the tumor has a favorable prognosis.

Clinical classification of Graves' ophthalmopathy. Identification of risk factors for optic neuropathy.

Clinical signs of Graves' ophthalmopathy were correlated with extraocular muscle volumes in 50 patients. Significant correlations were obtained for horizontal, vertical, and total extraocular muscle limitation, as well as periorbital swelling. Proptosis correlated to a lesser extent. Optic nerve involvement was found to be correlated with both total extraocular muscle volume and limitation of ocular motility. From this information, no risk, future risk, and immediate risk categories of disease were defined quantitatively. The results of the study imply that optic nerve involvement is more likely to occur in association with noncompliant, fibrotic muscle than with more supple muscle of the same total volume.

Quantitative computed tomography of Graves' ophthalmopathy. Extraocular muscle and orbital fat in development of optic neuropathy.

Quantitative assessment of computed tomographic (CT) scans was performed on 98 orbits of 49 patients with Graves' ophthalmopathy. Extraocular muscle volume and orbital fat volume were determined, according to whether optic neuropathy was absent, had developed during follow-up, or was present at the time of scanning. No differences in muscle volume were found between the group already having optic neuropathy and the group in which optic neuropathy developed during follow-up. Both optic neuropathy groups, however, had significant increases in extraocular muscle volume compared with the group without optic neuropathy. The absolute amount of orbital fat was the same for all groups, but the relative amount of orbital fat tended to decrease as total orbital volume increased with development or presence of optic neuropathy. This study establishes a quantitative relationship between optic neuropathy and extraocular muscle enlargement in Graves' ophthalmopathy. Orbital fat, however, does not play an important role in the disease.

Red blood cell distribution width in untreated pernicious anemia.

The red blood cell distribution width (RDW) was studied in 26 unselected patients with untreated pernicious anemia. RDW changes were also sequentially followed after therapy in 12 patients. The mean (+/- 1 SD) RDW values were significantly higher in pernicious anemia patients than in controls (21.7 +/- 9.1% vs. 13.2 +/- 1.1%, P less than 0.0001). Nevertheless, 31% of the patients had normal RDWs. There were no consistent findings among those who had normal RDW. Most of them were in the early stages of deficiency, but some had advanced deficiency. Over half of those with normal RDW also had normal mean corpuscular volume (MCV). Overall, 9 of the 26 patients (35%) had normal MCV. Of eight patients whose RDW fell with therapy, some showed a steady fall while others had a transient rise followed by a progressive drop. Despite current advocacy that a high RDW is a sensitive and consistent finding in vitamin B12 deficiency, our findings show that a large proportion of untreated pernicious anemia patients have normal RDWs and that in contrast to iron deficiency, elevation of RDW is not necessarily the earliest indicator of vitamin B12 deficiency.

Platelet counts in three racial groups.

Documented differences exist in red blood cell (RBC) and granulocyte counts between black and white people. However, little comparative information is available on differences in platelet counts in the two racial groups. Therefore, this study was performed to compare platelet counts in healthy white (94), black (92), and Latin-American (63) persons. Black women had significantly higher platelet counts than did white women (P less than 0.025). Latin-American women were between the other two groups. No differences were noted among men. Black women also had a significantly higher prevalence of iron deficiency and microcytosis of RBCs than did white women. After exclusion of women with either microcytosis or iron deficiency, racial differences in platelet counts were no longer evident. The authors conclude that the differences in the platelet counts between black and white women were secondary to common RBC differences (such as iron deficiency and other causes of microcytic anemia) and were not intrinsic to the platelets. These and other factors that can affect platelet counts should be excluded before determining the reference ranges for proper interpretation of the platelet counts.