Chemotherapy for lung cancer.

LETTERS AND CORRECTION

Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: We give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style. Aspirin and Postoperative Bleeding T o T H E EDITOR: Torosian and colleagues (1) have reported increased postoperative bleeding in patients receiving aspirin within a week of surgery. Although the effects of aspirin last for the lifetime of exposed platelets, 5 to 7 days, the bleeding time is normal within 2 days after administration of aspirin (2, 3), and platelets collected from donors receiving aspirin 36 h before donation can correct abnormal bleeding times in recipients (4). Although aspirin-exposed platelets do not release their own A D P , if sufficient normal platelets are present the entire platelet pool appears to function normally, at least as measured by bleeding time. Therefore, it seems important to know whether the interval between stopping aspirin therapy and having surgery was an important determinant of bleeding in their patients. Also, considering that patients often do not consider aspirin a drug and often do not know what medicines contain aspirin, the use of patient-provided information to allocate patients to the aspirin group may be naive. It is unfortunate that bleeding times or other platelet studies were not obtained in all patients to identify potential aspirin ingestors in the "control" group. R I C H A R D S. S T E I N , M . D .

Vanderbilt University; Nashville, T N 37232 REFERENCES 1. TOROSIAN

ten difficult to obtain with accuracy, but in our study this information was determined by two independent interviews at admission, as well as by telephone confirmation in the follow-up period (as discussed in our Methods section). Our study merely represents a preliminary, although provocative, attempt to alert physicians to the postoperative bleeding consequences of commonly prescribed medications. We agree that more sophisticated studies are now warranted. M. T O R O S I A N , M . D .

E . L . MlCHELSON, M.D. Hospital of the University of Pennsylvania; Philadelphia, P A 19104 J. MORGANROTH, M.D. H . MACVAUGH I I I , M.D. Lankenau Hospital; Philadelphia, P A 19151 T o T H E EDITOR: A reliable, simple way to minimize aspirin-related bleeding after coronary-artery bypass surgery is to perform a preoperative platelet function test, the template bleeding time. In the study reported by Torosian and associates (1), no preoperative platelet function testing was done to screen for a thrombasthenia. I suspect that had template bleeding times been measured as a routine preoperative coagulation test, then the aspirin-associated postoperative bleeding problems would have been avoided or at least minimized. In our hospital, template bleeding time is measured the day before surgery on all patients who are to undergo cardiopulmonary bypass surgery. The template bleeding time is used as a screening test to minimize the incidence of aspirin-induced postoperative cardiopulmonary bypass surgery bleeding. D A V I D PRAGER, M.D.

Allentown-Sacred 18105

Heart

Hospital

Center;

Allentown, P A

REFERENCE M , MlCHELSON

E L , MORGANROTH

J, M A C V A U G H H I I I :

Aspirin- and Coumadin®-related bleeding after coronary-artery graft surgery. Ann Intern Med 89:325-328, 1978

bypass

1. TOROSIAN M, M I C H E L S O N EL, M O R G A N R O T H J, M A C V A U G H H III:

Aspirin- and Coumadin®-related bleeding after coronary-artery graft surgery. Ann Intern Med 89:325-328, 1978

bypass

2. H I R S H J, S T R E E T D, C A D O JF, A M Y H: Relation between bleeding time

and platelet connective tissue reaction after aspirin. Blood 1973

41:369-377,

3. S T U A R T MJ, M U R P H Y S, OSKI FA, E V A N S AE, D O N A L D S O N

MH,

G A R D N E R FH: Platelet function in recipients of platelets from donors ingesting aspirin. N EnglJ Med 287:1105-1109, 1972 4. O ' B R I E N JR: Effects of salicylates on human platelets. Lancet 1:779-783, 1968

In comment: Dr. Stein addresses three relevant points concerning our finding of increased bleeding in postcoronary surgical patients who have ingested specific drugs in the immediate preoperative period. We have also been interested in the potential predictive value of the bleeding time and specific in-vitro platelet function tests on the quantity of postoperative bleeding. Our own preliminary data (unpublished) in patients ingesting either aspirin or diazepam have suggested that these tests, when abnormal, predict increased bleeding, but when they are normal, unfortunately, they are not sensitive to minor platelet abnormalities associated with increased bleeding. Thus a normal bleeding time may still be associated with increased bleeding in patients who have previously ingested aspirin, diazepam, or other platelet inhibitory agents. Unfortunately, the number of aspirin users in our present study was too small to determine the relation between the time of discontinuation of aspirin preoperatively and the amount of postoperative bleeding. We agree that medication history is of-

Assessing the Severity of Aortic Stenosis T o T H E EDITOR: Assessment of the severity of aortic stenosis is one of the most difficult problems in clinical cardiology. T h e development of an accurate noninvasive technique to assist in this judgment would indeed be an important advance, and I therefore read the recent article by Schwartz and colleagues (1) with great interest. Unfortunately there are several potentially misleading features of the paper, and I am concerned by the authors' overall conclusion that " a n accurate estimate of the aortic valve gradient" can be made in most patients and the need for invasive studies in many patients may be obviated. These concerns are heightened by the appearance of the article in an internal medicine journal, whose readers may lack the sophistication to evaluate critically its content. The authors attempt to estimate the severity of aortic stenosis but do not include important data that would allow the reader to determine the significance of the given gradient. They do not provide cardiac output measurements or the calculated aortic valve area, which is a better indicator of the severity of stenosis. The inclusion of 15 patients with aortic insufficiency, without any quantitation of regurgitant flow, makes it difficult to interpret the gradient data. The authors should also indicate whethLetters and Correction

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er the patients have a history of hypertension, since this could independently affect ventricular thickness and size and thus these patients might not behave in accordance with the assumptions required to calculate wall stress. The correlation between the echocardiographic and catheterization gradients (r = 0.75), while statistically significant, is not close enough to be clinically reliable, even after the exclusion of several groups of patients. Thus, patients with a calculated echo gradient of 65 to 70 m m Hg actually had gradients ranging from 45 to 160 m m Hg; conversely, patients with gradients of 35 to 40 mm Hg had calculated gradients ranging from 5 to 105 mm Hg. Most clinicians use the echocardiogram empirically to assess aortic stenosis qualitatively. In a patient with clinical features of stenosis and normal blood pressure, the presence of left ventricular hypertrophy suggests severe obstruction, while the finding of normal wall thickness goes against significant stenosis. In fact, a simple ratio of systolic pressure to posterior wall thickness calculated from the authors' data proved as useful as the calculated gradient. When patients with accompanying aortic regurgitation, from whom the gradient data are difficult to interpret, and the same patients with impaired contractile function are excluded, the correlation with the gradient measured at catheterization (r = — 0.74) is similar. All patients with a ratio > 7.5 had gradients < 20 m m Hg, while all with a ratio < 7.5 had gradients above 20 m m Hg (14 of 15 were > 35 m m Hg). It would probably be better to use mean blood pressure and correlate the ratio with aortic valve area rather than gradient, but nonetheless such a ratio appears to be simpler to obtain and at least as accurate for screening purposes as the authors' calculated gradients. Perhaps more importantly, this ratio can be more easily identified as a qualitative indicator and not inappropriately taken as a quantitative measurement of the severity of stenosis, which remains beyond the capability of echocardiography.

regurgitation, and this was confirmed in eight patients by supravalvular aortography. Although generally in patients with "clinical features of stenosis and normal blood pressure, the presence of left ventricular hypertrophy suggests severe obstruction," the absence of left ventricular hypertrophy does not exclude significant stenosis. Therefore a significant number of patients with aortic stenosis will not be identified when diastolic wall thickness is used as a selection criterion. The problem is heightened by the fact that a large number of elderly patients have associated systolic hypertension. Therefore the finding of increased diastolic wall thickness in this group lessens the sensitivity of this finding when screening patients for associated aortic stenosis. However, since the effects of hypertension and aortic outflow obstruction are additive when one considers systolic wall stress, the estimated left ventricular pressure will reflect the effects of both. By subtracting cuff systolic blood pressure, one can determine how much of the increased systolic wall thickness is related to hypertension and how much to aortic stenosis. Although the ratio of systolic blood pressure to posterior wall thickness that Dr. Massie mentions is interesting, I believe it adds little to our formulation. T h e approach we used made it unnecessary to exclude patients with aortic regurgitation for the reasons outlined above. In addition, we believe that most clinicians would feel more familiar with an estimate of left systolic pressure rather than another obscure echocardiographic ratio. P A U L A. V I G N O L A , M . D .

Massachusetts General Hospital; Boston, M A 02114 REFERENCE 1. B E N N E T T DH, E V A N S DW, R A J MVJ: Echocardiographic left ventricu-

lar dimensions in pressure and volume overload. Their use in assessing aortic stenosis. Br Heart J 37:971-977, 1975

BARRY MASSIE, M.D.

University of California; San Francisco, C A 94121 Ambulatory Electrocardiography REFERENCE 1. S C H W A R T Z A, VIGNOLA PA, W A L K E R HJ, K I N G ME, G O L D B L A T T A:

Echocardiographic estimation of aortic-valve gradient in aortic stenosis. Ann Intern Med 89:329-335, 1978

In comment: I believe that Dr. Massie's concern that the readers of Annals of Internal Medicine "may lack the sophistication to evaluate critically" our recent paper is unwarranted. Quite the contrary—my colleagues and I specifically chose this journal because of the considerable sophistication of its readership. The choice seems even more appropriate when one considers that internists, not cardiologists, evaluate and care for most patients with cardiac murmurs. The purpose of the technique we describe is not to calculate aortic valve areas or, for that matter, to predict the actual aortic valve gradient within 10 m m Hg. Rather it is intended as a screening procedure so that patients with suspected aortic stenosis can be more knowledgeably selected for invasive study. In our study we found that a nonivasively estimated valve gradient of less than 25 m m Hg correctly identified 14 of 16 patients with catheterization gradients less than 40 m m Hg. More important, no patient with a catheterization gradient of greater than 50 m m Hg was incorrectly judged to have mild obstruction. As for the technique, it matters little if a patient with good left ventricular function and an echo gradient of 60 m m Hg actually has a catheterization gradient of 110 m m Hg. T h e point is that this patient was correctly identified as a patient who needs to be catheterized. It matters little if a patient with good left ventricular function and an echo gradient of 15 m m Hg actually has no gradient at catheterization. The point is that this patient was correctly identified as a patient who does not need to be catheterized. Since aortic regurgitation does not invalidate the basic assumption of the technique (1), it seemed reasonable to include those 15 patients with aortic stenosis who had associated aortic regurgitation. All were thought clinically to have trival aortic 124

T o T H E EDITOR: A "natural history" follows the introduction of a new or innovative diagnostic technology as reported in the medical literature and may be described as follows: [1] initial reports exploring potential applications of the technology; [2] enthusiasts seeking and reporting advantages and usefulness of the new technology; [3] objective reports of the limitations or errors of such technology; and [4] correct clarification of the technology with regard to its indications, limitations, and adjunctive value for the practicing clinician. It seemed that the recent article by Crawford and associates (1) would contribute data to the third step of the "literary natural history" of ambulatory electrocardiography. However, several aspects of the study are unsettling and deserve comment. The comparison of a treadmill exercise test using a modified Bruce protocol that most commonly employs a fairly rigorous design (fasting state, graduated exercise, and a controlled environment) to an ambulatory E C G recording described as obtained "for at least 12 h, during which time the patients were told to be active," shows considerable bias for increased efficiency of the treadmill test and a limited understanding of ambulatory electrocardiology. Whereas the exercise test seeks to identify abnormal cardiovascular function and E C G changes induced by a prescribed physical work load in a relatively controlled environment, the ambulatory electrocardiogram measures dynamic E C G changes within a changing physical and psychoneurological environment. In the described study, more rigorous design in performing ambulatory electrocardiography might have reduced the occurrence of false-positive results by [a] routine pre-examination and identification of body-position related ST segment changes; [b] diary-recorded times of medication ingestion to identify drug-induced secondary ST segment changes; and [c] diary identification of autonomic-induced ST segment changes that may be associated with micturition or defecation. Similarly, decreased occurrence of false-negatives would be expected by performing the ambulatory E C G exami-

January 1979 • Annals of Internal Medicine • Volume 90 • Number 1


nation for a complete diurnal cycle (24 h) and by examining the patient on an ambulatory outpatient basis, during which time the patient is subjected to the physical and psychoneurological stresses of his usual activities. Despite these design biases, the data nonetheless show only marginal differences (5%) favoring treadmill exercise testing for greater sensitivity and less false-negative data in detecting the 39 coronary artery disease patients, and only 14% difference in more specificity and less false-positive data in detecting noncoronary artery disease patients. Further, when the predictive accuracy of a positive test is derived from the data (2), the treadmill exercise test was only slightly more accurate (26 of 34 patients, or 7 6 % ) than ambulatory monitoring (24 of 36 patients, or 6 7 % ) . These data show no statistical difference (P < 0.05) and are even less impressive when it is realized that the prevalence of coronary artery disease in the population studied was 5 6 % (39 of 70) (3). Considering these aspects, why, then, is the emphasis of this study on "Limitations of Continuous Ambulatory Electrocardiogram Monitoring for Detecting Coronary Artery Disease"? I suspect it is somewhat rooted in the expected evolution and "vogue" of "literary natural history." The time seems imminent for valid reports of the limitations and errors of such technology, but care must be exercised to insure proper use of the technology without bias. More important, when such reports do appear, the practicing clinician must critically examine the data and determine its merit without being swayed by headlines. For in so doing, he helps define the final phase of this process—determining the indications, limitations, and adjunctive value of the technology. These data do not warrant the authors' conclusion that ambulatory monitoring is of limited value for detecting coronary artery disease in symptomatic patients with normal resting electrocardiograms. H A R O L D L.

KENNEDY,

M.D.

U.S. Public Health Service Hospital; Baltimore, M D 21211 REFERENCES 1. C R A W F O R D MH,

M E N D O Z A CA,

O ' R O U R K E RA,

W H I T E DH,

BOU-

CHER CA, G O R W I T J: Limitations of continuous ambulatory electrocar-

diogram monitoring for detecting coronary artery disease. Ann Intern MedS9:\-5, 1978 2. FEINSTEIN AR: Clinical biostatistics. XXXI. On the sensitivity, specificity, and discrimination of diagnostic tests. Clin Pharmacol Ther 17:104116, 1975 3. VECCHIO TJ: Predictive value of a single diagnostic test in unselected populations. N Engl J Med 274:1171-1173, 1966

In comment: We understand ambulatory electrocardiology fully and agree that there are inherent biases in the technique. In fact, Dr. Kennedy's letter enumerates several of the reasons why the ambulatory E C G lacks specificity. Our objection is with the previous studies of this technique, which probably fall into Stage 2 of Dr. Kennedy's "natural history" of a technique and claim that the ST-T wave changes observed on ambulatory monitoring are highly sensitive and specific for coronary artery disease. This is clearly not so. Some of the reasons for this are discussed in our paper and others are presented in Dr. Kennedy's letter. We emphasized the ambulatory monitoring data because there are numerous studies in the literature detailing the inadequacies of treadmill exercise studies. Our data show that ambulatory electrocardiography was useful in a few patients but was certainly of limited value overall in accurately detecting coronary artery disease in our patients. Dr. Kennedy suggests that our ambulatory monitoring technique may have negatively influenced the results. First, E C G tracings in the lying, sitting, and standing positions were run in the laboratory before each patient left, and no significant changes were noted. Second, 61 of our 70 patients (87%) had 24 h of monitoring, and the data in this subgroup were no different from those in the whole group. Third, many of our subjects were outpatients at the time of the ambulatory E C G study, and the hospitalized patients often were escorted through various activities that previously had produced their symptoms, in addi-

tion to being admonished to be active t h a i day. Finally, in an effort to obtain a large number of patients for the study, we did not select subjects for the obsessive-compulsive traits necessary to fill out the type of diary that would satisfy Dr. Kennedy. Our patients were instructed to keep detailed diaries, but unfortunately their quality varied, and no consistent relation was observed between the events recorded in these diaries and the ambulatory E C G recordings. We believe that a more strictly supervised ambulatory monitoring period would not have greatly improved the results of the study and such efforts would rarely be applied in the usual clinical setting. M I C H A E L H. C R A W F O R D , C A R L O S A. M E N D O Z A , R O B E R T A. O ' R O U R K E , D A V I D H. W H I T E , C H A R L E S A. B O U C H E R , JEFFREY G O R W I T ,

University of Texas Health Science Center; San Antonio, TX 78284

Chemotherapy for Lung Cancer T o T H E EDITOR: In their recent article Hansen and associates (1) state that the superiority of their four-drug therapy ( C C N U , cyclophosphamide, methotrexate, vincristine) over the threedrug regimen (CCNU, cyclophosphamide, methotrexate) is "easily accepted as related to the use of vincristine." One aspect of their data leads us to question this conclusion and provokes several thoughts on their study. Patients with the longest survival (median, 256 days) were those responding to the four-drug regimen, a result that is easily accepted because these patients had the longest remissions (median, 186 days). It was therefore surprising to find that the survival of those responding to the three-drug regimen (median, 190 days) was not appreciably longer than the survival of those not responding to the four-drug regimen (median, 178 days). Response to chemotherapy has been previously shown to result in increased survival for patients with oat-cell carcinoma of the lung (2), as well as for others with drug-sensitive neoplasms such as multiple myeloma (3) and histiocytic lymphoma (4). Furthermore, the degree of tumor cytoreduction (complete response, partial response, and so forth) is usually reflected in lengths of remission and survival. The results reported by Hansen and associates, therefore, raise questions regarding the similarity of the two treatment groups. This is heightened by the finding that both responders and nonresponders on the four-drug regimen survived significantly longer (P < 0.05) than their respective counterparts on the three-drug regimen. One can then argue that although patients on the four-drug protocol survived longer, this occurred irrespective of their response to chemotherapy and thus may not represent a beneficial effect of vincristine. On the other hand, it is possible that the four-drug regimen was truly more effective even though this was not reflected in the response rates. Hansen and associates defined a response as 50% reduction in measurable tumor volume. All others were considered nonresponders. If, however, smaller orders or response (minimal response, stable disease, and so forth) occurred with greater frequency among those patients receiving the fourdrug regimen, one might expect a survival advantage for these "nonresponders." The paper by Hansen and associates also does not comment on the subsequent therapy of nonresponders. If their management was not conducted uniformily, important differences in survival could result. Finally, it would have been preferable for Hansen and associates to present the survival curves for responders and nonresponders on each regimen. In comparing the median survival of each treatment group we have to assume that the shapes of the survival curves are similar. If the shapes are different, a meaningful difference in survival at the tail of the curve may not be reflected in the median survival. Letters and Correction


M.D. M.D. M.D. M.D. M.D. M.D.

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It may be that the survival difference between the two treatment groups was related to the use of vincristine. We would, however, argue that this cannot be easily concluded from this study and suggest that further analysis of the data, looking at variables other than histologic subtype, might identify factors important in the evaluation of the response and survival results. A L E X E. D E N E S , M . D . C A R Y A. PRESANT, M.D.

Washington University School of Medicine; St. Louis, MO 63110

REFERENCES 1. H A N S E N HH, DOMBERNOWSKY P, H A N S E N M, HIRSCH F: Chemothera-

py of advanced small-cell anaplastic carcinoma. Superiority of a fourdrug combination to a three-drug combination. Ann Intern Med 89:177181, 1978 2. C O H E N MH, C R E A V E N PJ, FOSSIECK BE J R , BRODER LE, S E L A W R Y

OS, JOHNSTON AV, W I L L I A M S CL, M I N N A JD: Intensive chemotherapy

of small cell bronchogenic carcinoma. Cancer Treat Rep 61:349-353, 1977 3. A L E X A N I O N R, BERGASEL DE, M I G L I O R E PJ, V A U G H N WK,

HOWE

CD: Melphalan therapy for plasma cell myeloma. Blood 31:1-10, 1968 4. D E V I T A VT J R , C A N E L L O S G P , C H A B N E R B, SCHUIN P, H U B B A R D S,

YOUNG RC: Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1:248-250, 1975

In comment: Denes and Presant are challenging our conclusions that a four-drug combination chemotherapy including vincristine is superior to the same combination without vincristine. Our conclusion is based on survival curves and duration of response in a randomized trial after careful staging of the patients including stratification for performance status (1, 2). Denes and Presant find it "surprising" that the survival of the responders on the three-drug regimen was not "appreciable" longer than that of the nonresponders in the four-drug regimen. The fact that the number of nonresponding patients on the four-drug treatment was only 11 makes us cautious in putting too much emphasis on this difference, considering the high degree of statistical uncertainty of a median survival in so few patients. Evaluation of a response in patients with lung cancer is by itself subjected to a considerable degree of observer variability, and depends furthermore on the number of evaluation procedures done such as chest roentgenogram, repeat bronchoscopy, bone-marrow biopsy, peritoneoscopy with liver biopsy, and so forth. For these reasons we believe that survival curves still are the most important and exact way of comparing two different treatment schedules in patients with lung cancer. Accordingly, we can only share the opinion of Denes and Presant on the importance of uniform subsequent therapy in patients with progressive disease. Therefore, we wish to give the additional information that there was no difference in our study of the subsequent therapy in the two treatment arms. Thus, considering that all present known prognostic factors were equal distributed, the only difference to explain the different results between the two groups still remains the fact that patients on the three-drug treatment never received vinca alkaloids. H E I N E H. H A N S E N , P. D O M B E R N O W S K Y , M. H A N S E N , F. H I R S C H ,

M.D. M.D. M.D. M.D.

Chemotherapy Department R, Finsen Institute; Copenhagen, Denmark

REFERENCES

prognostic features in small-cell anaplastic bronchogenic carcinoma. Semin Oncol 5:280, 1978

Asthma and Nonsteroidal Anti-Inflammatory Drugs T o THE EDITOR: We have recently studied (1) a 55-year-old patient suffering from bronchial asthma whose attacks were relieved by aspirin and whose case was in many respects similar to the interesting case recently reported by Kordansky and colleagues (2). In our patient the airway obstruction was strikingly relieved by aspirin and by three other cyclo-oxygenase inhibitors (indomethacin, mefenamate, and fenoprofen), but not by two other analgesics (salicylamide and benzydamine), which do not inhibit prostaglandin biosynthesis. We assumed, therefore, that pharmacologic removal of a product of arachidonic acid cyclo-oxygenation from the respiratory tract of our patient helped him to overcome the airway obstruction. Similarly, in the case studied by Kordansky and colleagues, cyclo-oxygenase inhibitors, namely aspirin, mefenamic acid, and ibuprofen, produced a marked improvement in spirometric values, whereas tartrazine and sodium salicylate, both lacking inhibitory action against cyclo-oxygenase, led to nonsignificant spirometric changes, similar to those induced by placebo. The results of indomethacin and phenylbutazone challenges seemed at first, however, to be discrepant with our assumption of participation of a prostaglandin mechanism in the case discussed. Indomethacin, a potent cyclo-oxygenase inhibitor, produced only modest improvement in forced expiratory volume in 1 sec (FEV,). The observation, however, was stopped 2 h after ingestion of the drug, when FEV, values were still increasing, and the authors suggested that perhaps a greater degree of bronchodilatation would have been seen had the patient been kept under observation for a longer period. This was, indeed, the case with our patient in whom the effects of indomethacin were most pronounced 3 and 4 h after the challenge. When the patient of Kordansky and colleagues took 200 mg of phenylbutazone, his specific airway conductance showed no improvement, while FEV, decreased by about 20%. The authors suggest that this lack of bronchodilatory effect could have been due to specific disturbance in PGF 2 a/PGE 2 metabolism by phenylbutazone, as observed in certain animal tissues. In our opinion, another likely possibility is that the dose of phenylbutazone was too small to induce bronchodilatation. Phenylbutazone is not a strong inhibitor of cyclo-oxygenase (3). Furthermore, in patients with aspirin-induced asthma, who seem to constitute a negative counterpart of the two patients described by Kordansky and colleagues and by us, doses above 200 mg of phenylbutazone are usually necessary to induce positive bronchial reactions (4, 5). In summary, we believe that in these two patients metabolites of arachidonic acid cyclo-oxygenation precipitated bronchial obstruction. A . SZCZEKLIK, M.D. R. J. G R Y G L E W S K I , M . D .

E. NlZANKOWSKA, M.D. Institute of Internal Medicine and Department of Pharmacology, Copernicus Academy of Medicine; Skawiiiska 8, 31-066 Krakow, Poland REFERENCES

1. SZCZEKLIK A, GRYGLEWSKI RJ, NIZANKOWSKA E: Asthma relieved by

aspirin and by other cyclo-oxygenase inhibitors. Thorax, in press 2. KORDANSKY D, ADKINSON N F J R , N O R M A N PS, R O S E N T H A L

RR:

Asthma improved by nonsteroidal anti-inflammatory drugs. Ann Intern Med 88:508-511, 1978 3. GRYGLEWSKI RJ: Screening for inhibitors of prostaglandin and thromboxane biosynthesis, in Prostaglandins and Thromboxanes, edited by BERTI F, SAMUELSSON B, VELO GP. New York and London, Plenum Press, 1977, pp. 85-109

1. LAGAKOS SW: Prognostic factors for survival time in inoperable lung Cancer, in Lung Cancer, edited by STRAUSS MJ. New York, Grune and Stratton, 1977, pp. 271-280

4. SZCZEKLIK A, G R Y G L E W S K I RJ, C Z E R N I A W S K A - M Y S I K G: Relationship

2. H A N S E N HH, DOMBERNOWSKY P, HIRSCH F: Staging procedures and

5. SZCZEKLIK A, G R Y G L E W S K I RJ, C Z E R N I A W S K A - M Y S I K G: Clinical pat-

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of inhibition of prostaglandin biosynthesis by analgesics to asthma attacks to aspirin sensitive asthma. Br Med J 1:67-69, 1975



terns of hypersensitivity to nonsteroidal anti-inflammatory their pathogenesis. J Allergy Clin Immunol 60:276, 1977

drugs and

Mitomycin and Interstitial Pneumonitis T o THE EDITOR: Orwoll and others (1) have reported in the September issue on the association of mitomycin with interstitial pneumonia. In the past 2 years we have seen two patients who died with unexplained severe interstitial pneumonitis after receiving mitomycin chemotherapy. The first case was that of a 53-year-old man with adenocarcinoma of the pancreas who received weekly mitomycin, 5-fluorouracil, and cytosine arabinoside during an 18-week period for a total mitomycin dose of 50 mg. He developed progressive dyspnea leading to death within 3 weeks after a short preterminal period of progressive dyspnea. At autopsy, alveolar septal thickening and fibrosis were found as well as large numbers of pigmented macrophages. The second case was that of a 52-year-old man with carcinoma of the colon who received mitomycin and 5-fluorouracil during a 15-week period for a total mitomycin dose of 87.5 mg. Because of his progressive dyspnea and a diffuse interstitial infiltrate on chest roentgenogram, an open lung biopsy was done a week before his death. The biopsy showed thickening of the alveolar capillary walls with collagen, hyperplasia of alveolar lining cells, iron laden macrophages, and minimal inflammatory cells.

There was no evidence of bacterial, viral, fungal, protozoan, or neoplastic disease in the lungs of our patients. They had not had apparent exposure to toxins, although the second patient did smoke cigars. Neither of our patients had any associated chemotherapy toxicity, hematologic or otherwise. Renal and hepatic functions were grossly normal. Steroids were not given in the first case and not given for a sufficient period of time in the second case to assess response. We support, therefore, the conclusion of Orwoll and his associates that interstitial pneumonia is a potential complication of mitomycin chemotherapy. The toxicity does not appear to be dose related. The interstitial pneumonia can be a fulminant one and lead to death by pulmonary insufficiency. Finally, to the list of chemotherapeutic drugs now known to cause pulmonary toxicity, namely methotrexate, bleomycin, busulfan, cyclophosphamide and mitomycin, the authors neglected to add chlorambucil (2), which was recently reported to cause a very similar picture. A. T H O M A S A N D R E W S , M . D . H E R B E R T S. B O W M A N , M . D . S H A S H I K A N T B. P A T E L , M . D . W I L L I A M M. A N D E R S O N , M . D .

Department of Medicine, Harrisburg Hospital; South Front Street; Harrisburg, PA 17101 REFERENCES 1. O R W O L L ES, KIESSLING PJ, PATTERSON JR: Interstitial

pneumonia

from mitomycin. Ann Intern Med 89:352-355, 1978 2. C O L E SR, M Y E R S TJ, KLATUSKY AU: Pulmonary disease with chloram-

bucil therapy. Cancer 41:455-459, 1978

As an example, the August 1978 issue of Infectious Diseases (7) simplifies these articles under the caption "SLE patients are safely vaccinated against flu," and the editor's introduction claims that the studies "clearly establish the safety of killed influenza vaccine for SLE patients, whether they are in remission or even have moderate disease." This impression should be qualified as unsubstantiated by the data and possibly dangerous. Our 1948 paper—the condensed data of which are more accessible in many libraries in a letter to Annals of Internal Medicine in 1975 (8)—referred not to a single vaccination but to repeated immunization injections with early minor reactions followed by recurring reactions of mounting severity and, in each of three instances, terminating in autopsy-proven lupus erythematosus. Initially appearing as unalarming forms of serum sickness, symptoms merged without break to disease and death, including a Dick-toxin exanthem that gradually transformed into the violaceous eruption of lupus erythematosus over the deltoid site of the original injections. In the June issue reports, all authors separately dismiss as inconsequential early fevers, arthralgias, myalgias, and other brief reactions. Referring to the role (etiologic or adjuvant) of viruses in lupus erythematosus, Williams neglects reference to ZiflTs comments on viruslike inclusions in human kidneys and the evidence for the persisting presence of virus as opposed to clinically apparent chronic infection (9). Of Brodman's group of 46 patients with lupus erythematosus vaccinated, 23 were receiving corticosteroids; because his "control" group was not on such medication, the "equal" number of reactions in the two groups is either meaningless or favors a higher (hidden?) incidence among patients with lupus erythematosus. Of the four study groups, only Brodman's received second vaccine injections, and these were followed by a slightly higher incidence (over control) of both nonspecific constitutional symptoms and specific symptoms related to lupus erythematosus. Although Brodman makes no reference to this in his discussion, the editorial highlights this occurrence and its implications. Ristow (29 patients with lupus erythematosus) and Louie (11 patients with lupus erythematosus) each report and consider unimportant one nephritis episode after vaccination; combined, this indicates nephritis in two out of 40, which seems high. (Again, the editorial emphasizes this). Model immunization situations with a clustering of multiple injections might more meaningfully be found among persons involved with school programs, foreign travel, employment under special circumstances, changing seasonal infections, and allergy skin-testing and desensitization. With regard to the latter category Dr. Naomi Rothfield has seen development and activity of lupus erythematosus in this setting among her large and ongoing studies (personal communication). The concentration of four unrelated reports and an editorial in a single issue of Annals of Internal Medicine has been used by some as constituting a definitive symposium, while the collective data suggest a perspective not found in the individual conclusions. Perhaps an effort should be made to correct this impression to warn against unestablished conclusions. L. F R E D A Y V A Z I A N , M . D .

Influenza Immunization and Lupus Erythematosus T o THE EDITOR: In four papers in the June 1978 issue, Drs. Williams, Brodman, Ristow, and Louie (all with coauthors) (14) report data and separately endorse the safety of influenza vaccination for persons with systemic lupus erythematosus, a view balanced with cautionary comments in a summarizing editorial by Drs. Hess and Hahn (5). Reference is made to Ayvazian's and Badger's report of lupus erythematosus among vaccinated student nurses (6), but the immunization patterns that we described were not at all duplicated by these new studies. These papers in the June issue are being quoted at conferences and cited by science writers as having definitively certified the safety of vaccinating patients with lupus erythematosus, a statement Annals of Internal Medicine did not flatly endorse.

College of Medicine and Dentistry of New Jersey; Piscataway, New Jersey 08854 REFERENCES 1. W I L L I A M S

GW,

STEINBERG A D ,

REINERTSEN

JL,

KLASSEN

2. BRODMAN R, G I L F I L L A N R, G L A S S D, SCHUR PH: Influenza vaccine

response in systemic lupus erythematosus. Ann Intern Med 88:735-740, 1978 3. R I S T O W SC, D O U G L A S R G J R , C O N D E M I JJ: Influenza vaccination of

patients with systemic lupus erythematosus. Ann Intern Med 88:786-789, 1978 4. L O U I E JS, N I E S KM, SHOJI KT, FRABACK RC, ABRASS C, B O R D E R W,

CHERRY JD, IMAGAWA D: Clinical and antibody responses after influenza immunization in systemic lupus erythematosus. Ann Intern Med 88:790-792, 1978 5. HESS EV, H A H N B: Influenza immunization in lupus erythematosus: safe, Letters and Correction


LW,

DECKER JL, DOLIN R: Influenza immunization in systemic lupus erythematosus. A double-blind trial. Ann Intern Med 88:729-734, 1978

127

effective? (editorial). Ann Intern Med 88:833-834, 1978 6. AYVAZIAN LF, BADGER TL: Disseminated lupus erythematosis occurring among student nurses. N Engl J Med 239:1-18, 1948 7. SLE patients are safely vaccinated against Flu in two test studies. Infect Dis 8:18, 1978 8. AYVAZIAN LF: Risks of repeated immunization (letter). Ann Intern Med 82:589, 1975 9. Z I F F M: Viruses and the connective tissue diseases. Ann Intern Med 75:951-958, 1971

In comment: We agree with Dr. Ayvazian's cautionary comments on the too freely interpreted extrapolations from the four scientific articles and editorial in the June 1978 issue of Annals of Internal Medicine. The authors of all four papers and we in our editorial clearly stated that the safety of the immunizations were specific to the New Jersey and the Victoria whole influenza virus vaccines, the stated schedules for same, the populations studied, and the duration of follow-up. These set the allowable limits for extrapolation and speculation. As Dr. Ayvazian notes, his observations in 1948 referred to repeated immunization with many different vaccines. The illnesses of the three of 750 young student nurses were certainly bizarre and occurred in the days of relatively unsophisticated knowledge of systemic lupus erythematosus between 1932 and 1946. There remains the question of a balance between the morbidity and mortality of severe infections in patients with lupus erythematosus and the risk of disease relapse. For this and other reasons, we suggest that the role of immunization in immunologic disorders is worth continued clinical and basic investigation. E V E L Y N V. H E S S , M . D .

Immunology Division, Department of Medicine, University of Cincinnati Medical Center; Cincinnati, Ohio 45267 BEVRA H A H N , M.D.

Rheumatology Division, Department of Medicine, Washington University School of Medicine; St. Louis, MO 63110

several investigators. Furthermore there are a number of reasons for suspecting that even the nuclease-treated KB still contained ssDNA. Briefly, these include: lack of a significant decrease in positive sera after such treatment; the presence of several sera that bound this antigen far out of proportion to the results of the CL-IF assay; and finally the experience of a number of investigators including ourselves that extraordinary precautions with handling and storage (which, not being described, are presumed not to have been adhered to) are necessary to prevent reappearance of s s D N A in such nuclease-treated preparations. Hence, as a test for anti-dsDNA, the CL-IF is compared with assays that appear not to have been optimally performed so that the reported conclusions regarding its relative merits in this regard must in my view remain tentative. (The reported use of CL-IF for detecting complement-fixing antibodies, specifically, is of course not affected by this objection and clearly represents an advantage over alternate assays.) It is evident that to show rigorously even operational freedom from contamination with immunologically significant amounts of non-dsDNA antigen is a formidable task when dealing with D N A from a natural source such as KB cells. The proposals to use the crithidial kinetoplast or dAT as convenient and reliable sources of d s D N A antigens were attempts to solve this problem and to provide clinically applicable information. Whether either or both approaches are successful seems still to require additional data. C H A R L E S R. S T E I N M A N , M . D .

Mount Sinai School of Medicine of The City University of New York; New York, N Y 10029 REFERENCES 1. CHUBICK A, SONTHEIMER R D , G I L L I A M JN, Z I F F M: An appraisal of

tests for native D N A antibodies in connective tissue diseases. Clinical usefulness of Crithidia luciliae assay. Ann Intern Med 89:186-192, 1978 2. STEINMAN CR, DEESOMCHOK U, SPIERA H: Detection of anti-DNA

antibody using synthetic antigens. Characterization and clinical significance of binding of poly (deoxyadenylate-deoxythymidylate) by serum. / Clin Invest 57:1330-1341, 1976 3. A A R D E N LA, L A K M A K E R F, F E L T K A M P TEW: Immunology of D N A II.

The effect of size and structure of the antigen on the Farr assay. / nol Methods 10:39-48, 1976.

Assay for Antibodies to Double-Stranded DNA T o THE EDITOR: I read with interest the report of Chubick and associates (1) comparing the crithidial immunofluorescence (CL-IF) method for detecting antibodies to double-stranded D N A (dsDNA) with selected alternate assays. As is increasingly recognized, at least two sorts of information about the D N A antigen used in such assays are necessary for adequate evaluation of data and for duplication of results. First is careful definition of the antigenic sites present (particularly with regard to possible contamination, chiefly with single-stranded D N A [ssDNA] and perhaps nucleoprotein) as well as of the D N A size. Although the authors say they recognize the importance of these variables, information regarding them is lacking for the three noncrithidial antigens used for comparison with the CLIF assay, making it difficult to adequately interpret the reported findings. Our experience using the Farr assay (2), as well as that of others (3), clearly indicates that size of the radiolabeled D N A is a critical variable, particularly when using the synthetic copolymer, dAT, and can, if not controlled, result in false-positive results such as those reported in this study, particularly if, as we have found with some preparations, the dAT is supplied in a highly aggregated state. When size is adequately controlled as has been described (2), the dAT/Farr binding assay has, in our hands, resulted in fewer than 1% false-positive results with an experience of more than 3000 assays, many done on sera from patients without lupus erythematosus but with positive tests for antinuclear antibody. As for the remaining two antigens with which CL-IF was compared, the first apparently being untreated, routinely prepared KB D N A , was almost certainly contaminated with immunologically significant amounts of s s D N A as reported by 128

In comment: We are in agreement with much of what Dr. Steinman has written regarding the measurement of n D N A antibodies and will restrict our reply to the technical points raised. In both the filter and Farr assays, using untreated human tumor cell (KB) D N A , prefiltration by Millipore filter (Millipore Corporation, Bedford, Massachusetts) was used to remove macroaggregates. In the filter assay using polydeoxyadenylatedeoxythymidylate (poly dAT), sonication was done 2 weeks before use and the solution stored as previously described by Steinman, Deesomchok, and Spiera (1). All sera were run simultaneously for each D N A preparation used. Although slightly higher binding was found in normals in our study (mean + 2 SD, 10%; range, 0.6 to 18) than by Steinman and associates, the poly dAT results in our study correlated significantly with those obtained using endonuclease-treated K B D N A (r = 0.91). It may be that additional sonication of the poly dAT would have decreased false-positive results and increased true positives; however, in a clinical setting sonication of different dAT batches to a standard size would be technically impractical. Longitudinal determination of anti-DNA, using this approach, would require sonication before each run and measurement of anti-DNA in a series of controls each time. If a given sonication did not meet specifications, the process would have to be repeated. This would be difficult in a hospital laboratory. As Dr. Steinman has shown, poly dAT does eliminate the problems caused by single-stranded D N A (1). However, as with other D N A preparations, poly dAT is also plagued by the problem of variability in molecular size. In the filter assay using endonuclease-treated D N A , the method of Steinman and associates (1) was carefully followed using the same D N A and endonuclease sources. After endonu-



Immu-

clease digestion and separation of D N A on Sephadex G50 (Pharmacia Fine Chemicals, Piscataway, New Jersey), the eluate contained two peaks, an excluded peak presumably containing double-stranded D N A , and a second peak, presumably small oligonucleotides, indicating an endonuclease effect. The "extraordinary precautions in handling and storage" alluded to by Dr. Steinman were not adhered to because this preparation was used immediately after separation and not stored. That the preparation was significantly different from untreated KB D N A is indicated by the difference in mean binding values in normal controls. Untreated KB D N A produced a mean binding in normals of 15.7% (range, 0 to 70; upper limit of normal, 33.9); endonuclease-treated D N A values were mean binding, 0.2% (range, 0 to 1.6; upper limit of normal, 0.5). It is obvious that endonuclease treatment of this D N A significantly reduced binding by normal sera. Dr. Steinman suggests that contamination with single-stranded D N A can be inferred from the fact that several sera bound endonuclease-treated KB D N A out of proportion to the results of the CL-IF assay. We refer Dr. Steinman to the paper by Aarden and colleagues (2) showing wide variability in D N A binding using different sources of D N A . This variability may be due to differences in molecular size or configuration of human and Crithidia D N A (3), or may be secondary to variations in antibody avidity. In conclusion, we believe that our assessment of the CL-IF test is valid. Its freedom from the major problem of other assays, D N A variability as well as its low cost, renders it very useful for routine clinical laboratory use. Our results with both the CL-IF assay and the endonuclease-treated D N A assays confirm the association of n D N A antibodies with nephritis in lupus erythematosus. We would welcome a multicenter approach to the analysis of various anti-nDNA tests. A N D R E W CHUBICK, M . D . R I C H A R D D. SONTHEIMER, M . D . J A M E S N. G I L L I A M , M . D . M O R R I S ZIFF, M . D .

The University of Texas Health Science Center at Dallas; Department of Internal Medicine, Rheumatic Diseases Unit, Dallas, TX 75235

REFERENCES 1. STEINMAN CR, DEESOMCHOK U, SPIERA H: Detection of anti-DNA

antibody using synthetic antigens. Characterization and clinical significance of binding of poly (deoxyadenylate-deoxythymidylate) by serum. / Clin In vest 57:1330-1341, 1976 2. A A R D E N LA, L A K M A K E R F, D E G R O O T ER, SUAAK AJG, F E L T K A M P

TEW: Detection of antibodies to D N A by radioimmunoassay and immunofluorescence. Scand J Rheumatol 1 l(Suppl):12-19, 1975 3. L A U R E N M, V A N ASSEL S, S T E I N E R T M: Kinetoplast D N A . A unique

macromolecular structure of considerable size and mechanical resistance. Biochem Biophys Res Comm 43:278-284, 1971

cells of the macrophage series, though some workers restrict the term to lesions characterized by epitheloid cells and giant cells arranged in follicular groups, in which case the terms 'granulomatoid' and 'tuberculoid' are synonymous." The authors conclude by indicating that "granulomatous" inflammation is a term without precise meaning, and it is wise not to use it without qualification. Other authors (2) believe that "granulomatous inflammation is difficult to define precisely, and is used as a wastebasket for patently dissimilar reaction patterns." However, none of these authors mention vascular involvement as being a necessary component of a "granuloma," which thus by definition is not an angiitis. This is not to say that a vasculitis may not have a granulelike appearance macroscopically, nor be associated with an inflammatory response of the macrophage series. How, then, has the term granulomatosis, which implies a multiple state of granulomas, come to be associated with the description of a number of conditions primarily associated with a vasculitis, such as Wegener's, allergic, midline, lymphatoid, and necrotising "sarcoid" (3)? Indeed, one might question the term lymphomatoid also. Taken literally, this means a "form of lymphoma," but is this the intention? The adjectival form "lymphomatous" would be equally incorrect, and in any event, as has been pointed out (4), "lymphomatoid granulomatosis" may be an extension of benign lymphocytic angiitis. We do not yet know the precise cause of any of the conditions included in the broad generalization of "granulomatoses," and it does not help us to cloud our ignorance with words of expanded vagueness. It would be safer and simpler to restrict the term granuloma, and thus granulomatous and granulomatosis, to conditions typified by the classic reaction of granulomas as defined above, and describe those other conditions of a sometimes granular appearance as forms of angiitis or vasculitis, without introducing the tongue twisting plurals angiitides and vasculitides. Thus sarcoidosis, tuberculosis, berylliosis, and farmer's lung are granulomas, whereas Wegener's, allergic granulomatosis, lymphomatoid granulomatosis, and others are subgroups of necrotising angiitis involving varying sizes of vessels, inciting some degree of macrophage (or granulomatous) tissue response. The group of disorders entitled "necrotising angiitis" would then include the subgroups [I] Wegener's and limited angiitis of Wegener's type; [II] lymphomatoid or, better, "lymphoma like"; and [III] necrotising "sarcoid." These usually involve small blood vessels (3), while [IV] polyarteritis nodosa; [V] giant cell arteritis; and [VI] nodular (Weber-Christian) usually involve medium and large blood vessels. Bronchocentric granulomatosis is probably neither a true granuloma nor a vasculitis (5). Such a reconsideration of terminology might help to clarify an area of present confusion to clinicians, and possibly pathologists, without prejudice to the possibility of etiologic and immunologic homogeneity between certain granulomas and the conditions associated primarily with a vasculitis. Indeed, as a terminologic concession, the second group could be styled "granulomatous vasculitis," as envisioned in the editorial.

Terminology for Granulomatous Disorders T o THE EDITOR: The editorial by Dr. Fauci in the December 1977 issue, "Granulomatous Vasculitides: Distinct but Related" (Ann Intern Med 87:782-783, 1977), reflects on an issue other than that addressed at the time, and this is the question of terminology. Granulomatous vasculitis may be a sound description for a group of disorders variously encumbered by such terms as "granulomatosis," "lymphatoid," and necrotising "sarcoid" angiitis. It may be time for some clarification in this area of confusing terminology to avoid further proliferation of vague and portmanteau terms. A library search of a number of standard pathology books revealed a fairly uniform absence of a definition of the commonly used term "granuloma." However, one recent book does give a satisfactory definition (1): "A granuloma is defined as a chronic inflammatory reaction containing a predominance of

D A V I D NICHOLSON, M.D.

Veterans Administration Medical Center; Little Rock, A R 72114 REFERENCES

1. W A L T E R JB, ISRAEL MS: General Pathology, 4th ed. New York, Longman, Inc., 1974, p. 126 2. EPSTEIN WL, SKAHEN JR, K R A S N O B R O D H: The organized epitheloid

cell granuloma: differentiation of allergic (zirconium) from colloidal (silica) types. Am J Pathol 43:391-397, 1963 3. LIEBOW AA: Pulmonary angiitis and granulomatosis. Am Rev Respir Dis 108:1-18, 1973 4. ISRAEL HL, PATCHEFSKY AS, SALDANA MJ: Wegener's granulomatosis,

lymphomatoid granulomatosis, and benign lymphocyte angiitis and granulomatosis of lung. Recognition and treatment. Ann Intern Med 87:691699, 1977 5. K A T Z E N S T E I N AL, L I E B O W AA, F R I E D M A N PJ: Bronchocentric granu-

lomatosis, mucoid impaction and hypersensitivity reaction to fungi. Am Rev Respir Dis 111:497-537, 1975 Letters and Correction


129

Antifungal Agents T o THE EDITOR: We read with interest the report by Edwards and colleagues {Ann Intern Med 89:91-106, 1978) on severe candidal infections and new concepts in therapy. We agree with the authors that the suitable antifungal agents for disseminated candidiasis are very few. Moreover, the usefulness of the most reliable agent, amphotericin B sodium deoxycholate complex, is severely limited because of its well-known toxicity. The future of new antifungal drugs does not seem particularly promising, with the probable exception of the amphotericin B water-soluble derivative methyl ester hydrochloride, still under investigation (1). Thus it may be of some interest to point out the importance of a water-soluble derivative of nystatin synthesized by Rapi, Cocchi, and Belgodere (2). The main characteristics that limit the potential usefulness in systemic candidal infections of polyene macrolide antibiotics nystatin and amphotericin B are their low water-solubility and consequent inability to attain effective blood levels when given orally, plus the unsuitability of the parenteral route of administration. Among the different water-soluble derivatives obtained in our laboratory, the nystatin monohydrochloride seems to be the most promising as an antifungal agent. This derivative possesses a high in-vitro antimycotic activity quite superior to the parent nystatin base, while the difference in the spectrum of antifungal activity is poor (3). Preliminary tests have shown that the acute toxicity of nystatin hydrochloride is considerably low, even when parenterally administered, and that nystatin hydrochloride possesses remarkable therapeutic efficacy against experimental Candida albicans systemic infection in animals, even when administered orally (Goss WA, JAMBOR WP, WHITTEAKER HE: Personal communication). Nystatin hydrochloride has been subjected to preliminary clinical trials in 10 cases of candidal systemic infections in infants and children (4). These infections included bronchopulmonary types, arising during the course of intensive and prolonged wide spectrum antibiotic therapy and associated with other localized candidal infections. The patients responded favorably to oral treatment with nystatin hydrochloride in doses of 5 to 30 mg per day. Administration of the drug did not result in any inconvenience, either local or general. In four adults affected by deep fungus infections, nystatin hydrochloride administered orally or by aerosol has likewise given good results. An appreciable loss of the biologic activity of nystatin hydrochloride was shown after 2 to 3 weeks' storage at room temperature, but nystatin hydrochloride is sufficiently stable at 0 to 3°C, as dried powder in the dark. Despite this limitation, the experiments on laboratory animals and the preliminary clinical results obtained with this derivative may be important because of the still-present difficulties in obtaining clinically active antimycotic agents. GlANFRANCO RAPI, PH.D. Istituto di Chimica Organica; Firenze, Italy PIETRO COCCHI, M.D.

Universita di Firenze; Firenze, Italy REFERENCES

1. YOUNG LS: New concepts in therapy for disseminated candidiasis, pp. 101-103 in E D W A R D S JE J R (moderator): Severe candidal infections. Clinical perspective, immune defense mechanisms, and current concepts of therapy. Ann Intern Med 89:91-106, 1978 2. R A P I G, COCCHI P, B E L G O D E R E E: Biologically active, water-soluble

derivatives of nystatin—chemical studies. Chemotherapia (Basel) 6:326343, 1963 3. COCCHI P, RAPI G: Biologically active, water-soluble derivatives of nystatin—microbiological studies. Chemotherapia (Basel) 6:319-325, 1963 4. COCCHI P, BARTOLOZZI G: Water-soluble derivative of nystatin. Preliminary clinical experiences. Chemotherapia (Basel) 8:175-187, 1964

Palpable Spleens: Ten-Year Follow-Up T o THE EDITOR: In 1967 we reported that 63 of 2200 (2.9%) freshmen at Dartmouth College had a palpable spleen at the 130

time of routine physical examination (1). Fifty-eight of the students were found to have normal hematocrits, reticulocyte counts, blood smears, and heterophil titers. These students gave no history of disease and were asymptomatic. Four had infectious mononucleosis at the time of examination and one had a history of malaria. In the 58 without associated disease, there was no obvious difference in the prior frequency of infection or other illnesses compared to their classmates without palpable spleens. There was no difference in the body habitus and the ability to relax between those in whom a palpable spleen was found and their classmates. At that time, we concluded that there was no disease process as a cause of a palpable spleen in young, asymptomatic, male college freshmen. Since that report, we have received frequent inquiries about the health of the students with palpable spleens. These have often come from physicians confronted with a young man in good health who has a palpable spleen on routine examination. Ten years later we conducted a mail survey of the group with palpable spleens and a control group to detect possible differences in the health of the two groups (see Table 1). The control group was selected by picking from alphabetized lists members of each of the three classes represented who were within two names above and two names below each member of the study group. One hundred seventy-eight control subjects were thus selected. The control and study groups were then mailed the following questionnaire. 1. Have you been hospitalized since graduation from Dartmouth? Yes No If yes, give dates and discharge diagnosis. 2. Have you had any illnesses that confined you to bed for longer than 1 week since graduating from Dartmouth? Yes No If yes, give date of confinement and diagnosis given to you by your physician. 3. Have you had occasion to seek medical attention for any but routine annual physical examinations since graduation from Dartmouth? Yes No If yes, what was the reason? The results indicate that there was a higher (P < 0.05) frequency of infection and physician office visits in the group with palpable spleens than in the control group. The pattern of infection with respect to likely cause and site of infection is quite similar for the two groups. It is, of course, possible that the difference in reported infecTable 1. Results of Mail Survey of thei Group with Pa Ipable S pleens and the Control Group Fresl lmen wi th Palp able Spl een

Studied Responded to questionnaire Hospitalized M.D. office visit (not including hospitalization) * Infection other than "flu or cold" * "Cold orflu"only Infection plus "cold or flu"* Allergy Trauma Cardiovascular disease Renal stone Skin cancer Death Hemorroidectomy Psoriasis Gout Diabetes



Con trol Subjects

no.

%

no.

63 52 15

100 83 29

178 150 45

100 84 30

19 16 6 22 1 7 2 1 0 0 3 1 0 2

36 31 12 43 2 13 4 2 0 0 6 2 1 4

31 21 15 36 9 27 4 2 1 0 2 2 1 1

21 14 10 24 6 18 3

* P < 0.05; chi = square analysis with 1fates' cor rection.

0

tions represents a spurious finding. The fact that the study group was aware they had palpable spleens and knew of our interest in following their history may have led them to report infections that the control group had forgotten. On the other hand, the size of the spleen is in large measure determined by the load placed on the reticuloendothelial system (2). The reporting of an increased frequency of infection is the first suggestion of a plausible cause for the presence of a palpable spleen in this group of patients. It is reassuring to find no evidence of lymphoreticular malignancy in the group with palpable spleens and that their health, apart from the possible increase in infections, is no different from that of the control subjects 10 years later. F R A N K L I N G. E B A U G H , JR., M . D .

Stanford University Medical Center; Stanford, CA 94305 O. R o s s M C I N T Y R E , M . D . Dartmouth-Hitchcock Medical Center; Hanover, N H 03755

and in fact were negative in Dr. Miller's paper. Allergic reactions confined to one organ are rare. Allergies are usually permanent, yet halothane "allergy" lasts only 1 to 3 months. Further, repeated challenges with halothane do not always precipitate an attack. Children, the most allergy-prone group, rarely, if ever, get halothane hepatitis (3, 5). A single case of Klatskin and Kimberg (their Reference 2) is used to support halothane sensitivity. However, this same patient who had a positive halothane challenge also had several negative challenges. Further, he had two relapses without a halothane challenge. Halothane hepatotoxicity is now thought to be secondary to an abnormal metabolic pathway that produces an hepatotoxin. This pathway is enhanced by reductive enzymatic conditions and enzyme induction (4, 5). M I C H A E L C. B R A U N S T E I N , M . D .

C C A . A . , Inc.; Las Vegas, NV 89109

REFERENCES

REFERENCES

1. MCINTYRE OR, EBAUGH FG JR: Palpable spleens in college freshmen. Ann Intern Med 66:301-306, 1967

1. DYKES MHM: Unexplained postoperative fever. Its value as a sign of halothane sensitization. JAMA 216:641-644, 1971

2. JACOB HS, MACDONALD RA, JANDL JH: Regulation of spleen growth

2. DYKES MHM, GILBERT JP, SCHUR PH, COHEN EN: Halothane and the

and sequestering function. J Clin Invest 42:1476, 1963

Mast Cell Counts T o T H E EDITOR: I have read with interest the paper by Yoo, Lessin, and Jensen (Ann Intern Med 88:753-757, 1978) that reports an attempt to quantitate the degree of bone marrow mast cell proliferation in various hematologic disorders. This was accomplished by a semiquantitative counting technique using a calibrated optical micrometre to examine bone marrow aspiration smears. Although this method appears to be reproducible for bone marrow aspiration smears, I question its validity for quantitation of bone marrow mast cell proliferation. It has been previously reported (1) in a subjective evaluation that bone marrow clot sections are far superior to bone marrow aspiration smears in demonstrating mast cell proliferation. My impression is that even when mast cells are shown to be abundant in bone marrow clot sections and bone marrow biopsy sections, they may be absent or scanty in bone marrow smears. It would be significant to know whether Dr. Yoo and his group evaluated the possibility of mast cell variation being a function of the type of bone marrow specimen examined (that is, aspiration smear versus clot section versus bone marrow biopsy). If this possibility is true, their method for quantitation of mast cell proliferation in bone marrow would be invalid, and their conclusion on the relation of mast cell proliferation to lymphoproliferative disease would be in question. R I C H A R D G. P A T T O N , M . D .

Northwest Hospital; Seattle, W A 98133

REFERENCE

1. JOHNSTONE JM: The appearance and significance of tissue mast cells in human bone marrow. / Clin Pathol 7:275-279, 1954

Halothane Hepatotoxicity T o T H E EDITOR: Miller, Dwyer, and Klatskin state in their paper "Halothane Hepatitis: Benign Resolution of a Severe Lesion" (Ann Intern Med 89:212-215, 1978) that halothane hepatitis is a sensitization reaction. There is no evidence for this mechanism at the cellular level and little evidence at the clinical level. At the cellular level, the antigen has not been found. At the clinical level, there is also little support. Fever is no more common after halothane than after other anesthetics (1). The causes of eosinophilia are legion and include viral hepatitis (2, 3). Tests for antimitochondrial antibodies are conflicting (4)

liver: a review of the epidemiologic, immunologic and metabolic aspects of the relationship. Can J Surg 15:217-238, 1972 3. DAL SANTO G (ed.): Biotransformation of general anesthetics. Int AnesthesiolClin 12(2): 1-182, 1974 4. VAN DYKE RA: Current concepts of halothane metabolism. Audio Digest 19(9), 1977 5. BROWN BR: Current concepts of halogen hepatotoxicity. Audio Digest 18(5), 1976 In comment: The severe hepatitis associated with halothane does not meet the criteria for a true hepatotoxicity reaction: the lesion is not dose related, it cannot be reproduced in laboratory animals (the histologic lesion produced in rats and other animals bears no resemblance to the lesion in humans), and occurs very rarely, irrespective of the amount given. On the other hand, the hepatitis is often associated with features of hypersensitivity and is more common in patients with atopy and a high frequency of previous drug reactions. The relation of fever to halothane exposure, eosinophilia, and history of atopy and drug reactions were used by us as supportive evidence for a hypersensitivity, rather than toxic, reaction; in terms of clinical evidence, surely Dr. Braunstein would agree that these points are not characteristic of a pure toxic liver injury. While we agree that all Koch's postulates for proving cause and effect are not present and that it would be ideal to have a diagnostic test for halothane-associated hepatitis, we are not as convinced, as Dr. Braunstein appears to be, that the lesion is secondary to production of a metabolite that results in liver injury independent of any reaction on the part of the immune system. Allergy has been denned as "untoward physiologic events mediated by a variety of different immunological reactions" (1); conceivably the antigen is generated only in some persons who produce an abnormal metabolite. In this respect, the metabolism of halothane may be the crucial factor, but exclusion of any role of the immune response in the genesis of the liver injury is not justifiable in light of the clinical facts. In using the term sensitization reaction, we imply only that the immune response plays a part; we do not rule out that metabolic factors may be equally important. In response to Dr. Braunstein's specific points, [a] the fact that fever in the first postoperative week is as frequent after halothane as after other anesthetics is not relevant to the issue, since the paper referred to included all patients with fever on the second postoperative day. Fever accompanying halothane sensitization occurs, on average, a week after the first exposure; [b] eosinophilia is not commonly caused by viral hepatitis, as evidenced by this entity not being mentioned as a cause of eosinophilia in three comprehensive reference works (2-4). Indeed, in the review referred to by Dr. Braunstein, viral hepatitis did not appear amongst the 75 listed causes of eosinophilia; [c] the significance of antimitochondrial antibody was not alluded to in our discussion; [d] the patient reported by Klatskin and Letters and Correction


131

Kimberg did not undergo a negative challenge, and the relapses without a challenge occurred when he returned to work (as an anesthesiologist) and therefore could have been exposed to halothane; [e] allergic reactions confined to one organ are explicable if the antigen is localized to this organ; [f] the author's contention that "halothane 'allergy' lasts only 1 to 3 months" is not referenced and is not consistent with the reported cases; [g] children have a lower incidence of many types of drug reactions (5)—this is not confined to halothane.

patients might improve because of dialysis. To date, however, dialytic therapy has no substantiated value in any chronic disorder other than uremia. The authors thank Dr. Lazlo Biero for confirming the diagnosis of psoriasis and doing the skin biopsy. ELI A. F R I E D M A N , M . D . B A R B A R A G. D E L A N O , M . D .

Department of Medicine, Downstate Medical Center; Brooklyn, N Y 11203

D E N I S J. M I L L E R , M . D . G E R A L D KLATSKIN, M.D.

REFERENCES 1. T W A R D O W S K I ZJ, N O L P H K D , R U B I N J, A N D E R S O N PC: Peritoneal

Yale University School of Medicine; New Haven, CT 06510

2.

REFERENCES

1. FARR RS, SPECTOR SL: What is asthma, in The Asthmatic Patient in Trouble, edited by PETTY TL. Greenwich, Connecticut, C.P.C. Communications, Inc., 1975

3. 4.

2. W I L L I A M S WJ, B E U T L E R E, ERSLEY AJ, R U N D L E S RW (eds.): Hematol-

dialysis for psoriasis. An uncontrolled study. Ann Intern Med 88:349351, 1978 BUSELMEIER TJ: Dialysis and psoriasis (letter). Ann Intern Med 88:842, 1978 MUSTON HL, CONCEICAO S: Remission of psoriasis during haemodialysis. Br Med J 1:480-481, 1978 VAN SCOTT EJ, FARBER EM: Psoriasis in Dermatology in General Medicine. New York, McGraw Hill Book Company, 1971, p. 230 P E R E Z GO, OSTER JR: A critical review of the role of dialysis in the treatment of liver disease, in The Kidney In Liver Disease, edited by Epstein M. New York, Elsevier North-Holland, Inc., 1978, pp. 325-336

ogy. New York, McGraw-Hill, 1972, p. 657 3. W I N T R O B E MM: Clinical Hematology, 7th ed. Philadelphia, Lea & Febiger, 1974, p. 1285

5.

4. M I D D L E T O N E J R , R E E D CE, E L L I S E F (eds.): Allergy: Principles

and

6. P O R T FK, K R O L L P D , S W A R T Z R D : The effect of hemodialysis on schiz-

5. B I E R M A N CW, V A N A R S D E L PP J R : Penicillin allergy in children: the

ophrenia: a survey of patients with renal failure. Am J Psychiat 135:743744, 1978

Practice, vol. 2. St. Louis, C. V. Mosby, 1978, p. 604 role of immunological tests in its diagnosis. J Allergy 43:267-272, 1969

Hyponatremia in Legionnaires' Disease Psoriasis Developing De Novo During Hemodialysis T o THE EDITOR: Uncontrolled trials of dialytic therapy in psoriasis (1-3) have recently indicated remarkable improvement in skin lesions and well being. The rationale for beneficial peritoneal or hemodialysis in psoriasis is the extraction of "noxious exogenous or endogenous substance(s)" or, alternatively, "absorption of some beneficial substance from dialysis solution" (1). Because psoriasis is a disease that "in some patients may undergo spontaneous improvement . . ." (4) the effect, if any, of dialysis may be difficult to interpret. We report the case of a patient who, while undergoing effective and adequate maintenance hemodialysis, developed typical psoriasis. A 58-year-old married white woman, mother of three living children, began regular hemodialysis treatments 7 years ago because of uremia due to polycystic kidney disease. With the exception of a serious air embolism suffered during the initiation of dialytic therapy, the patient has successfully done self-dialysis at home throughout her course. Four years ago a pathologic left hip fracture developed, and the patient underwent total parathyroidectomy for extensive skeletal demineralization in the presence of a normal serum calcium concentration. No hospitalization for any cause has been required for the past 4 years. Residual renal function is negligible. Urinary output is less than 50 ml/24 h. Dialyses are performed thrice weekly for 5 h each treatment using a Travenol 100L recirculating tank (Travenol Laboratories, Artificial Organs, Deerfield, Illinois) and an EX23 coil. Vascular access is effected by double venipuncture of the left arm, which has an internal arteriovenous fistula. The patient has been well, travels to Florida each winter, and assumes responsibility for supervision of her household. Typical predialysis laboratory values indicating satisfactory dialysis include hematocrit volume, 30%; serum creatinine, 10.8 mg/dl; total bicarbonate, 16 mmol/litre; serum calcium, 9.9 mg/dl; and serum phosphorous, 3.5 mg/dl. Neither clinical nor laboratory evidence of peripheral neuropathy has been noted; nerve conduction velocity in the left posterior tibial nerve was 47 m / sec and in the right median nerve was 50 m/sec. About 2 years ago the patient complained of a scaly, pruritic rash on her scalp, chest, and arms. Cutaneous lesions are typical of psoriasis. A skin biopsy of a representative back lesion was interpreted by Dr. A.B. Ackerman as showing confluent parakeratosis, diminution of the granular zone, psoriasiform epidermal hyperplasia, and dilated blood vessels diagnostic of psoriasis. For the next 2 years through the present typical psoriasis has persisted unaffected by hemodialysis although transient improvement occurs in Florida.

Failure to confirm early enthusiastic reports of the value of dialytic therapy in liver coma (5) and schizophrenia (6) underscores the need for carefully selected control patients in evaluating therapy that may have a significant placebo effect. That psoriasis may arise for the first time in a well-dialyzed patient, as in our report, does not exclude the possibility that other 132

T o THE EDITOR: The article of Dr. Kirby and associates (1) on legionnaires' disease mentions hyponatremia as a common laboratory finding in their 24 patients with Legionnaires' disease. They attribute this to possible inappropriate secretion of antidiuretic hormone secondary to bacterial pneumonia. Fourteen of their 24 patients had serum sodium levels of less than 130 m e q / litre. I believe this may be otherwise explained, with the information given for 13 of the 14 patients. Six patients had evidence of renal impairment; five had cardiopulmonary disease, implying possible abnormal volume status, or the use of diuretics as part of their therapy; two died. Hyponatremia in a premorbid state may result from hypotension, oliguria, and hypotonic fluid replacement. The time of measurement of sodium level was not stated. In addition, many patients had diarrhea, which can result in volume depletion. Several patients were on steroids, with no assessment made as to possible Cortisol insufficiency as a cause of hyponatremia (2). The diagnosis of inappropriate antidiuretic hormone secretion can be made only in the patient with a normal volume status who has no evidence of renal, adrenal, thyroid, or hypopituitary insufficiency; is not on diuretics; and cannot maximally dilute his urine in face of a low serum osmolarity (3). Thus, with the information in this article, I believe we can ascribe the hyponatremia to other causes and need not implicate inappropriate antidiuretic hormone secretion. VICTOR RICHARDS, M.D.

Renal Electrolyte Section, Hospital of the University of Pennsylvania, Philadelphia, PA 19104 REFERENCES 1. K I R B Y BD, SNYDER KM, M E Y E R R D , F I N E G O L D SM: Legionnaires'

disease: clinical features of 24 cases. Ann Intern Med 89:297-309, 1978 2. A G U S Z, GOLDBERG M: Role of antidiuretic hormone in the abnormal water diuresis of anterior hypopituitarism in man. / Clin Invest 50:14781489, 1971 3. H A Y S RM, L E V I N E SD: Pathophysiology of water metabolism, in The

Kidney, edited by BRENNER B, RECTOR S. Philadelphia, W. B. Saunders Company, 1976, pp. 594-595

In comment: The letter of Dr. Richards correctly states the rigid requirements that must be met in order to establish the diagnosis of the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. As we stated in our article (1), this



diagnosis was sought in only two patients during acute illness. In both of these patients, data suggested SIADH secretion as the cause of hyponatremia. Some patients had underlying diseases that could be associated with hyponatremia. However, in all instances the patients who had hyponatremia during acute illness (Legionnaires' disease) had had normal premorbid serum sodium levels. Furthermore, all survivors had normal serum sodium levels during convalescence. Insufficient data are available to state whether or not any other patients had SIADH secretion, and the mechanism of hyponatremia in these patients remains speculative. We are unaware of hyponatremia in association with chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, or atherosclerotic heart disease in the absence of congestive heart failure. N o patient had evidence of adrenal insufficiency. The association of SIADH and Legionnaires' disease has been noted by other investigators (2). The exact incidence of this association has yet to be defined. BARBARA D. KIRBY, K I M M. S N Y D E R , RICHARD D. MEYER, S Y D N E Y M. F I N E G O L D ,

M.D. M.D. M.D. M.D.

Veterans Administration Wadsworth Hospital Center; Los Angeles, CA 90073 REFERENCES 1. K I R B Y BD, SNYDER KM, M E Y E R R D , F I N E G O L D SM: Legionnaires'

disease: clinical features of 24 cases. Ann Intern Med 89:297-309, 1978 2. NUSSER RA, TARKOFF MP: Legionnaires' disease causing adult respiratory distress syndrome. West J Med 128:443-448, 1978

Saline-Resistant Hyperkalemia in Addison's Disease

T o T H E EDITOR: We have had the opportunity to see an addisonian diabetic patient with saline-resistant hyperkalemia. This presentation should suggest the possibility of hyperglycemia-induced hyperkalemia, an entity described in diabetic persons with (1) and without (2) selective aldosterone deficiency. The patient was a 28-year-old white man who had had diabetes mellitus since age 13. Past history included appendectomy in 1955, and he had craved salt since about 1976. Since March 1976, treatment at other institutions for arterial insufficiency of the lower extremities had included sympathectomy, bilateral arterial bypass operations, left above-the-knee amputation, and right below-the-knee amputation. Stump infection necessitated right above-the-knee amputation on 25 April 1977. Treatment for postoperative stupor, fever, tachycardia, and atelectasis included glucocorticoids. On 19 May the patient experienced an episode of collapse, hypotension, hyponatremia, hyperkalemia, and azotemia. Empiric resumption of glucocorticoids produced rapid resolution. From that time he was maintained on therapy for Addison's disease with hydrocortisone but without mineralocorticoid. On 11 February 1978 he was referred to us for evaluation of asymptomatic abnormalities of the coagulation profile, eventually attributed to an unidentified circulating anticoagulant. At time of physical examination the blood pressure was 160/90 mm Hg in the right arm with the patient recumbent and 140/80 mm Hg with the patient sitting. The skin was sallow with increased freckling and areolar hyperpigmentation. Of the multiple surgical scars, only the appendectomy scar was unpigmented. On admission plasma glucose was 504 mg/dl; blood urea nitrogen, 26 m g / dl; creatinine level, 1.4 mg/dl; sodium, 129 meq/litre; potassium, 7.2 meq/litre; chloride, 94 meq/litre; carbon dioxide content, 24 mmol/litre. There was 4 -|- proteinuria. Initial therapy with insulin, saline, hydrocortisone, and polystyrene sulfonate reduced the potassium to 4.5 meq/litre within 9 h. Fluctuations between normokalemia and hyperkalemia occurred thereafter. Dexamethasone was substituted for hydrocortisone. Forty units of corticotropin between 8 a.m. and 4 p.m. and an average of 2140 ml normal saline daily were infused for 6 days. On the sixth day 17-hydroxycorticosteroids were less than 1 mg/24 h, and 4 p.m. cortisol-radioimmunoassay was 4 jag/ dl. On day 5, 24-h urinary excretion of sodium and potassium were 255 and 40 meq/litre, respectively. On day 5 plasma sodium was 134 meq/litre; potassium, 6.4 meq/litre; and glucose, 321 mg/dl; and on day 6 sodium was 133 meq/litre; potassium, 5.8 meq/litre; and glucose, 392 mg/dl. All random simultaneous plasma glucose and potassium levels measured before mineralocorticoid therapy are plotted (Figure 1). Mineralocorticoid therapy was initiated at discharge.

Figure 1 . Linear regression of points representing plasma potassium versus simultaneous plasma glucose.

Hyperkalemia in the addisonian patient, often accompanied by dehydration, azotemia, and hyponatremia, generally responds to saline infusion. In the diabetic addisonian patient, the hyperkalemia of sodium depletion must be distinguished from hyperglycemia-induced hyperkalemia. Saline infusion failed to protect this patient against paradoxical rises of potassium during acute hyperglycemia. Maintenance of daily insulin therapy cannot provide the rapid modulation of plasma insulin levels necessary to prevent acute hyperglycemia or hyperkalemia in the suspectible patient (Figure 1). Others have shown a protective effective of mineralocorticoid (1, 2). Perhaps extrarenal actions of mineralocorticoid exert a hypokalemic effect unobtainable by sodium repletion. S U S A N S. B R A I T H W A I T E , M . D . F R A N K L I N L. P E R K I N S , M . D . R A L P H G. R Y A N , M . D . G E R A L D M. G A W L I K , M . D .

The Department of Internal Medicine, Loyola University Medical Center, May wood, IL 60153 REFERENCES 1. G O L D F A R B S, C o x M, SINGER I, G O L D B E R G M: Acute hyperkalemia

induced by hyperglycemia: hormonal mechanisms. Ann Intern Med 84:426-432, 1976 2. AMNION RA, M A Y WS, N I G H T I N G A L E SD: Glucose-induced hyperkale-

mia with normal aldosterone levels. Studies in a patient with diabetes mellitus. Ann Intern Med 89:349-351, 1978

Podophyllin Therapy

T o THE EDITOR: The recommendation by Stoehr, Peterson, and Taylor (1) that podophyllin toxicity be prevented by limiting applications to small areas of intact skin is totally unrealistic; what good could that possibly do to a condyloma acuminatum? Their recommendation that the drug be removed after 1 h is also unrealistic; 4 to 6 h is a minimum time, and condylomas that have a pretty stout epithelial covering may require that it be left on for 12 to 24 h. What they should have recommended is that a "large" condyloma—one measuring, let us say, in excess of 10 to 20 cm 2 — should seldom be painted with a stronger than 5% solution of podophyllin, or 10% at most, and should under no circumstances be repainted with it in less than a week or 10 days, after subsidence of the initial reaction to the drug. Three applications of a 20% solution in 24 h was overly zealous even for a very small condyloma, let alone a very large one. Nevertheless, this vivid reminder that systemic toxicity may Letters and Correction


133

result from the topical use of this potent compound was timely and useful, and I am grateful for it.

Regardless of the method of application the patient should be closely monitored for signs of podophyllin toxicity.

H A R R Y L. A R N O L D , J R . , M . D .

G A R Y P. S T O E H R , P H A R M . D . A N N L. P E T E R S O N , M . D . W I L L I A M J. T A Y L O R , P H A R M . D .

University of Hawaii School of Medicine, Honolulu, HI 96813 REFERENCE

Duke University Medical Center, Durham, N C 27710

1. STOEHR GP, PETERSON AL, TAYLOR WJ: Systemic complications of local podophyllin therapy. Ann Intern Med 89:362-363, 1978

REFERENCES 1. STOEHR GP, PETERSON AL, TAYLOR WJ: Systemic complications of local podophyllin therapy. Ann Intern Med 89:362-363, 1978 2. W A R D JW, CLIFFORD WS, MONACO AR, BICHERSTAFF JH: Fatal systemic poisoning following podophyllin treatment of condyloma acuminata. South Med 7 47:1204-1206, 1954. 3. GRABER EA, BARBER HRK, O ' R O U R K E JJ: Simple surgical treatment for condyloma acuminatum of the vulva. Obstet Gynecol 29:247-250, 1967.

In comment: Dr. Arnold's points are well taken. The usual contact time for topical podophyllin is 4 to 6 h. However, our recommendation (1) that topically applied podophyllin be removed within 1 h agrees with the recommendation of Ward and colleagues (2). Admittedly, this is conservative treatment, but our experience has shown the need for caution when using this potent drug. Should the first application prove unsuccessful, then additional treatment with longer contact time may be necessary. The value of podophyllin treatment of large condylomas has been questioned (3), and applying the drug over a large surface area only increases the risk of systemic toxicity. Applying the drug to areas of broken skin—areas that have been biopsied or are friable or bleeding—facilitates systemic absorption and also increases the risk of systemic toxicity.

134

Correction: Degree for Dr. Charles R. Cagin

T o T H E EDITOR: In the by-line for the article "Bullets, Lead Poisoning, and Thyrotoxicosis" in the October issue {Ann Intern Med 89:509-511, 1978), the degree for Charles R. Cagin should have been the D.O., not the M.D. M A R Y OLLISON

Department of Medicine, Mount Sinai Hospital, Chicago, IL 60608



Response Evaluation of Chemotherapy for Lung Cancer.

Chemotherapy for lung cancer: still alive!

Chemotherapy of lung cancer.

Salvage surgery for primary lung cancer after chemotherapy in octogenarians.

A rehabilitation program for lung cancer patients during postthoracotomy chemotherapy.

Intensive chemotherapy for extensive-stage small-cell lung cancer (SCLC)

Hospitalization during chemotherapy for small cell lung cancer.

Changes in serum erythropoietin levels during chemotherapy for lung cancer.

Chemotherapy in non-small cell lung cancer: opportunities for advancement.

Preoperative chemotherapy for non-small-cell lung cancer.

Chemotherapy advances in small-cell lung cancer.

Chemotherapy of small cell lung cancer.

Alternating chemotherapy in small cell lung cancer.

Targeted versus chrono-targeted chemotherapy for inhaled chemotherapy in non-small cell lung cancer.

Adjuvant chemotherapy for T1-2NOMO small cell lung cancer: single-agent or combination chemotherapy?

Bevacizumab plus chemotherapy versus chemotherapy alone for preventing brain metastasis derived from advanced lung cancer.

Effect of platinum-based chemotherapy for non-small cell lung cancer patients with interstitial lung disease.

Biomarkers for cancer-related fatigue and adverse reactions to chemotherapy in lung cancer patients.

Chemotherapy for gastric cancer.

Lung transplantation for pleuroparenchymal fibroelastosis after chemotherapy.

Chemotherapy for pancreatic cancer.

Surgery plus adjuvant chemotherapy for T1-3N0M0 small-cell lung cancer. Rationale for current approach.

Use of chemotherapy in patients with metastatic lung cancer.

Chemotherapy-induced anemia in patients with primary lung cancer.