#{188}. /7

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A Subsidiary of Harcourt Brace Jovanovich, Publishers

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© 1980, Grune & Stratton, Inc. 1 1 1 Fifth Avenue, New York 10003

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rvMan, Cancer and Immunity

A.J. CochranUniversity Deportment of Pathology, Western Infirmary, Glasgo w, Scotland

1978, 2O6pp. 0.12.177550.X

Evidence has been accumulating during the last decade to suggest that some cancerpatients react against their tumours,�and that the immune system is involved in thisreaction. In this book, studies in vivo and in vitro, which demonstrate such interactions,

are critically discussed. These include assessments of membrane characteristics of tumourcells, the different classes of tumour-associated antigens, the immunological reactions tosuch antigens and the mechanisms whereby tumour cells may survive and proliferate inthe presence of established anti-tumour immunity. Also considered are the more clinicalaspects, detection and quantification of immune responses to tumour cells and the effectsof conventional forms of treatment of cancer on such responses. The utility of immuno-logical assessment in cancer diagnosis, prognosis, treatment planning and monitoring theclinically tumour free individual is discussed. Whereas much of the previously publishedwork on this subject has devoted attention to studies in animals, in this volume theauthor concentrates on studies in Man.

“The best parts of this book are those which deal with Dr Cochran ‘s extensive research onthis subject, for we are following an explorer on his own voyages ofdiscovery. When he isrecounting his own work the book is vivid, well illustrated, and written in a strong andeager prose which carries the reader along with little effort. The o ther sections of thebook also have many virtues. “ British Medical Journal, Jan. 1979

Academic Press London New York San FranciscoA Subsidiary of Harcourt Brace Jovanovich, Publishers24-28 Oval Road, London NW!, England.

�rLl Fifth Avenue, New York, NY 10003, USA APL 0001

FROM PARKE-DAVIS RESEARCH

A BREAKTHROUGHIN THE TREATMENT OF

A MAJORVIRAL DISEASE

1

�‘ ...� : . #{149}f�’ . , .�- ,‘; � .-‘

© 1979 Wamer-Lambert Company

Parenteral

(vidarabinefor

infusion)

N�=1O

80-

Fig. I Morbidity and mortality in biopsy-proved Herpes simplex

virus encephalitis

NIAIDSTUDY N=18

100-

0 ALIVE, NO OR MINORSEQUELAE

I ALIVE, MODERATESEOUELAE

U ALIVE, SEVERESEQUELAE

U DEAD

‘National Instituteof Allergy andInfectious Diseases-adapted from Whitley, at at’

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VIRA-A’ PLACEBO’THERAPY

‘P - 0.03 AT DAY 30

Early diagnosis and treatment are essential

A significant contributionin reducinS mortality of patients withHerpes simplex virus encephalitis

Controlled studies indicate that VIRA-A

(vidarabine for infusion) reduced the

mortality caused by Herpes simplex

virus encephalitis from 70% to 28%

(Chi-square analyses, P 0.03) (Fig. 1).1

Of 28 patients who were brain-biopsy

positive for Herpes simplex virus,

18 received VIRA-A and 10 received

1

There is a direct relationship between

the outcome of therapy and the state of

consciousness at the time that VIRA-A

therapy is initiated. Once the comatose

state is reached in the patient with

Herpes simplex virus encephalitis,

therapy may be futile.’ In the same

double-blind placebo-controlled study of

VIRA-A, over half the comatose patients

died in spite of active drug therapy,

and all the survivors were severelyneurologically debilitated. But no deaths

occurred among lethargic patients

treated with VIllA-A, and six of seven

survivors had only minor or moderate

neurologic complications.’

After localization of an intracerebral

lesion by brain scan, electroencepha-

lography, and/or computerized axialtomography, brain biopsy is required to

confirm the etiologic diagnosis by means

of viral isolation in cell cultures. Detec-

tion of Herpes simplex virus in the

biopsied brain tissue can also be reliably

done by specific fluorescent antibody

techniques.

Recommended Dosage:ISmg/kg/dayfor lOdays

Note: There are no clinical studies

available to indicate that VIRA-A

(vidarabine for infusion) is effective in

the management of encephalitis due to

varicella-zoster or vaccinia viruses.

VIRA-A is not effective against RNA

viral or adenoviral infections. It is also

not effective against bacterial or fungal

infections. There are no clinical data to

indicate efficacy against cytomegalovirus,

vaccinia virus, or smallpox virus.

Some degree of immunocompetence

must be present in order for VIRA-A to

achieve clinical response.

Please see following page for completeprescribing information, includingcontraindkations, warnings, precautions,and adverse reactions. �

LA.�ATO9.ESAC

.

are among the malignancies that have responded to Adriamycin

Among the other disseminated neoplastic conditions

that have responded to Adriamycin are Hodgkin’sdisease. breast carcinoma. acute lymphoblastic leukemia.

acute myeloblastic leukemia, Wilms’ tumor, bone andsoft tissue sarcomas, neuroblastoma, ovarian

carcinoma, transitional cell bladder carcinoma, thyroidcarcinoma, and bronchogenic lung carcinoma inwhich the small cell histologic type is the most responsive

compared to other cell types. Adriamycin shouldbe administered only under the direction of specialistsqualified in the administration of such drugs.

Severe local tissue necrosis will occur if there is

extravasation during administration.Severe irreversible myocardial toxicity with delayed

congestive failure often unresponsive to any cardiacsupportive therapy may be encountered as total dosageapproaches 550 mg/m2. This toxicity may occur atlower cumulative doses in patients with prior mediastinalirradiation or on concurrent cyclosphosphamide therapy.

The incidence of bone marrow depression is high.

Hematopoietic toxicity may limit dosage.In patients with impaired hepatic function, dosage

should be reduced.For information on the use OfADRIAMYCIN, call collect:(614) 764-8100.

(Photomicrographs courtesy of Dr. J.E. Ultrnann and Dr. R.S. Stein)

1 #{149} S TM

Auriamvcin(doxorubicin�hydroch1oride)for InjectionFOR INTRAVENOUS USE ONLY10 mg and 50 mg vials

For complete prescribing information, please see the following page.

Noduiar iymphoma - poorly differen-

tiated lymphocytic. The cells are

lymphocytes with marked nuclear

variations. Nuclei are round to oval.

and show indentation and

Diffuse lymphoma - histiocytic.

Larger cells than in poorly differen-

tiated type. Nuclei vary in size.

Prominent. large nucleoli are

present in some cells.

Although the cells are probably

transformed lymphocytes.

histiocytic lymphoma” remains

the standard terminology.

or eceivea f reec opyo ft her eview,N on-Hodgkin’sI �mphomas:A

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Parenteral

�i1RkAMdaraL�nefor infusion)

A significant contribution to medicineFULL PRESCRIBING INFORMATION

Description. Vira-A for infusion (ara-A, vidarabine, adenine arabinoside) is a sterile anti-viral drug for intravenous administration only Vira-A (Vidarabine for Infusion) is a purinenucleoside obtained from fermentation cultures of Streptoinyces anbbiot;cus Each millili-ter of suspension contains 200 milligrams of vidarabine monohydrate equivalent to 1874milligrams of vidarabine. Each milliliter contains 0.1 milligram Phemerol� lbenzethoniumchloride) as a preservative: sodium phosphate, USP. 1 8 milligrams, and sodiumbiphosphate. USP, 4.8 milligrams. as buftering agents. Hydrochloric acid may have beenadded to adjust pH Vira-A is a white, crystalline solid with this empirical formulaCH3NsO3.H�O The molecular weight is 285.2: the solubility is 0.45 mgml at 25CC: andthe melting point ranges from 26O� to 270C. The chemical name is 9-j�-D-arabinofur-anosyladenine monohydrate, with the following structural formula.Clinical Pharmacology. Following intravenous admin-istration. Vira-A is rapidly deaminaled mb arabinosyl-hypoxanthine lAra-Hx). the principal metabolite. which NH2Is promptly distributed into the tissues. Peak Ara-Hxand Ara-A plasma levels ranging from 3 to 6 pg/mI and N.�0 2 to 0 4 �g/ml. respectively. are attained after slow in-travenous infusion of Vira-A doses of 10 mg/kg of body I Iweight. These levels reflect the rate of infusion and .s� Nshow no accumulation across time The mean half-life Nof Ara-Hx is 3 3 hours Ara-Hx penetrates into the cere-brospinal fluid (CSF) to give a CSF/plasma ratio of ap-proximately 13. HO-CH2 ‘H20

Excretion of Vira-A is principally via the kidneys.Urinary excretion is constant over 24 hours Forty-oneto 53’� of the daily dose is recovered in the urine as H OHAra-Hx with 1 to 3� appearing as the parent corn-pound. There is no evidence of fecal excretion of drug H Hor rnetabolites. In patients with impaired renal function OH HAra-Hx may accumulate in the plasma and reach levelsseveral-told higher than those described above.Microbiology. Wa-A possessesin vitro andin vivoantiviral activity against Herpesvirus simplex Herpes simplex viruxf types 1 and 2.

The antiviral mechanism of action has not yet been established. The drug ix converted intonucleofidex which appear to be involved with the inhibition of viral replication. In KB cells in-fected with Herpes simplex virus type 1 . Vira-A inhibits viral DNA synthesis. I/ira-A ix rapidlydeaminated to Ara-Hx. the principal metabolite, in cell cultures, laboratory animals, andhumans.

Ara-Hx also possessesin vitro antiviral activity but this activity ix significantly less than theactivity of Vira-A.Indications and Usage. Vira-A is indicated in the treatment of Herpes simplex virus en-cephalitis. Controlled studies indicate that Vira-A therapy will reduce the mortality caused byHerpes simplex virus encephalitis from 70 to 28� Vira-A therapy does not appear to altermorbidity and resulting serious neurological sequelae in the comatose patient. Therefore.early diagnosis and treatment are essential.

Herpes simplex virus encephalitis should be suspected in patients with a history of anacute febrile encephalopathy associated with disordered mentation, altered level of con-sciousness and focal cerebral signs

Studies which may support the suspected diagnosis include examination of cerebrospinalfluid and localization of an intra-cerebral lesion by brain scan, electroencephalography orcomputerized axial tomography (CAT)

Brain biopsy is required in order to confirm the etiological diagnosis by means of viral isola-ion in cell cultures

Detection of Herpes simplex virus in the biopsied brain tissue can also be reliably done byspecific fluorescent antibody techniques Detection of Herpes virus-like particles by electronmicroscopy or detection of intranuclear inclusions by histopathologic techniques only pro-vides a presumptive diagnosis

There are no reports available to indicate that Vira-A for infusion is effective in the manage-ment of encephalitis due to varicella-zoster or vaccinia viruses Vira-A us not effective againstinfections caused by adenovirus or RNA viruses It is also not effective against bacterial orfungal infections There are no data to support efficacy of Wa-A against cytomegalovirus.vaccinia virus, or smallpox virus.Contraindications. Wa-A is contraindicated in patients who develop hypersensitivity reac-tions to it

Warnings. Vira-A should not be administered by the intramuscular or subcutaneous routebecause of its low solubility and poor absorption.Precautions. Treatment should be discontinued in the patient with a brain biopsy negative forHerpes simplex virus in cell culture.

Special care should be exercised when administering \Iira-A to patients susceptible to fluidoverloading or cerebral edema. Examples are patients with CNS infections and impaired re-nal function

Patients with impaired renal function. such as post-operative renal transplant recipients.may have a slower rate of renal excretion of Ara-Hx Therefore. the dose of Vira-A may needto be adjusted according to the severity of impairment. These patients should be carefullymonilored

Patients with imoaired liver function should also be observed for possible adverse effectsAlthough clear evidence of adverse experience in humans from simultaneous Vira-A

and allopurinol administration has not been reported. laboratory studies indicate that al-lopurinol may interfere with Vira-A metabolism Therefore. caution is recommended whenadministering Vira-A to patients receiving allopurinol

Appropriate hematologic tests are recommended during �uira-A administration since he-moglobin. hematocrit. white blood cells. and platelets may be depressed during therapy

Some degree of immunocompetence must be present in order for Vira-A to achieve clinicalresponse

Usage in Pregnancy: Vira-A given parenterally is teratogenic in rats and rabbits. Doses of5 mg/kg or higher given intramuscularly to pregnant rabbits during organogenesis inducedfetal abnormalities Doses of 3 mg/kg or less did not induce teratogenic changes in pregnantrabbits. ‘(ira-A doses ranging from 30 to 250 mg/kg were given intramuscularly to pregnantrats during organogenesis. signs of maternal toxicity were induced at doses of 100 mg/kg orhigher and frank fetal anomalies were found at doses of 150 to 250 mg/kg

A safe dose for the human embryo or fetus has not been establishedConsequently. the use of Vira-A in pregnant patients should be limited to life-threatening

illnesses where the possible benefits outweigh the potential risks involvedIt is not known whether Vira-A is excreted in human milk As a general rule. nursing should

not be undertaken while a patient is under treatment since many drugs are excreted in hu-man milk However. Vira-A is rapidly deaminated in the gastrointestinal tractAdverse Reactions. The principal adverse reactions involve the gastrointestinal tract andare anorexia. nausea. vomiting, and diarrhea These reactions are mild to moderate. and sel-dom require termination of Vira-A therapy

CNS disturbances have been occasionally reported at therapeutic doses These aretremor. dizziness. hallucinations, confusion. psychosis. and ataxia

Hematologic clinical laboratory changes noted in controlled and uncontrolled studies werea decrease in hemoglobin or hematocrit, white blood cell count. and platelet count. SGOTelevations were also observed. Other changes occasionally observed were decreases inreticutocyte count and elevated total bilirubin.

Other symptoms which have been reported are weight loss. malaise. pruritus. rash, hema-ternesis. and pain at the intection site.Overdosage. Acute massive overdose of the intravenous form has been reported withoutany serious evidence of adverse effect. Acute water overloading would pose a greater threattothe patientthan Wa-A. due to its low solubility Doses of Vira-A over 20 mg/kg/day canproduce bone marrow depression with concomitant thrombocytopenia and leukopenia If amassive overdose of the intravenous form occurs. hematologic, liver. and renal functionsshould be carefully monitored

Acute massive oral ingestion is not expected to be toxic because drug absorption from thegastrointestinal tract is minimal. The oral LD5, for Vira-A is greater than 5.020 mg/kg in miceand rats.Dosageand Administration. CAUTION-THE CONTENTS OF THE VIAL MUST BEDILUTED IN AN APPROPRIATE INTRAVENOUS SOLUTION PRIOR TO ADMINISTRA-TION. RAPID OR BOLUS INJECTION MUST BE AVOIDED

Dosage. Herpes simplex virus encephalitis-15 mgi kg/day for 10 days.Method ofPreparation. Each vial contains 200 mg of Vira-A per ml of suspension. The

solubility of Vira-A in intravenous infusion fluids is limited Each one mg of Vira-A requires2.22 ml of intravenous infusion fluid for complete solubilization Therefore. each one liter ofintravenous infusion fluid will solubilize a maximum of 450 mg of Wa-A.

Any appropriate intravenous solution is suitable for use as a diluent EXCEPT biologic orcolloidal fluids (e.g . blood products. protein solutions. etc

Shake the Vira-A vial well to obtain a homogeneous suspension before measuring andtransferring.

Prepare the Vira-A solution for intravenous administration by aseptically transferring theproper dose of Vira-A into an appropriate intravenous infusion fluid. The intravenous infusionfluid used to prepare the Vira-A solution may be prewarmed to 35’ to 40’C (95#{176}to 100’F) tofacilitate solution of the drug following its transference Depending on the dose to be given,more than one liter of intravenous infusion fluid may be required. Thoroughly agitate the pre-pared admixture until completely clear Complete solubilization of the drug. as indicated by acompletely clear solution, is ascertained by careful visualinspection Final filtration with an in-line membrane filter (0.45 p pore size or smaller) is necessary

Once in solution. the drug has been found to be chemically stable at room temperature (be-low 86#{176}F(for at least two weeks. Dilution should be made just prior to administration andused at least within 48 hours. Subsequent agitation. shaking. or inversion of the bottle is un-necessary once the drug is completely in solution

Administration. Using aseptic technique. slowly infuse the total daily dose by intravenousinfusion IPrepared as discussed abovel at a constant rate over a 12. to 24-hour periodHow Supplied. N 0071-4150-08(Steri-Vial5 4150) Vira-A )Vidarabine for Infusion), a sterilesuspension containing 200 mg/mI. is supplied in 5-mi Steri’Vials. packages of 10Animal Pharmacology and Toxicity. Acute Toxicity: The intraperitoneal LD5( for Vira-Aranged from 3,890 to 4,500 mg/kg in mice, and from 2.239 to 2,512 mg/kg in rats, suggestinga low order of toxicity to a single parenteral dose Hepatic megalocytosis was observed inrats after single. intraperitoneal inlections at doses near and exceeding the LD50 value. Thehepatic megalocytosix appeared to regress completely over several months Acute intrave-nous LD50 values could not be obtained because of the limited solubility of Vira-A.

Subacute Toxicity. Rats. dogs. and monkeys have been given daily intramuscular injec-tions of Vira-A as a 20% suspension for 28 days. These animal species showed dose relateddecreases in hemoglobin. hematocrit. and lymphocytes Bone marrow depression was alsoobserved in monkeys. Except for localized, inlection-site injury and weight gain inhibition orloss. rats tolerated daily doses up to 150 mg/kg. and dogs tolerated daily doses up to 50 mg/kg Megalocytosix was not seen in the rats dosed by the intramuscular route for 28 days.Rhesus monkeys were particularly sensitive to Vira-A Daily intramuscular doses of 15 mg/kgwere tolerable. but doses of 25 mg/kg or higher induced progressively severe clinical signs ofCNS toxicity. Three monkeys given slow intravenous infusions of V’ira-A in solution at a doseof 15 mg/kg daily for 28 days had no significant adverse reactions.

Tumorigenicity. Chronic parenteral )IM) studies of vidarabine have been conducted inmice and rats.

In the mouse study, there was a statistically significant increase in liver tumor incidenceamong the vidarabine-treated females In the same study. some vidarabine-treated malemice developed kidney neoplasia. No renal tumors were found in the vehicle-treated controlmice or the vidarabine-treated female mice.

In the rat study. intestinal. testicular. and thyroid neoplasia occurred with greater frequencyamong the vidarabine-treated animals than in the vehicle-treated controls The increases inthyroid adenoma incidence in the high-dose (50 mg/kg) males and the low-dose (30 mg/kg)females were statistically significant

Hepatic megalocytosis. associated with vidarabirie treatment. has been found in short- andlong-term rodent (rat and mouse) studies It is not clear whether or not this represents apreneoplastic change

Mutagenicity. Results ofin vitro experiments indicate that vidarabine can be incorporatedinto mammalian DNA and can induce mutation in mammalian cells mouse L5178Y cell line).Thus farm vivo studies have not been as conclusive. but there is some evidence (dominantlethal assay in mice) that vidarabine may be capable of producing mutagenic effects in malegerm cells.

It has also been reported that vidarabine causes chromosome breaks and gaps whenadded to human leukocytesin vitro While the significance of these effects in terms of muta-genicity is not fully understood. there is a well-known correlation between the ability of van-ous agents to produce such effects and their ability to produce heritable genetic damage

YH

Reference: 1 Whitley RJ. Soong S-j Doiin R. et al. Adenine arabinoside therapy of biopsy-proved henpex’simplex encephalitis National Institute of Allergy and Infectious DiseasesCollaborative Antiviral Study. N EnglJ Med 297.289-294. August 11, 1977.

PARKE-DAVIS

Division of Warner-Lambert CompanyMorris Plains, NJ 07950

WARNINGS1. Severe local tissue necrosis will occur f there is extravasation during administration

Adriamycin must not be given by the intramuscular or subcutaneous route.

2. Serious irreversible myocardial toxicity with delayed congestive failure often unrespon-sive to any cardiac supportive therapy may be encountered as total dosage approaches550 mg/m’. This toxicity may occur at lower cumulative doses in patients with priormediastinal irradiation or on concurrent cyclophosphamide therapy

3. Dosage should be reduced in patients with impaired hepatic function

4. Severe myelosuppression may occur

5. Adriamycin should be administered only under the supervision of a physician who isexperienced in the use of cancer chemotherapeutic agents.

Adria LaboratorIes Inc.

ADRIAMYCIN “ (doxorubicin hydrochloride) for Injection

FOR INTRAVENOUS USE ONLY

DESCRIPTiONDoxorubicin is a cytofoxic anthracyctine antibiotic isolated from cultures of Seepiomyces peucelxJs

var. raestis It is supplied in the hydrochloride form as a freeze�dnied powder containing lactose.

CUNICAL PHARMACOLOGYThough not completely elucidated, the mechanism of action of doxorubscin is related to its ability

to bind to DNA and inhibit nucleic acid synthesis. Cell culture studies have demonstrated rapid cellpenetration and peninucleolar chromatin Landing. rapid inhibition of mitotic activity and nucleic acid

synthesis. mutagenesis and chromosomal aberrations. Animal studies have shown activity fl a

spectrum of experimental tumors, immunosuppression, carcinogenic properties in rodents, inductionof a variety of toxic effects. including delayed and progressive cardiac toxicity in rabbits. myelosup-pression in all species and atrophy to testes in rats and dogs.

Pharmacokinetic studies show the ntravenous administration of normal or radiolabeled Adnia-mycin (doxorubicin hydrochloride) for Injection is followed by rapid plasma clearance and significanttissue binding. Urinary excretion. as determined by fluorimetric methods. accounts for approxi-mafely 4-5% of the administered dose in five days. Biltary excretion represents the major excretion

route, 40-50% of the administered dose being recovered in the b,Ie or the feces in seven daysImpairment of liver function results in slower excretion. and. consequently. increased retention and

accumulation in plasma and tissues. Adriamycin does not cross the blood brain barrier

INDICATiONSAdniamycin has been used successfully to produce regression in disseminated neoplasfic condi-

tions such as acute lymphoblaslic leukemia, acute myeloblastic leukemia. Wilms’ tumor. neuroblas-toma. soft tissue and bone sarcomas. breast carcinoma. ovarian carcinoma. transitional cell bladdercarcinoma, thyroid carcinoma. tymphomas of both Hodgkin and non-Hodgkin types and bronchogeniccarcinoma in which the small cell histologic type is the most responsive compared to other celltypes. A number of other solid tumors have also shown some responsiveness but in numbers toolimited to iustifv specific recommendation. Studies to date have shown malignant melanoma. kidneycarcinoma. large bowel carcinoma. brain tumors and mefastases to the central nervous system notto be significantly responsive to Adriamycin therapy.

CONTRAINDICAT1ONSAdniamycin therapy should not be started in patients who have marked myelosuppression induced

by previous treatment with other antitumor agents or by radiotherapy. Conclusive data are notavailable on pre-existing heart disease as a co-factor of increased risk of Adriamycin inducedcardiac toxicity. Preliminary data suggest fhat in such cases cardiac toxicity may occis at doseslower than the recommended cumulative limit It is therefore not recommended to start AdniamycinIn such cases Adniarnycin treatment is contraindicated in patients who received previous treatmentwith complete cumulative doses of Adriamycin and/or daunorubicin.

WARNINGSSpecial attention must be given to the cardiac toxicity exhibited by Adriamycin. Although

uncommon, acute left ventricular failure has occurred. particularly in patients who have receivedtotal dosage of the drug exceeding the currently recommended limit of 550 mg/m’ This limitappeans to be lower (400 mg/rn’) in patients who received radiotherapy to the mediaslinal area orconcomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide The totaldose of Adniamycin administered to the individual patient should also take into account a previous orconcomitant therapy with related compounds such as daunorubicin. Congestive heart failure and/orcardiomyopathy may be encountered several weeks after discontinuation of Adriamycin therapy

Cardiac failure is often not favorably affected by presentty known medical or physical therapy forcardiac support. Early clinical diagnosis of drug induced heart failure appears to be essential for

successful treatment with digitalis. diuretics. low salt diet and bed rest. Severe cardiac toxicity mayoccur precipitously without antecedent EKG changes. A baseline EKG and EKGs performed prior toeach dose or course after 300 mg/rn’ cumulative dose has been given is suggested Transient EKGchanges consisting of T�wave flattening, S-T depression and ai-rhythmias lasting for up to two weeksafter a dose or course of Adriamycin are presently not considered indications for suspension ofAdniamycin therapy. Adriamycin cardiomyopathy has been reported to be associated with a per-sistent reduction in the voltage of the CR5 wave, a prolongation of the systolic time interval and areduction of the ejection fraction as determined by echocardiography or radionuclide angiography.None of these tests have yet been confirmed to consistently identify those individual patients thatare approaching their maximally tolerated cumulative dose of Adria’nycin. If test results indicatechange in cardiac function associated with Adriamycin the benefit of continued therapy must becarefully evaluated against the risk of producing irreversible cardiac damage.

Acute life-threatening arrhythmias have been reported to occur during or within a few hours afterAdriamycin administration.

There is a high incidence of bone marrow depression. primarily of leukocytes, requiring carefulhematologic monitoring. With the recommended dosage schedule, leukopenia is usually transient.reaching its nadir at 10-14 days after treatment with recovery usually occurring by the 21st day.White blood cell counts as low as 1000/mm’ are to be expected during treatment with appropriatedoses of Adniamycin. Red blood cell and platelet levels should also be monitored since they may alsobe depressed Hematologie toxicity may require dose reduction or suspension or delay of Adniamycintherapy Persistent severe myelosuppression may result in superintection or hemorrhage.

Adniamycin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophos-phamide induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurinehave been reported. Radiation induced toxicity to the myocardium. mucosae. skin and liver havebeen reported to be increased by the administration of Adriamycin.

Toxicity to recommended doses of Adrianycin is enhanced by hepatic impairment: therefore. priorto the individual dosing, evaluation of hepatic function is recommended using conventional clinicallaboratory tests such as SGOT. SGPT. alkaline phosphatase and bilirubin (See Dosage and Adminis.tration)

On intravenous administration of Adniamycin extravasation may occur with or without an

accompanying stinging or burning sensation and even if blood returns well on aspiration of theinfusion needle. It any signs or symptoms of extravasation have occurred the injection or infusionshould be immediately terminated and restarted in another vein.

Adriamycin and retated compounds have also been shown to have mutagenic and carcinogenicproperties when tested in experimental models.

� use of Adriamycin in pregnancy has not been established. AdniamycinIs embryotoxic and teratogenic in rats and embryotoxic and abortifacient in rabbits. Therefore. the

benefits to the pregnant patient should be carefully weighed against the potential toxicity to fetusand embryo. The possible adverse effects on fertility in males and females in humans or expenimen-fal animals have not been adequately evaluated.

PRECAUTIONSInitial treatment with Adrialtycin requires close observation of the patient and extensive labora-

lory monitoring. It is recommended, therefore. that patients be hospitalized at least during the firstphase of the treatment.

Like other cytotoxic drugs, Mriarnycin may induce hyperuricemia secondary to rapid lysis ofneoplastic cells The clinician should monitor the patients blood uric acid level and be prepared touse such supportive and pharmacologic measures as might be necessary to control this problem

Adriamycin imparts a red coloration to the urine for 1-2 days after administration and patientsshould be advised to expect this during active therapy.

Adriamycin is not an anti-microbial agent.

ADVERSE REACTiONSDose limiting toxicities of therapy are myelosuppression and cardiotoxicity (see Warnings( Other

reactions reported are:Cutaneous-Reversible complete alopecia occurs in most cases. Hyperpigmentation of nailbeds

and dermal creases. primarily in children, have been reported in a few cases. Recall of skin reactiondue to prior radiotherapy has occurred with Adriamycin administration.

Gastrointestinal-Acute naisea and vomiting occurs frequently and may be severe This may bealleviated by antiemetic therapy. Mucositis (stomatitis and esophagitis) may occur 5-10 days afteradministration. The effect may be severe leading to ulceration and represent a site of origin forsevere infections. The dose regimen consisting of administration of Adriamycin on three successivedays results in the greater incidence and severity of mucositis. Anorexia and diarrhea have beenoccasionally reported.

Vascular-Phlebosclerosis has been reported especially when small veins are used or a singlevein is used for repeated administration. Facial flushing may occur if the injection is given toorapidly

!�Q.�A! - Severe cellulitis, vesication and tissue necrosis will occur if Adriamycin is extravasatedduring administration. Erythematous streaking along the vein proximal to the site of the injection hasbeen reported. (See Dosage and Administration.)

Hypersensitivity - Fever, chills � urticaria have been reported occasionally Anaphylaxis mayoccur A case of apparent cross sensitivity to lincomycin has been reported.

Qiti�.t - Conjunctivitis and lacrimation occur rarely.

DOSAGE AND ADMINiSTRATIONCare in the administration of Adriamycin will reduce the chance of perivenous infiltration It may

also decrease the chance of local reactions such as urticaria and erythentatous streaking.The recommended dosage schedule is 60�75 mg/rn’ as a single intravenous injection adminis-

fered at 21�day intervals. The lower dose should be given to patients with madequate marrowreserves due to old age. or prior therapy. or neoplastic marrow infiltration. An alternative doseschedule is 30 mg/rn’ on each of three successive days repeated every 4 weeks. Adriamycin dosagemust be reduced if the bilirubin is elevated as follows: Serum Bilirubin 1.2-3.0 mg/lOU mi-give /�

normal dose, > 3 mg/tOO mI-give ‘/4 normal dose.Preparation of Solution: Adriamycin � rog vials and 50 mg vials should be reconstituted with 5 ml

and 25 ml respectively of Sodium Chloride injection U.S.P. or Sterile Water for injection U.S.P. to givea final concentration of 2 m9/mI of doxorubicin hydrochloride. An appropriate volume of air shouldbe withdrawn from the vial during reconstitution to avoid excessive pressure build-up. Bactenio-static diluents are not recommended.

Skin reactions associated with Adriamycin have been reported. Caution in the handling andpreparation of the powder add solution must be exercised and the use of gloves is recommended. IfAdniamycin powder or solution contacts the skin or mucosae. immediately wash thoroughly with

soap and water.After adding the diluent, the vial should be shaken and the contents allowed to dissolve. The

reconstituted solution is stable for 24 hours at room temperature and 48 hours under refrigeration(4�1O�C). It should be protected from exposure to sunlight and any unused solution should bediscarded.

It is recommended that Adriamycin be slowly administered into the tubing of a freely runningintravenous infusion of Sodium Chloride Injection U.S.P. or 5% Dextrose Injection U.S.P. The tubingshould be attached to a Butterfly needle inserted preferably into a large vein. It possible. avoid veinsin extremities with compromised venous or lymphatic drainage. The rate of administration isdependent on the size of the vein and the dosage. However the dose should be administered in notless than 3 to 5 minutes. Local erythematous streaking along the vein as well as facial flushing maybe indicative of too rapid an administration. A horning or stinging sensation may be indicative ofperivenous infiltration and the infusion should be immediately terminated and restarted in another

vein. Perivenous infiltration may occur painlessly. If it is known or suspected that subcutaneousextravasation has occurred local infiltration with an injectable corticosteroid and flooding the sitewith normal saline has been reported to lessen the local reaction. The area should subsequently befrequently examined and plastic surgery consuftation should be obtained. If ulceration begins, earlywide excision of the involved area should be considered

Adniamycin should not be mixed with heparin or 5-fluorouracil since it has been reported thatthese drugs are incompatible to the extent that a precipitate may form. Until specific compafibilitydata are available. it is not recommended that Adriamycin be mixed with other drugs.

Adriamycin has been used in combination with other approved chemotherapeutic agents. Thoughevidence is available that at least in some types of neoplastic disease combination chemotherapy issuperior to single agents. the benefits and risks of such therapy have not yet been fully elucidated

HOW SUPPLIEDADRIAMYCIN “ (doxorubicin hydrochloride) for Injection is available in two sizes:10 mg-Each vial contains 10 mg of doxorubscin HCI and 50 mg of lactose U.S.P as a sterile

red-orange Iyo#{216}tilizedpowder. Packaged and supplied in 1O�vial cartons NDC 38242-874�1O50 mg-Each vial contains 50 mg of doxorubicin HCI and 250 mg of lactose U.S.P. as a sterile

red-orange lyophilized powder. Packaged and supplied in a single vial cartonNDC 38242-875-50.

‘Rudolph. R. et al: Skin Ulcers Due to Adriwnycin. Cancer 38:1087-1094. Sept.. 1976.

8740102-1/80

�.�r:I�n � Distributed by Adria Laboratories Inc., Columbus. Ohio 43215._______________Manufactured by: Farmitalia Carlo Erba SpA.. Italy.

LA�ATO9ESAC

R.vis.d January 1980

NOWAVAILABLE FROMIVES LABORATORIES

VIALS, containing 20 mg daunorubicin equivalent

ID(DAUNORUBICINHCI) for injection

FOR REMISSION INDUCTION IN ACUTENONLYMPHOCYTIC LEUKEMIA (MYELOGENOUS,

MONOCYTIC, ERYTHROID) IN ADULTS

in 1980 ives Labo�aio�’es inc

*adapfurj from Wiernik and SerpickFor Brief Summary, please seefollowing page.

Ceru bidi ne#{174}daunorubicin HCI),

a salt of an anthracyclinecytotoxic antibiotic, has beenunder clinical investigationsince 1965In the past 12 years, the Cancer and LeukemiaGroup B (CALGB) has treated 2,500 patientswith acute nonlymphocytic leukemia (ANLL)�using Cerubidine alone or in combinationwith other agents. In these and other exten-siVe studies2-� it has emerged as the singlemost effective agent in the treatment of ANLL’and is in part responsibleforthe improve-ments in complete remission rate and sur-vival time that have been achieved in patientswith ANLL�

Complete remission ratesof 40% to 50% when used as asingle agentThe table below compares the response totherapy with daunorubicin alone to that of acombination of prednisone, vincristine,6-mercaptopurine, and methotrexate (POMP).With daunorubicin a complete remissionrate of 50% was achieved in a median of 19days; with POMP, the complete remission ratewas 28% and took a median of 64 days. Add i-tionally, the median survival of responders todaunorubicin therapy was greater than thatof nonresponders.3

Complete remission ratesof 53% to 65% when combinedwith cytosine arabinosideIn one study, the CALGB achieved an overallcomplete remission rate of 53% in 208 pa-tients with ANLL-57% in patients less than60 years of age-usingthe “7 and 3” induc-tion regimen of seven consecutive days ofcytosine arabinoside and three consecutivedays of Cerubidine� With the same inductionregimen the Baltimore Cancer ResearchCenter achieved a complete remission rateof 63% in 30 patients and concluded thatthis combination “� . . achieves remissionmore rapidly and effectively than anywe pre-viously studied�’4The UCLA Acute LeukemiaStudy Group, using high-dose, sequential,seven-day courses of cytosine arabinoside,thioguanine, and cerubidine, achieved acomplete remission rate of 79%�

Should be administeredonly by physicianswith experience inleukemia chemotherapySevere myelosuppression occurs at thera-peutic doses. Contraindicated in patientswith preexistingdrug-induced bone marrowsuppression unless the benefit warrants therisk. Preexisting heart disease and previoustherapy with doxorubicin are cofactors ofincreased risk of daunorubicin-inducedcardiac toxicity, and the benefit to riskratio should be weighed before startingdaunorubici n.

CERUBIDINE#{174}(DAUNORUBICIN HCI) for injection

for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) in adults

WARNINGS1 . Cerubidine must be given into a rapidly flowing intravenous in-fusion. It must never be given by the intramuscular or subcuta-neous route. Severe local tissue necrosis will occur if there isextravasation during administration.2. Myocardial toxicity manifested in its most severe form by p0-tentially fatal congestive heart failure may be encountered whentotal cumulative dosage exceeds 550 mg/m2. This may occur ei-ther during therapy or several months after termination of therapy.Treatment with digitalis, diuretics, sodium restriction and bed restis indicated.3. Severe myelosuppression occurs when used in therapeuticdoses.4. It is recommended that Cerubidine be administered only byphysicians who are experienced in leukemia chemotherapy andin facilities with laboratory and supportive resources adequate tomonitor drug tolerance and protect and maintain a patient com-promised by drug toxicity. The physician and institution must becapable of responding rapidly and completely to severe hemor-rhagic conditions, and/or overwhelming infection.5. Dosage should be reduced in patients with impaired hepatic orrenal functton.

Warnings: Therapy should not be started in patients with preexistingdrug-induced bone marrow suppression unless the benefit warrantsthe risk. Preexisting heart disease and previous therapy with doxoru-bicin increase the risk of Cerubidine-induced cardiac toxicity; thebenefit to risk ratio should be weighed before starting Cerubidine insuch patients.

Bone Marrow-Cerubidine is a potent bone marrow suppressant.Suppression will occur in all patients given a therapeutic dose of thisdrug.

Cardiac Effects-At total cumulative doses less than 550 mg/m2,acute congestive heart failure is seldom encountered, but rare in-stances of pericarditis-myocarditis, not dose-related, have been re-ported; at cumulative doses exceeding 550 mg/m2, the incidence ofdrug-induced congestive heart failure increases. This limit appearslower, 400 mg/m2, in patients who received radiation therapy that en-compassed the heart; the total dose administered should also takeinto account any previous or concomitant therapy with other poten-tially cardiotoxic agents or related compounds such as doxorubicin.Although there is no reliable method for predicting acute congestiveheart failure, certain changes in the electrocardiogram and a de-crease in the systolic ejection fraction from pretreatment baselinemay help to recognize those patients at greatest risk; a decreaseequal to or greater than 30% in limb lead ORS voltage has been as-sociated with a significant risk of drug-induced cardiomyopathy. Anelectrocardiogram and/or determination of systolic ejection fractionshould be performed before each course of Cerubidine; if one ofthese predictive parameters occurs, the benefit of continued therapymust be weighed against the risk of producing cardiac damage. Earlyclinical diagnosis of drug-induced congestive heart failure appears tobe essential for successful treatment with digitalis, diuretics, sodiumrestriction, and bed rest.

Evaluation of Hepatic and Renal Function-Since significant hepaticor renal impairment can enhance the toxicity of the recommendeddoses of Cerubidine, hepatic and renal functions should be evalu-ated with conventional clinical laboratory tests prior to administration.

Pregnancy-Cerubidine can cause fetal harm when administered to

a pregnant woman; patients using this drug during pregnancy, or whobecome pregnant while taking this drug, should be apprised of thepotential hazard to the fetus.

Extravasation atlnjection Site-Extravasation of Cerubidine at thesite of intravenous administration can cause severe local tissuenecrosis.

Precautions: Therapy with Cerubidine requires close observationof the patient and extensive chemical and laboratory monitoring.Hyperuricemia secondary to rapid lysis of leukemic cells may beinduced; blood uric acid levels should be monitored and appropriatetherapy initiated if hyperuricemia develops. Appropriate measuresmust be taken to control any systemic infection before beginningtherapy with Cerubidine. Therapy with Cerubidine may transientlyimpart a red coloration to the urine , and patients should be advisedto expect this.

Pregnancy Category D: See Warnings Section.

Adverse Reactions : Dose-limiting toxicity includes myelosuppres-sion and cardiotoxicity (see Warnings). Other reactions include: Cu-taneous-Reversible alopecia in most patients. Gastrointestinal-Acute nausea and vomiting, usually mild, and antiemetic therapymay be of some help; mucositis, three to seven days after adminis-tration; diarrhea. Local- If extravasation occurs during administra-tion, tissue necrosis can result atthe site. Acute Reactions-Fever,chills, skin rash.

Consult direction circular before prescribing.

References1 . Data on file, Ives Laboratories.2. Freireich EJ, Keating MJ, Gehan EA, et al: Therapy of acute mye-logenous leukemia. Cancer 42 (August suppl): 874-882, 1978.3, Wiernik PH, Serpick AA: A randomized clinical trial of daunorubi-cm and a combination of prednisone, vincristine, 6-mercaptopurine,and methotrexate in adult acute nonlymphocytic leukemia. CancerRes 32:2023-2026, 1972.4. Chang P. Wiernik PH, Lichtenfeld JL, Schiffer CA: Levamisole (L),cytosine arabinoside (Ara-C), and daunorubicin (DNR) inductiontherapy of adult acute nonlymphocytic leukemia (ANLL), abstracted(C-254). Proc AACR ASCO 19:370, 1978.5. Gale RP, Cline MJ: High remission-induction rate in acute myeloidleukaemia. Lancet 1:497-499, 1977.

IVES LABORATORIES INC.New York, NY 10017DEDICATED TOIMPROVING THE QUALITY OF LIFE THROUGH MEDICINE’

BLOOD-THE JOURNAL OF THE ASH xxi

ADJUVANTRAPYOF

CANCER HEdited by STEPHEN E. JONES, M.D.

and SYDNEY E. SALMON, M.D.

Among the important developments pre-

sented ar the favorable results in adju-

vant chemotherapy in early breast cancer

which were clearly confirmed by many stud-

ies and suggest efficacy in postmenopausal

as well as premenopausal women. Other

papers reflect the progress made and the

ongoing work in the areas of; hematologic

malignancies, genitourinary tumors, osteo-

sarcoma, childhood tumors, head and neck,

thyroid, and brain tumors, ovarian cancer,

melanoma and soft tissue sarcoma, lung

cancer, and gastrointestinal tumors. This

volume comprises the edited proceedings

of the Second International Conference on

the Adjuvant Therapy of Cancer, held in

March 1979.1979, 624 pp., ISBN.’ 0-8089-1213-5

GS 0074

GRUNE & STRATTONA Subsidiary of llarcoiirt Briar-c’ Jot’anoticli, Pi,bljsI,r’,-.�

I I I FIFTH AVENUE, NEW YORK, N.Y. 1000324-28 OVAL ROAD, LONDON NWI 7DX

.‘

Inte ronEditor-in-Chief: ION GRESSER

Board of Editors: KARl CANTELL,EDWARD DeMAEYER, MAURICE LANDY,

MICHEL REVEL, and JAN VILCEKVolume 1,

CONTENTS: K. Cantell, WHY IS INTERFERON NOT

IN CLINICAL USE TODAY? Introduction. How do

you make Large Quantities of Human Interferon?Purification and Safety. Pharmacokinetics andTreatment Schedules. Accumulating Clinical Data.How can Interferon be used Most Effectively? Whyis Interferon not in Clinical Use Today? Will Inter-

feron be in Clinical Use Tomorrow? W. E. StewartII, VARIED BIOLOGIC EFFECTS OF INTERFERON.

Introductory and Historical Aspects. Some of theThings Interferon Can do. Defining Interferon. R. M.

Friedman, INTERFERONS: INTERACTIONS WITH

CELL SURFACES. Introduction. The Cell Surfacein the Establishment of Antiviral State. Alterationsin the Plasma Membrane as a Consequence of In-terferon Binding. Discussion. E. De Maeyer and

J. Do Maeyer-Guignard, CONSIDERATIONS ON

MOUSE GENES INFLUENCING INTERFERON PRO-

DUCTION AND ACTION. Introduction. What are theIf Loci? In Depth Study of If-i. Evidence for GenesInfluencing the Interaction of Interferon and the

Immune System. Scope for Future Research. M.

Revel, MOLECULAR MECHANISMS INVOLVED INTHE ANTIVIRAL EFFECTS OF INTERFERON. Stud-

ies of the Antiviral Effect of Interferon in Intact

Cells: the SV4O System. Studies in Cell-free Sys-tems: Interferon-Induced Translation Regulation.

The Interferon Receptor and Early Events in Inter-

feron’s Action.

References appear at the end of each chapter.1980, 176 pp., $23.00

ISBN: 0-12-302250-9

Send payment with order and save postage and handlingcharge.

Prices are subject to change without notice.

ACADEMIC PRESS, INC.A Subsidiary of Harcourt Brace Jovanovich, Publishers

111 FIFTH AVENUE, NEW YORK, N.Y. 1000324-28 OVAL ROAD, LONDON NW1 7DX

GS 0100

.4

for automatic friarvesting of specificcomponents ina continuous flow

sealless systemThe CS-3000TM Blood Cell Separator represents asignificant advance in blood processing. It allowsautomatic collection of blood components fortherapeutic or research purposes.

A built-in microcomputer controls each operationas well as provides continuous monitoring ofinstrument safety alarms and automaticadjustment of blood pumps and centrifuge tomaximize the efficiency of component collection.

Designed to protect both donor and patientR Continuous flow, closed system without rotating sealsreduces the threat of contamination or leaks duringblood processing.$ Programmed automatic instrument shutdown underabnormal operating conditions further assuresdonor/patient safety.

. Low extracorporeal volume reduces risk of problems

associated with donor hypovolemia.

Designed to improve operator convenienceand efficiencyU Automated collection procedures assure highcomponent yields while minimizing operator time.

. Simple to set up and operate.

. Mobile unit may be used in donor room or atpatient’s bedside.

(� Copyright 1980 Traveno� Laboratories. Inc All rights reserved

New from Fenwal Laboratories“.1

BLOOD CELLSEPARATOR

For fully automatic, high yield harvestingof blood components

1 The ready-to-use.disposable

Apheresis KIt fIts easilyinto the CS-30001MSeparator. Themonitor assemblyshown here containsseveral safety andalarm monitorIngsystems.

4 During theprocedure. the

monitor assembly andmicrocomputercontinuously check forabnormal conditions.

2 The collection andseparation

containers, which arepart of the ApheresisKit, are placed in theirrespective holders. Thesystem is automaticallyprimed and the properfunction of variousmonitors and alarmsystems is verified priorto each procedure.

5 The continuous flowseparation

procedure is relativelyrapid. As an example,the time required toharvest a therapeuticdose of plateletsranges from 90 to 120minutes

1) Blood processing is�J activated by thepress of a button. Eachcollection procedure iscarried out undermicrocomputer control.A manual mode ofoperation is availablewhen desired.

6 At the completion ofthe procedure, the

collection container isremoved from theApheresis Kit. Thecollected componentmay then be stored oradministered to therecipient directly fromthe collection container.

Brief StatementThere are no known contraindications for use of the �S�3OOO’� Blood Cell Separator to har�

vest blood components Platelets should not be harvested for subsequent transfusion if the

donor has recently ingested aspirin or other drugs known to adversely affect platelet functionApheresis procedures in other than normal healthy donors should be undertaken only

under supervision of a qualified physician who has evaluated each patient and prescribedthat use of the instrument is necessary:�: FENWAL LABORATORIES

]�, DlVI�ON OFTRAVENOL LABORATORIES, INC.DEERFIELD. ILLINOIS. USA 60015

CELLULAR and

MOLECULAR REGULATIONof HEMOGLOBIN SWITCHING

Edited byG. STAMATOYANNOPOLOUS, M.D.

and ARTHUR W. NIENHUIS, M.D.

Based on the proceedings of a conference heldon Hemoglobin S�t’itc’1ziiig in Seattle, June 1978

SECTIONS: DEVELOPMENTAL HEMO-

GLOBINS IN MAN AND ANIMAL MOD-

ELS. Human Fetal Hemoglobin. Physiology of

Hemoglobin Switching. Hemoglobins in Early

Development. HEMOGLOBIN SWITCHING

AND ERYTHROID CELL DIFFERENTIA-

TION. Regulation of Erythropoiesis. Hemo-

globin Switching in Culture. Commitment and

Biochemical Differentiation of Erythroid Cells.

MOLECULAR BIOLOGY OF HEMOGLO-

BIN SWITCHING. Organization of Globin

Genes. Globin mRNA Structure. Metabolism

of Globin mRNA. Control of Globin Gene

Expression./979, 797 pp.. I.SBN 0-8089-0611-7

GRUNE & STRATTONA .‘ri,b.siilia,� of IIa,uoiirt 1lI.(l(�(’ JOI1l�1OI’i(ll , Piibli.sIie,’.s

111 FIFTH AVENUE. NEWYORK. N.Y. 10003

24-28 OVAL ROAD. LONDON NWI 71)X

GS 0041

xxx BLOOD-THE JOURNAL OF THE ASH

PROGRESS IN HEMO STASISAND THROMBOSIS

VOLUME 4

Edited by THEODORE H. SPAET, M.D.

Volume 4 presents the first intensive discussion ofa rational approach to gastrointestinal bleedingand its management, an examination of variousfunctions of platelet contractile proteins not hith-erto characterized systematically, and an explana-tion of how membrane properties influence plateletfunction. Other highlights are thorough discussionsof the role of prostaglandins in platelet functionand of transport through endothelial cells.

CONTENTS: M. Frojmovic, Rheo-optical Studiesof Platelet Structure and Function. G. D. Wilner,The Molecular Basis for Measurement of Circu-lating Fibrinogen Derivatives. S. I. Shattil andR. A . Cooper, The Role of Membrane Lipid Corn-position, Organization, and Fluidity in HumanPlatelet Function. A . P. Kaplan, Initiation of theIntrinsic Coagulation and Fibrinolytic Pathwaysof Man: The Role of Surfaces, Hageman Factor,Prekallikrein, High Molecular Weight Kininogen,and Factor XI. I. M. Gerrard and J. G. White,Prostaglandins and Thromboxanes:” Middle Men”Modulating Platelet Function in Hemostasis andThrombosis. H. Chien, Transport Across ArterialEndothelium. D. A. Gilbert et al., The Nonsurg-ical Management of Acute Nonvariceal UpperGastrointestinal Bleeding. R. I. Friedman andE. R. Burns, The Role of Platelets in the Prolif-erative Response of the Injured Artery. L. Harker,Platelet Survival. T. Pollard and R. F. Adeistein,Platelet Contractile Proteins. S. F. Shapiro, Pro-thrombin.

1978, 432 pp., iSBN: 0-8089-1096-5

GS 0076

GRUNE & STRATTONA Subsidiary of Harcourt Brace Jovanovich, Publishers

I I1 FIFTH AVENUE, NEW YORK, N.Y. 1000324-28 OVAL ROAD, LONDON NW! 7DX

Immuneul rs

Tran r FactorEdited by AMANULLAH KHAN, CHARLES H. KIRKPATRICK and N. 0. HILL

The Third International Symposium on Transfer Factor, held onOctober 12-14, 1978, at Wadley Institute of Molecular Medicine,Dallas, Texas.

Serving as a forum for investigators interested in transfer factor topresent and discuss their work, the meeting consisted of full lengthpresentations and a poster session. Ample time was provided fordiscussion following each paper and general discussion at the end ofeach session. The papers submitted for the meeting, the postersessions, and the discussions are included in this volume.

Transfer factor, a dialyzable component of Ieukocyte lysates, hasbeen shown to affect cellular immunity in many in vivo and in vitrotests. This substance has proven useful in immunodeficiencydiseases, viral illnesses, fungal and parasitic diseases. There arealso reports of its usefulness in malignant diseases. The spectrum ofclinical trials ranges from phase I studies to randomized controlledtrials. This volume by leading researchers presents the state of theart in testing for transfer factor and its various components,preparation, purification, and characterization of the molecules,animal models for testing transfer factor activity, and clinicalinvestigations.1979, 750 pp. ISBN: 0-12-406060-9

AP 7854

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BLOOD-THE JOURNAL OF THE ASH xxxiii

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INFORMATION FOR CONTRIBUTORS

SUBMITTING THE MANUSCRIPT

BLOOD, The Journal of the American Society of Hematology,

provides an international forum for the publication of original

articles, in English, describing basic laboratory and clinical inves-

tigations encompassed in the broad discipline of hematology.

The scope of the journal covers all aspects of hematology,

including disorders of leukocytes, both benign and malignant,

erythrocytes, platelets, hemostatic mechanisms, and immunolo-

gy, as well as major developments in clinical laboratory diagnosis

and blood banking.

Manuscripts are accepted for consideration on the condition

that they are contributed solely to BLOOD. No substantial part of

a paper may have been or may be published elsewhere, except

for an abstract of 500 words or less. Manuscripts will be

critically reviewed by the Editor or an Associate Editor with

appropriate independent referees drawn from the Editorial Board

and other experts. Authors may recommend appropriate review-

ers or may indicate individuals they wish excluded from the

review process. Insofar as possible the Editor and Associate

Editors will incorporate these suggestions in the review process.

Acceptance of papers for publication is based upon the originality

of the observation or investigation, the quality of the work

described, and the clarity of the presentation. Papers will ordi-

narily be published in the order in which they are finally accepted

for publication and not in the order of submission.

Acknowledgments to other investigators for advice, assist-

ance, and data must be substantiated by written authorization to

the Editor-in-Chief specifically granting permission to the authors

for such citations.

Concise Reports: BLOOD will consider for rapid editorial

review and decision concise reports of original investigations of

scientific importance within the broad discipline of hematology in

order to speed up the publication process for accepted manu-

scripts that meet the criteria for Concise Reports. Such manu-

scripts must represent original and definitive studies and include

adequate description of experimental methods, documentation

of findings, and references to the literature. The Editors will

provide decisions on such manuscripts within three weeks of

receipt at the BLOOD Office. These decisions will not be

accompanied by detailed reviewers’ comments such as are

returned with manuscripts handled in the ordinary manner.

Papers deemed not suitable for rapid publication as Concise

Reports may be resubmitted for consideration as regular manu-

scripts. Request for consideration as a Concise Report should be

made in the author’s covering letter upon submission. Concise

Reports cannot exceed 1 0 typed pages, including tables,

figures, and references (count 2 graphs or 1 photomicrograph as

a typed page). Authors must accept the responsibility of

conforming to the instructions in ‘ ‘Information for Contribu-

tors. �‘

Letters to the Editor: Letters to the Editor are welcomed

and will be published if appropriate. They should be typewritten,

double spaced, and generally, should not be more than two

typewritten pages in length.

Editorials, Brief Reviews: Editorials and Brief Reviews may

be solicited by the Editors, and may be submitted for considera-

tion without solicitation. These manuscripts must be prepared in

a manner appropriate for any other papers and will be reviewed

as are original articles submitted for consideration.

Articles, editorials, letters to the editor, and other text mate-

rial in BLOOD represent the opinions of the authors and do not

reflect the opinions of the American Society of Hematology, the

publisher, or the institution with which the author is affiliated,unless the contrary is clearly specified.

In order to comply with the requirements of the insurance

carrier, authors of accepted manuscripts and letters will be

requested to provide the following signed statement: ‘ ‘The

writer/author represents and warrants that his/her part of the

work as submitted will in no way violate any copyright, or any

other right, and will contain nothing libelous or otherwise

unlawful.”

Submit papers, with a $50.00 check, money order, or

institutional purchase order to cover the cost of manuscript

handling, to:

Dr. Paul A. Marks, Editor

BLOOD

Columbia University College of Physicians

and Surgeons

701 West 168 Street

NewYork, N.Y. 10032

Receipt of a manuscript will be acknowledged by a card

bearing the name and address of the Editor or Associate Editor

who is assigned responsibility for the review process. All further

correspondence concerning the manuscript should be addressed

to the responsible Editor or Associate Editor.

Papers reporting human experimentation will be reviewed in

accordance with the precepts established by the Helsinki Decla-

ration. Copies of this declaration may be obtained by writing to

the American Medical Association, 535 North Dearborn Street,

Chicago, Ill. 606 10. Such papers must include a statement that

the human investigations were performed after approval by a

local Human Investigations Committee and in accord with an

assurance filed with and approved by the Department of Health,

Education, and Welfare where appropriate.

All manuscripts dealing with recombinant DNA research must

include a description of the physical and biologic containment

procedures practiced to aid and forewarn others who might

consider repeating the work, in accord with the National Insti-

tutes of Health Guidelines for Research Involving Recombinant

DNA Molecules.

Authors submitting a manuscript do so on the understanding

that if it is accepted for publication, copyright in the article,

including the right to reproduce the article in all forms and media,

shall be assigned exclusively to the Publisher. The Publisher will

not refuse any reasonable request by the author for permission to

reproduce any of his or her contributions to the journal.

xxxiv BLOOD-THE JOURNAL OF THE ASH

(Continued from preceding page)

PREPARING THE MANUSCRIPT

The original and two complete copies of the manuscript must

be submitted. Manuscripts must be typewritten, double or triple

spaced on good quality 8’/2-by-1 1-inch white paper with margins

of at least one inch. Please do not use erasable bond.

The first page of the manuscript should contain the following

information: ( 1 ) title of the paper; (2) authors’ names; (3) name

of institution in which work was done; (4) acknowledgments for

research support; (5) name and address of the author to whom

communications regarding the manuscript should be directed;

(6) a short title, not to exceed 40 characters (including spaces),

to be used as a running title.

The second page should contain an abstract of 200 words or

less, summarizing the reason for the study, the methods used,

the results, and the major conclusions. Do not include a

summary at the end of the paper. The remainder of the paper

should be written as concisely as possible.

PREPARING ILLUSTRATIONS

AND TABLES

Tables and illustrations must be cited in order in the text using

arabic numerals. All line drawings should be submitted as clear,

glossy, black and white photographs. Legible copies may be

used with the duplicate manuscripts. Photomicrographs and

other photographic illustrations must be submitted in duplicate;

copies are not acceptable. Legends for illustrations should be

typewritten, double spaced, on a separate sheet, and included at

the end of the manuscript. A legend must accompany each

illustration. Contributors will pay all charges involved in process-

ing and printing of color photographs.

Figures, especially charts, graphs, and line drawings, are

generally reduced in size for publication (consult a recent issue of

the journal for examples). To maintain legibility it is important

that all numbers, letters, and symbols be large enough originally

so that when reduced they will remain at least Y,2 inch (2 mm)

high (i.e. , approximately the same size as used for this line of

type). Figures not properly prepared will have to be returned to

the contributor for revision or will be relettered by the printer and

the cost charged to the contributor.

Each table should be typed on a separate sheet and appro-

priately numbered. Legends should be typed on the same sheets

as the tables.

REFERENCES

References should be compiled at the end of the article

according to the order of citation in the text. They should be

typewritten, double spaced under the heading REFERENCES.

Abbreviations for titles of medical periodicals should conform to

those used in the latest edition of Index Medicus. (A � ‘List of

Journals Indexed in Index Medicus’ ‘ -with abbreviations-is

obtainable from the Superintendent of Documents, U . S. Govern-

ment Printing Office, Washington, D.C. 20402, at a modest

charge.) References to abstracts and Letters to Editors must be

identified as such. Inclusive page numbers of references are not

required.

Personal communications and references to publications in

press by authors other than those submitting the paper must be

substantiated by a letter from the investigator(s) concerned

confirming the data or observations and granting the authors

permission to cite the material.

EXAMPLES OF REFERENCES

Journal article, one author:

1 . Beutler E: The effect of methemoglobin formation on

sickle cell disease. J Clin Invest 40: 1 856, 1961

Journal article, two or more authors:

2. Karpatkin 5, Charmatz A: Heterogeneity of human platel-

ets. Ill. Glycogen metabolism in platelets of different sizes. Br J

Haematol 19:135, 1970

Journal article, in press:

3. O’Malley JE, Eisenberg L: The hyperkinetic syndrome.

Semin Psychiatry (in press)

Complete book:

4. Lillie RD: Histopathologic Technic and Practical Histo-

chemistry (ed 3). New York, Blakiston, 1965, p 39

Chapter of book:

5. Moore G, Minowada J: Human hemopoietic cell lines: A

progress report, in Fames P (ed): Hemic Cells In Vitro, vol 4.

Baltimore, Williams & Wilkins, 1969, p 100

Chapter of book that is part of published meeting:

6. Natvig JB, Kunkel HG, Gedde-DahI T Jr: Genetic studies of

the heavy chain sub-groups of G 9lobulin, in Killander J (ed):

Gamma Globulins, Proceedings of the Third Nobel Symposium.

New York, Wiley, 1967

Chapter of book that is part of unpublished meeting:

7. Polliak A: A morphologic study of the lymphoproliferative

lesions induced by excess vitamin A. First Meeting, European

Division, International Society of Hematology, Milan, 197 1 , p

181

Abstract:

8. Curnutte JT, Karnovsky ML, Babior BM: Manganese-

dependent NADPH oxidation by a particulate preparation from

guinea pig granulocytes: An alternative interpretation. Clin Res

23:271A, 1975 (Abstr)

Letter to the Editor:

9. Seeler RA: Sickle cell anemia monthly variations. Blood

47:879, 1976 (Letter)

PROOFREADING

Contributors are provided with galley proofs and are asked to

proofread them for typesetting errors. Important changes in data

are allowed, but authors will be charged for excessive alterations

in proof. Galley proofs should be returned within 48 hours.

REPRINTS

Reprints of articles can be furnished to contributors when

ordered in advance of publication. An order form, showing cost

of reprints, is sent with proofs. Individuals wishing to obtain

reprints of an article that appeared in BLOOD can do so by

contacting the author at the address given in the journal.

ANNOUNCEMENTS

Announcements of meetings, conferences, and the like that

are of interest to the readership of BLOOD should be sent to the

Editor at least three months before the first day of the month of

issue. These items should be as concise as possible. When

considered appropriate, they will be published as promptly as

possible, subject to the availability of space in the journal.