. .,,,
`
`I
`
`CHEST
`
`for
`P'U L MONOLOOl•T•, CARDIOLOOl•T•, CARDI OTHORACIC
`SURO•ON • A ND R•LAT• D •P'•CIALtaT•
`
`Atherosclerosis and Aneurysm of Aorta
`in Relation to Smoking Habits and Age
`Auerbach, Garfinkel
`
`Pulmonary Function Testing in Interstitial
`Pulmonary Disease (Clinical Significance
`of Pulmonary Function Tests)
`Keogh, Crystal
`
`Postoperative Hypertension in Open
`Heart Surgery Patients
`Meretoja and colleagues
`
`Counterimmunoelectrohoresis in
`Diagnosis of H influenzae Pleural
`Effusion (in the department: Pediatric
`Cardiopulmonary Medicine and Surgery)
`Holsclaw, Schaeffer
`Editorial comment by Hilman
`
`First Call for Abstracts
`./7th Annual Scientific Assembly
`San Francisco, October 25-29, 1981
`
`Supplied by the British Library 29 Mar 2018, 18:30 (BST}
`
`
`
`1 of 5
`
`Celltrion, Inc. 1036
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`§illll CHEST
`
`Alfred Soffer, M.D., Editor-in-Chief
`
`Associate Editors:
`David W. Cugell, M.D., Chicago /Kenneth M. Rosen, M.D., Chicago /John T. Sharp, M.D., Hines, 11/inois
`
`EDITORIAL BOARD
`
`Ezra A. Amsterdam, M.D., Davis, California
`Peter B. Barlow, M.D., Hanover, N.H.
`Robert L. Berger, M.O., Boston
`Saroja Bharati, M.O., Chicago
`
`A. Jay Block, M.O., Gainesville, Florida
`Edward H. Chester, M.D., Cleveland
`
`John J. Collins, Jr., M.D., Boston
`
`Joel D. Cooper, M.D .. Toronto
`Thomas B. Ferguson, M.D., St Louis
`
`Jack D. Fulmer, M.D .. Birmingham
`Robert E. Goldstein, M.D .. Bethesda
`Richard H. Helfant. M.D .. Philadelphia
`Millicent W. Higgins. M.D .. Ann Arbor
`Bettina C. Hilman, M.D .• Shreveport
`Richard L. Hughes, M.D., Chicago
`W. G. Johanson, Jr., M.D., San Antonio
`Richard S. Kronenberg, M.D., Minneapolis
`Peter T. Kuo, M.D .• Piscataway, N.J.
`Richard Mintzer, M.D .. Chicago
`
`Robert H. Moser, ,M.D., Philadelphia
`Shahbudln H. Rahlmtoola, M.8.
`Los Angele.s
`William C. Roberts, M.D., Bethesda
`Richard 0 . Russell, M.D., Birmingham
`Richard C. Talamo, M.D .. Boston
`William M. Thurlbeck, M.D., Winnipeg
`John G. Weg, M.D .. Ann Arbor
`Max Harry Weil, M.D., Los Angeles
`
`Correapondinc Editor
`Julius M. Gardin, M.D., Irvine, California
`
`International Editors
`Donato Alorcon·Se,govla, M.D., Mexico
`Jose Luis Barros, M.D., Spain
`Gerald L. Baum, M .0., Israel
`Gunner Blorck, M.D., Sweden
`Antonio Blasl, M.O., Italy
`Israel Bruderman, M.O., Israel
`Dirk Ourrer, M.O., The Netherlands
`Henry W. Herzog. M.D., Switzerland
`Ruben J. Jaen, M.D., Venezuela
`Paul Kes.zler, M.D., Hungary
`Stuart C. Lennox, M.D., England
`Chuzo Nagalshi, M.D., Japan
`Jo Ono, M.O., Japan
`George E. Poullas, M.O., Greece
`W. Laurence Simpson, M.O., Australia
`Jesse P. Teixeira, M.O., Brazil
`Cyr Voisin, M.D., Frence
`Juro Wede, M.O., Japan
`Ann J . Woolcock, M.D., Australia
`E. J. Zerblnl, M.D., Brazil
`
`Executive Office
`911 8 UfM Hl1i.....1. l'ar1l IUd1t, llllnob 60061, U.S.A.
`Ttlt111hon1 312·698·2200
`~~(~~ l!!~ih~. lht Anltrican Coll111 of Ch•t Physlclaru.
`
`Se<ond Cina Pot1111 l'ald a t Park RI~• . llllnol1
`i nd al addlllon1I m1lll~1 offl<M. lhtur• 1n4 lon•1nfln1
`Plllllt 111111r.1Md.
`Aon .. t Sub1e1lpd1na: P-nol - U.S. $40.00. C.Mdo,
`Mul111, Puerlo Rico $42. 00. $15.00 other ceuntrla.
`lrullMlont l - U.S. $55.00. Ctnada, Malec and P\tt<to
`~~:.~7i?°ie~~~.oo olhtr countri•. bias 1tfoetiff
`
`SJIKl• l ratu fw mld.nta. lnlt l'lll, mtcllcal d11Mnta,
`p1171lcl1n1 In tralnl .. : U.S. $30.00; Cuau. llafco
`and l'u~ Ille. $32.00; otMt -•Ill• ~5.00.
`
`National Advert/11/ng Representativ•
`HOWAllO L. HAOEMAllN
`H•llMl•n Aaoclalot
`911 lllSM Hlcflwy
`l'art llldct, 1111 .. 11 60068
`312/ 191°2200
`
`SYLVIA J. l'ffillSON
`EJtculhe EdlW
`MAA ClAll ET
`lllAJITl II EC:Z
`ClraiJ.tloo Mt u .. r
`MAllY QUN l'ICTOR
`Moertlil•• l'nlduc!J.n ....,.. . .
`
`Supplied by the British library 29 Mar 2018, 18:30 (BST)
`
`5
`
`
`
`2 of 5
`
`Celltrion, Inc. 1036
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`intercostal artery.9
`Massive hemoptysis has been controlled by surgical
`ligation of bronchial arteries without pulmonary resec·
`tion in a few reported instances. •-s
`To avoid complications, the catheter should be ad(cid:173)
`vanced selectively into the bleeding vessel and Gel(cid:173)
`foam particles injected very slowly in order to prevent
`inadvertent embolization of other organs. The presence
`of a major spinal artery is an absolute contraindication
`for an embolization procedure.•
`In the largest reported series, successful control of
`hemoptysis by embolization procedure without relapse
`within two months was achieved in approximately 90
`percent of patients with the exception of those with
`aspergilloma.
`The possibility of controlling hemoptysis by bronchial
`artery ligation with the aid of preoperative arteriograms
`may be worth consideration, especially in the patient
`with advanced pulmonary insufficiency who is incapable
`of tolerating pulmonary resection.
`The bronchial circulation becomes hyperplastic with
`an inBammatory process in the lungs and subsides to a
`normal state when the process is brought under control.•
`Whether interruption of a hyperplastic circulation alters
`the course of an inJlammatory process or the milieu for
`growth of tuberculosis organisms is a matter of specula(cid:173)
`tion. In our case 1 and in two other cases of tuberculosis
`in the literature,5· 10 the course of the patients following
`interruption of the bronchial circulation was one of rapid
`recovery.
`
`REFERENCES
`1 McCollum WB, Mattox KL, Guinn CA, et al Immediate
`operative treatment for massive hemoptysis. Chest 1975;
`67:152-55
`2 Mattox KL, Guinn CA. Emergency resection for massive
`hemoptysis. Ann Thorac Surg 1974; 17:377-83
`3 Wholey MH, Chamorro HA, Rao G, Ford WB, Miller
`WH. Bronchial artery embolization for massive hemop(cid:173)
`tysis. JAMA 1976; 236:2501-04
`4 Saw EC, Gottlieb LS, Yokoyama T, Lee BC. Flenble
`fiberoptic bronchoscopy and endobronchial tamponade in
`the management of massive hemoptysis. Chest 1976; 70-
`589
`5 Remy J, Viosin C, Dupuis C, et al Traitement '1es
`hemoptysies par embolisation de la circulation systemi(cid:173)
`que. Ann Radio 1974; 17:5
`6 Remy J, Arnaud A, Fardou H, et al. Treatment of
`hemoptysis by embolization of bronchial arteries. Radiol(cid:173)
`ogy 1977; 122:33
`1 Harley JD, Killien FC, Peck AC. Massive hemoptysis
`controlled by transcatheter embolizatioo of the bronchial
`arteries. Am J Radiol 1977; 128:302-04
`8 Remy J, Lemaitre ML, Lafitte fl, et al. Accidents de
`l'embolization dans le traitment des hemotysies. La Nou(cid:173)
`velle Presse Medicale 1978; 47 :4306
`9 Kardjiev V, Mymeonov A, Chankov I. Etiology, patho(cid:173)
`genesis and prevention of spinal cord lesions in selective
`arteriography of the bronchial and intercostal arteries.
`Radiology 1974; 112:81
`10 Lochard J, Bomilly J, Martin F. Hemostases par abord
`direct de caveme tuberculeuse pour hemoptysie grave.
`Ann Chir Thorac Cardio-Vasc 1972; 11:307
`
`Late, Late .Doxorubicin
`Cardiotoxicity •
`
`SteJ>hen L. Gofflieb, M.D.; W. Allon Edmlrion, Jr., M.D.;
`and L . Jullan H~ M.D.
`
`CudJK foDdty Ila a major complicatlon Which limits the
`111e of 8driamydn • a cbemodlenpeatlc llpllt. Cardlo(cid:173)
`myopatby Is frequent wbeB tile toCal doee exceeds 600
`met .r ud occan witbla oae to •
`lllOlltbs after emat(cid:173)
`Uon of tllerapy. A patient Is reported wbo developed pro(cid:173)
`pessive cardiomyopatby two ud one-half yam after re(cid:173)
`ceiTinc 580 mg/ m2 wblch appareedy npraents late, late
`canllotoDdty.
`
`Cardiac toxicity has been the major factor limiting the
`
`use of doxorubicin hydrochloride ( Adriamycin) as an
`effective antineoplastic agent.1 Cardiovascular effects o£
`doxorubicin are manifested by acute, transient and
`usually benign arrhythmias and by a late dose-depen(cid:173)
`dent cardiomyopathy.2 The incidence of cardiomyopa(cid:173)
`thy is greater than 30 percent among patients who
`receive a total dose of more than 600 mg/ sq m and
`usually occurs within one to six months after completion
`of therapy.3 •4 In this report, we describe a patient with
`progressive heart failure 23' years following completion
`of doxorubicin chemotherapy. We believe this represents
`a case of late, late doxorubicin cardiotoxicity.
`
`A 48-year-old white woman was hospitalized for pro(cid:173)
`gressive bivenbicular failure and eventually died from the
`severe low output state. Breast cancer had been diagnosed
`16 years previously, and she was treated with surgery and non(cid:173)
`mediastinal radiotherapy. Recunence two years later was
`treated with excision, local radiation, and oophorectomy. A
`right axillary ulcer was noted ten years later, and chemother(cid:173)
`apy, consisting of a six-month coune of cyclophosphamide
`(Cytoxan), methob'exate, and 5-ftuorouracil, was given. Be(cid:173)
`cause of booe metastasis, doxorubicin alone was then given at
`three-week intervals for six months. A total dose of 580
`mg/sq m was given. Upon completion of doxorubicin ther(cid:173)
`apy, an infusion of 30 mg/leg/day of 5-ftuorouracil was given
`for five days at monthly intervals for a total of 16 months.
`Finally, 400 mg of megestrol acetate (Megaoe) was given
`four times a day for eight months. The entire course of
`doxorubicin therapy was completed three years prior to the
`hospitalization for congestive heart failure (Table 1). The
`sympt.oms of congestive heart failure began six months prior
`to the final hospitalization. Serial chest x-ray films to follow
`the course of her malignancy had not shown cardiomegaly
`until the time of onset of symptoms. The patient had not been
`hypertensive.
`Physical examination at the time of the last admission
`revealed a cachectic, dyspneic, white woman with evidence
`of severe bivenbicular failure. She had blood pressure of 90/
`
`•From the Los An~les County-Univenity of Southem Cali-
`fornia Medical Center, Los Angeles.
`Reprint requem: Vt-. HtlflUJO(id. Loi Angeles County-USC
`Medkal Center, UOO Norlh Stale, Im Angele.t 90033
`
`llO GOTIUEB, EDMISTON, HAYWOOD
`
`CHEST, 78: 6, DECEMBER, 1980
`
`
`
`3 of 5
`
`Celltrion, Inc. 1036
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`Date
`
`Clinical Stat us
`
`1962 Breast cancer
`
`Therapy
`Mastectomy- local RT•
`
`1964 Chest wall recurrence
`
`RT to axilla and ovaries
`
`12/ 74 Bone metastases
`
`Cyclophoepbamide;
`methotrexate 1/75 to
`7 /75; ftuorouracil
`
`7 /75 Progression of bone mets; Doxorubicin 7 /75 to
`increased carcinoembryonic 2/76, 580 mg/sq m
`antigen
`total dose
`
`2/76 Clinically stable
`
`Fluorouracil weekly
`(2/ 76 to 6/ 77)
`
`6/ 77 Stable, no progression of Megestral acetate
`6/77 to 8/ 78
`disease
`
`8/78 Congestive heart failure
`
`Digitalis, diuretics
`
`1/79 Patient died
`
`•RT indicates radiation therapy; mets, metastasis.
`50 mm Hg, scleral icterus, marked jugular venous disten.tion,
`bibasilar rales, cardiomegaly, a summation gallop, a holosys(cid:173)
`tolic murmur consistent with bicuspid regurgitation, a pulsa(cid:173)
`tile liver, and pretihial edema. The ECG demonstrated normal
`sinus rhythm, diffuse low voltage, and marked left atrial
`enlargement (Fig 1 ). Chest x-ray film demonstrated marked
`generalized cardiomegaly with pulmonary vascular redis(cid:173)
`tribution. An echocardiogram revealed left atrial enlarge(cid:173)
`ment, increased mitral valve E-point septal separation, and
`decreased septal and podlerior wan motion consistent with
`congestive cardiomyopathy; there was no pericardial thick(cid:173)
`ening (Fig2 ).
`Hemodynamic investigation was performed because con(cid:173)
`strictive pericardial disease was considered a possible etiol(cid:173)
`ogy for the patient's cardiac dysfunction. The intracardiac
`pressures were as follows (mmHg): RA: m 11, a= 19, v = 16;
`RV: 29/ 12; PA 27/ 16, m 24; LV 84/17; aorta: 89/51. The
`•
`
`l
`
`I
`
`It ..
`"
`
`- ._I
`
`I
`
`AVR
`
`..
`
`I
`
`"
`
`II
`
`cardiac index was 2.1 L/sq m. The RA, RV, PA, and LV
`diastolic premues were similar but not identical. and the
`pressure tracing morphologic findings were not typical of con(cid:173)
`strictive pericardiW. A right atrial angiogram revealed no
`evidence of wall thickening. A left ventricular angiogram
`revealed a markedly dilated LV with diffU8e hypokinesis and
`an ejection fraction of 13 percent. The coronary arteries were
`normal. These data were interpreted u consisbmt with
`severe congestive cardiomyopatby. Despite diuretics, at(cid:173)
`tempted afterload reduction, and intensive inotroplc support,
`the patient deteriorated progressively and died
`from
`intractable biventricular failure. A post-mortem examination
`was refused by the family.
`
`DISCUSSION
`The exact process by which dox.orubicin produces
`cardiomyopathy is not clear. Histologic lesions consisting
`of myocyte damage with either myo6brillar depletion or
`vacuolar degeneration can be identi6ed in animals and
`human cardiac biopsy specimens after only a few
`doses. 2 •5 The toxicity is clearly related to total dosage,
`and the incidence of clinically signi6cant cardio(cid:173)
`myopathy has been controlled primarily by limitation of
`the total dose to 450 to 550 mg/sq m. Recently, several
`methods to monitor slowly changing cardiac function in
`patients receiving therapy have been reported. These
`include serial evaluation of R-wave ampUtude changes
`on ECG, serial systoUc time interval measurements, and
`echocardiographic and radionuclide methods to evaluate
`ventricular function. 2•• It is postulated that these meth(cid:173)
`ods will identify patients in whom a cumulative dose
`of 450 mg/sq m may be exceeded, if there is need for
`continued use of the drug.
`In this report, we have presented an unusual patient
`who developed severe cardiomyopathy 2l years after
`completion of doxorubicin chemotherapy. There had
`been no known cause of heart disease, prior evidence of
`cardiac decompensation, expo.rure to lcnown toxins or
`
`vl
`
`V2
`
`v3
`
`v~
`
`lo
`
`I/
`
`'"
`
`I
`I
`'
`
`1"
`
`l
`I
`1
`
`n:
`~
`I
`I
`
`I
`
`II
`
`I
`
`I
`l
`
`l
`l
`
`vs
`
`~
`
`n
`
`\
`
`l
`
`'
`I
`
`•
`
`I
`
`)
`
`1.1
`
`' •
`
`I.I
`IV
`~
`'
`
`I
`
`I
`I
`
`I
`AVL I
`
`ir
`
`It
`
`AYr
`
`-
`
`I1
`
`II
`
`II
`
`_,_
`
`- ru
`-
`
`-
`
`I
`
`I
`
`•
`
`FxCUllE I . Twelve-lead ECG: generalized low voltage is seen with marked left atrial enlarge(cid:173)
`ment indicated by the large negative P-wave de8ection in V 1 •
`
`CHEST, 78: 6, DECEMBER, 1980
`
`LATE, LATE DOXORUBIClll CARDIOTOXICITT 8tl
`
`
`
`4 of 5
`
`Celltrion, Inc. 1036
`Celltrion v. Genentech
`IPR2017-01122
`
`

`

`infectious agents, or other illness liXely to produce car(cid:173)
`diac dysfunction. Furthermore, the coronary arteries
`were normal, and there was no evidence of pericardia!
`thickening, constriction, or tamponade. We believe the
`patient's cardiac disease most likely represe.nts what we
`have termed late, late doxorubicin cardiotoxicity.
`This late presentation of congestive heart failure, 2"
`years after completion of doxorubicin therapy, may be
`due to a slowly progressive cardiomyopathic process.
`Studies in an animal model have suggested that the
`doxorubicin cardiomyopathic process may be delayed
`and progressive. 7 However, in a large retrospective hu(cid:173)
`man study of patients followed for up to seven years
`(mean approximately 200 days). doxorubicin-induced
`congestive heart failure occurred at a mean of 33 days
`after the last dose; the range was 0 to 231 days.8
`Although we believe that doxorubicin was the major
`factor in the development of congestive heart failure in
`our patient, additional facto.rs could have been the 5-
`ftuorouracil or the megestral acetate which she received
`during the three years following the completion of the
`doxorubicin therapy.
`Early deaths due to the malignancy and early and late
`cardiotoxicity limit the number of individuals who are
`lilc:ely to survive long enough to manifest late, late doxo(cid:173)
`rubicin cardiotoxicity. Nevertheless, as current methods
`of treatment increase the longevity of patients with
`malignant disease, it is possible that more patients will
`develop congestive heart failure under circumstances
`similar to our patient. Individuals who have not mani(cid:173)
`fested signs of toxicity earlier may develop such 6ndings
`later in their clinical course. Long-term survivors of
`malignancy who have received chemotherapy with
`doxorubicin should be evaluated periodically to detect
`this potential complication.s,8
`
`1 Henderson IC, Frei E III. AdriamyciD and the heart. N
`Engl J Med 1979; 300:310-12.
`2 Bristow MR, Mason JW, Billingham ME, et at Doxo(cid:173)
`rubiciD cardiomyopathy: evaluation by phonocardiogra(cid:173)
`phy, endomyocardial biopsy, and cardiac catheterization.
`Ann Intern Med 1978; 88:168-75.
`3 Minow RF A, Benjamin RS, Gottlieb JA. Adriamycin (NSC-
`123127) cardiomyopathy: an overview with determination
`of risk factors. Cancer Chemother Rep 1975; 6: 195-201.
`4 Lenaz L, Page JA. Cardioto:dcity of adriamyciD and re-
`
`FlcURE 2. Echocardiogram: Scan from aortic
`root to left ventricle reveals generalized cham(cid:173)
`ber dilatation and decreased wall motion.
`
`lated anthracyclioies. Cancer Treatment Rev 1976; 3:111-
`20.
`5 Billingham ME, Mason JW, Briston MR, et al. Anthra(cid:173)
`cycline cardiomyopathy monitored by morphologic
`changes. Cancer Treatment Rep 1978; 62:865-72.
`6 Alexander J, Dainialc N, Berger HJ, et al. Serial assessment
`of doxorubicin cardioto:dcity with quantitative radio(cid:173)
`nuclide angiocardiography. N Engl I Med 1979; 300:278-
`83.
`7 Jaenke RS. Delayed and progressive myocardial lesions
`after adriamyciD administration in the rabbit. Cancer Res
`1976; 36:2958-66.
`8 Von Ho.ff DD, Layud MW, Basa P, et al. Risk factors for
`doxorubiciD-induoed congestive heart failure. Ann Intern
`Med 1979; 91:710-17.
`
`Atypical Mycobaderial
`Lymphadenitis in an Adult*
`
`George S. Deepe, Jr., MD.;t Hobert CapJJareU, M.D.;t and
`J. Donald Coonrod, MD.t
`
`A 15-year-old w oman developed lympbadeaitll wftla
`Mycobactnium avium-int'facellulare. The clniw fea(cid:173)
`tures of the illness resembled those which have been
`reported In lympluldenitis with atyplw mycobacteria In
`children. The Infection was cured by reledloa of the
`Infected nodes.
`
`L ymphadenitis with atypical mycobacteria has been
`
`observed almost exclusively in children.1 •2 This re(cid:173)
`port describes the clinical features of submandibular
`lymphadenitis caused by Mycobacterium aoium-intT~
`cellulare in an adult.
`
`CASE fu:roRT
`A 25-year-oJd woman was referred with a two-month
`history of an asymptomatic right submandibular mass. There
`was no lcnown MPQSUre to tubel'Clllom. On physical ex(cid:173)
`amination a freely moveable, nootender mass measuring
`
`•From the Veterans Administration Hospital and the Divi(cid:173)
`sion of Infectious Diseases, Department of Medicine, Uni(cid:173)
`versity of Kentucky School of Medicine, Lexington, KY.
`tFellow, Division of Infectious Diseases.
`tAssociate Professor of Medicine and Chief of Infectious
`Diseases, Veterans Administration Hospital.
`Reprint requem: IX. Coonrod, VA Hospital (Cooper DrilJe),
`Lerington, Kentuclv 40511
`
`882 DEEPE, CAPPAREU.. COONROD
`
`CHEST, 78: 6, DECEMBER, 1980
`
`
`
`5 of 5
`
`Celltrion, Inc. 1036
`Celltrion v. Genentech
`IPR2017-01122
`
`