Document g2maMVOXj5YzN9KGRYZ3aDa19

X,- relative risk of 1.1 of testicular cancer for Army troops and a 1.3 risk for Marines who served in Vietnam. Other mortality studies conducted during the mid 1980s have seen no dif ference in testicular cancer deaths in Vietnam veterans or have not looked at the tumors. Hayes said some of those studies simply did not address the issue of testicular cancer when they reported their findings. A 1988 study by the Cen ters for Disease Control "saw an unex plained but significant decrease" in sperm motility and concentration.of "normal sperm cells" in Vietnam war veterans. Richard L. Schilsky, M.D., of th University of Chicago Medical Center wrote in an August 16,1989, editorial in this Journal that "The great majority of patients with testicular cancer also had diminished sperm production before therapy is initiated." He said that biop sies of the contralateral, non-tumor bearing testis found abnormalities including "hyalinzed tubules, spermatogenic arrest, absence of germinal epithelium, and carcinoma in situ," leading Schilsky to speculate that a common genetic or environmental fac tor may be responsible. The Armed Forces Institute of Pa thology necropsy reports on the dogs provided data for the Hayes study. AFIP's files are a unique resource for epidemiologists, Hayes said. Most of the dogs were German Shep herds, entered the military under 3 years of age, and had to pass rigorous physical examination. Each of the dogs was tattooed and permanent health re cords kept. When a dog died, regard less of circumstances of death or duty location, a necropsy was performed by a veterinarian and a standardized set of tissue specimens and major organs were sent to the Armed Forces Insti tute of Pathology in Washington, DC. --By FrancisX. Mahaney, Jr; Tamoxifen With or Without Chemotherapy? The American Society of Clinical Oncology meeting in Washington last month was the forum for results from two major studies of adjuvant therapy for node-positive breast cancer patients which, in effect, yielded contradictory results. The researchers involved, how ever, agreed that the studies couldn't re ally be compared in the first place. Chemo Plus A regimen of chemotherapy and tamoxifen was found far superior to tamoxifen alone in a study headed by Bernard Fisher, M.D., director of the National Surgical Adjuvant Breast and Bowel Project and professor of surgery at the University of Pittsburgh. "Patients who received chemother apy in combination with hormone ther apy had significantly increased disease-free and distant disease-free survival and significantly reduced mor- Dr. Bernard Fisher tality rates when compared with women who received the standard treatment of hormone therapy alone," explained Fisher. More than 1,100 women over 50 years of age with "tamoxifen-respon sive" tumors were randomized to tamoxifen alone, or Adriamycin, cyclo phosphamide, and tamoxifen. The group receiving ACT had a 50% reduc tion in mortality and a 41% reduction in treatment failure compared to those receiving tamoxifen alone. "Clearly, postmenopausal breast . cancer patients who are node-positive ' will have a greater chance of survival and less chance of disease recurrence if they are given a chemotherapy regime in addition to tamoxifen," said Fisher. Only Tamoxifen Meanwhile, Saul E. Rivkin, M.D., of the Swedish Hospital Medical Center Tumor Institute in Seattle, presented re sults of an Intergroup trial of chemo therapy verus tamoxifen versus both where all three treatment arms were equal in efficacy. In this trial, 966 postmenopausal, node-positive, estrogen-receptor posi tive women were treated with cyclo phosphamide, methotrexate, 5-FU, vincristine, and prednisone alone, CMFVP and tamoxifen, or tamoxifen alone. "CMFVP chemotherapy alone, or in combination with tamoxifen, was not shown to prolong survival or diseasefree surrival compared to tamoxifen alone, in ER-positive, node-positive, postmenopausal breast cancer," summed Rivkin. "The study results suggest that tamoxifen is the standard against which { Voi. 82, No. 12, June 20, 1990 NEWS 100 Excess of Seminomas Observed in Vietnam Service U.S. Military Working Dogs Howard M. Hayes,* Robert E. Tarane. Harold W. Casey, David L. Huxsoll During the Vietnam W ar, US military working dogs served with their compan ion dog handlers in close proximity, sharing common exposures to w ar-re lated activity, many zoonotic infectious agents, chemical pesticides, phenoxy herbicides, and extensive use of thera peutic drugs. To gain insight into the effects of the Vietnam experience, we investigated the occurrence of neo plasms in military working dogs based on standard necropsy examination by the Armed Forces Institute of Pathol ogy. We observed that these dogs expe rienced significant elevated risks for tes ticular seminoma and, independently, testicular dysfunction. Experimental evidence shows testicular dysfunction and impaired spermatogenesis in labo ratory animals exposed to phenoxy her bicides, dioxin, or tetracycline, an anti biotic used extensively in military working dogs in Vietnam. Because an unexplained significant decrease in sperm quality in Vietnam veterans has been observed by the Centers for Dis ease Control, further research is w ar ranted if we are to clarify military ser vice in Vietnam as a risk factor for testicular dysfunction. The testis should be made a priority site in the study of Vietnam experience-related cancers. [J Natl Cancer Inst 82:1042-1046, 1990] US military working dogs (MWD) proved to be sentinels for the presence of zoonotic infectious agents in their military dog handlers in southeast Asia (/.2). Be cause the dog has been demonstrated to be a useful indicator of carcinogenic risk to humans (J-5). examination of the occur rence of neoplasia in MWDs serving in southeast Asia may be useful in an assess ment of whether service in Vietnam led to increased cancer risk in humans. To deter mine if service in that country led to increased cancer risk in dogs, we com pared their experience with that of MWDs that served in the continental United States (CONUS) during the same time. Materials and Methods During the Vietnam conflict. MWDs were purchased by the US government from private citizens. Most of these ani mals were phenotypic German shepherds, although occasionally other breeds were obtained for special purposes. Each dog had to be 1 to 3 years of age. have suitable body conformation, and pass a rigorous physical and medical examination (6). About 91% of the MWDs were intact males. Each animal accepted for the MWD program was tattooed with a unique iden tity number which, with permanent ad ministrative and health records, accompa nied the MWD throughout its duty (7). Most MWDs either worked as scouts with forward elements or as sentries in security units at fixed installations (7,8). Each MWD was assigned to a military handler who was responsible for its imme diate care, feeding with standard rations, and day-to-day evaluation of perfor mance. Outpatient care was provided by a trained veterinary technician, who also updated the medical records; serious med ical problems were referred to a military veterinarian (9). When an MWD died, regardless of the circumstances of death or the duty loca tion. a necropsy was performed by a vet erinarian, and a standardized set of tissue specimens and major organs was submit ted to the Armed Forces Institute of Pa thology (AFIP) in Washington, D.C. for histopathologic evaluation (10). Evalua tions were made by at least two veterinary pathologists, including one who was board certified; final necropsy reports were maintained for historical purposes. One co-author (Casey) personally reviewed or supervised over 90% of all the histologic diagnoses considered in this study. Each necropsy report contains the MWD's breed (99% were German shepherds), tat too number, name, age, sex. date and circumstances of death, and duty location at time of death (11). Permanent military service records, which could be used to identify all MWDs with Vietnam service, are not available for computer access. Thus we could identify unequivocally as dogs with Vietnam ser vice only those animals listed on necropsy reports as having died in Vietnam, and 19` additional MWDs identified from military correspondence as having been returned alive from Vietnam in 1971-1973. usually to the United Slates. Sixty-four of these 199 dogs have been described in detail (2). Although military dog handlers usually rotated out of Vietnam after about 1year of service, the MWD typically remained to be teamed with a new handler. This pro cess. which involved evaluation and pos sibly retraining, often took place in Oki nawa. A considerable number of Vietnam MWDs undergoing rvaluation did not perform at acceptable levels and were eu thanized. Thus many MWDs with Viet nam service were reported on the AFIP records as having died in Okinawa. In other Asian duty stations (e.g., Japan, Korea, and Thailand), new dog handlers were usually united with their military dogs "in-country," thereby minimizing the possible diversion of MWDs to Vietnam and vice versa. Our analysis was restricted to the results of necropsies conducted on MWDs 3 years of age and older who were identified by a complete tattoo number. The AFIP records w-ere searched for necropsy reports of all such MWDs that died in CONUS, Vietnam. Okinawa. Japan, Korea, or Thailand from 1968, the first year of com plete data available for study, through 1973. Identified were 1,167 MWDs with known Vietnam service, 437 that died in Okinawa and thus may have served in Received March I, 1990: revised April 4. 1990: accepted April 11. 1990. H M. Hayes, R. E. Tarone. Epidemiology and Biostatistics Program. Division of Cancer Etiology . National Cancer Institute. Bethesda. Md. H. W. Casey, Department of Veterinary Pathol ogy. School of Veterinary Medicine. Louisiana State University. Baton Rouge, La. D. L. Huxsoll. U.S. Army Medical Research Institute of Infectious Diseases. Fort Detrick. Fred erick. Md. We thank L. R. Townsend and J. Manus for assistance in data verification; C. F. Conroy. S. V. James. J. M. Lyday. G. P. Wilson. J. S. Walker, and H. L. Hamby for background data; and M. A Tucker. P. S. Hartge, B. McKnight. and P. H. Gibb for review of the manuscript. 'Correspondenceto: Howard M. Hayes. D.V.M., Environmental Epidemiology Branch. Executive Plaza North. Rm 443. National Institutes of Health. Bethesda. MD 20892. 1042 Journal of the National Cancer Institute Vietnam. 483 that died in either Japan. Korea, or Thailand and probably did not see service in Vietnam, and 791 that died in CONUS and had no known Vietnam service. Of the 199 Vietnam veteran MWDs known to have left Vietnam alive. 18 were identified in AF1P records as MWDs dying in CONUS or elsewhere between 1971 and 1973: these IS were included in the Vietnam service cohort. We computed the prevalence of neo plasms at necropsy for each group and compared the prevalence rates from Asian duty stations with those from CONUS. Conditional maximum likelihood esti mates of prevalence odds ratio (OR) were calculated, with associated exact 95% confidence intervals (Cl), and adjusted for age and sex (12). Generally, the relation ship between rates for tumor incidence and prevalence at necropsy for occult tumors is not a simple one (13). For nonlethal tu mors such as seminomas in the dog. how ever. there is a direct relationship between incidence and prevalence rates (13), so that elevated prevalence ORs indicate ele vated relative risks for tumor incidence. Results There were no significant differences in the occurrence of tumors in general, ma lignant neoplasms of any cell type, carci nomas of any site, soft tissue sarcomas, or malignant lymphomas in any of the duty locations, compared with the CONUS ref erent MWDs (table 1). No present evi dence indicates that service in Vietnam led to increased risk in MWDs for soft tissue sarcoma or lymphoma, cancers for w'hich herbicide exposure has been proposed to be a risk factor in Vietnam veterans. How ever. statistically significant elevations in ORs w'ere evident for all testicular tumors combined and for testicular seminomas among MWDs with known Vietnam ser vice and those that died in Okinawa (table I). To corroborate or refute the excess rel ative risk for testicular seminoma among MWDs with known Vietnam service dy ing between 1968 and 1973, we searched ARP records through 1978 (the last year complete data were available for this study) for necropsy results about (hose Vietnam veteran MWDs known to have left Vietnam alive. Identified were 96 un neutered males that died between 1974 and 1978. With the same analytic method and using the necropsy reports of 682 CONUS MWDs without known Vietnam service dying in the period 1974-1978 as the standard (OR = 1). we observed the 96 Vietnam veteran MWDs to have a signifi cant excess risk for seminoma, which sup ported the findings in the earlier period. The incremental ORs by age for seminoma in Vietnam veteran MWDs are presented for both periods in table 2. Combined analysis of both cohorts, adjusted for age and time, gives an overall OR of 1.9 (Cl = 1.4, 2.8) for seminoma in MWDs known to have served in Vietnam. Abnormalities of spermatogenesis are common at the time of diagnosis of testis cancer in man (14,15); it has been sug gested that common genetic or envi ronmental factors are responsible for the impaired spermatogenesis and the devel opment of germ cell tumors of the testis (16.17). An examination of the AFIP necropsy records for MWDs dying be tween 1968 and 1973. excluding those with known endogenous factors related to altered spermatogenesis t i e. , those with testicular neoplasm, hypoplastic testis, or chitis or epididymitis, or those that were cryptorchid). revealed that testicular d>stuncuon (degeneration, atrophy, and'or oligospermatogenesis) was diagnosed sig nificantly more often in MWDs in Viet nam (OR = 1.7: Cl = 1.1. 2.6) and in Okinawa (OR = 2.0: Cl = 1.2.3.3). when compared with those in CONUS. Discussion No obvious sources of bias could have led to a spurious finding of increased risk of testicular dysfunction and testis tumors in Vietnam MWDs. If selection for service in Vietnam was based on factors or char acteristics that are also related to testicular tumor risk, this could have resulted in bias. Dogs were allocated to Vietnam in groups as needed, without consideration being given to characteristics of individual animals. For example, no difference was noted in the percentage of female MWDs serving in Vietnam and other duty sta tions. Bias also could have resulted if a cause of death was more common in Viet nam and Okinawa than in CONUS, and if this was positively associated with testicu- Table 1. Percent (%) frequency and prevalence OR. adjusted for age and sex, of certain neoplasms observed among necropsied MWDs by duty experience. 1968-1973* Neoplasm CONUS % OR % Vietnam OR 95% Cl Okinawa % OR 95% Cl Other Asian countriest % OR 95% Cl Tumor, any cell type Malignant tumor. any cell type Soft tissue sarcomas Carcinoma, any site Malignant lymphoma Testis tumor, any cell type Seminoma Interstitial cell tumor Sertoli cell tumor 15.2 4.7 2.0 1.6 0.8 7.34 4.7 2.1 1.4 1 13.3 1.1 1 3.3 0.9 1 0.8 0.5 1 1.5 1.2 1 04 06 1 8.5 l.8 1 6.3 l.9 1 2.0 1.7 1 1.0 1.0 (0.8. 1.4) (0.5, 1.5) 21.5 5.5 1.3 1.1 (0.2, 1.3) (0.5, 2.7) (0.2. 2.4) 2.5 1.2 2.1 1.2 0.5 0.5 (1.2. 2.7) 15.4 2.2 (1.2, 3.0) 11.2 2.6 (0.8. 3.6) 3.7 1.8 (0.4, 2.6) 2 2 1.6 (1.0, 1.9) 14.8 0.8 (0.6, 1.1) (0.7, 2.0) 7.6 1.6 (0.9. 2.6) (0.5, 2.8) (0.5, 3.1) (0.1, 2.6) (1.5, 3.4) 2.3 1.0 (0.4. 2.4) 2.5 1.4 (0.6, 3.3) 1.2 1.3 (0.4. 4.5) 5.8 0.7 (0.4. 1.2) (1.6. 4.3) (0.8, 3.9) (0.6, 4.3) 4.2 0.8 (0.4. 1.5) l.l 0.5 (0.2, 1.5) 0.9 0.6 (0.2. 2.2) Of the MWDs identified, 791, 1,167, 437, and 483 served in CONUS (known Vietnam veterans excluded), Vietnam. Okinawa, and other Asian countries, respectively. +Data for Japan, Korea, and Thailand are combined. $ Data are sex specific; for unneutered male dogs: CONUS 727, Vietnam = 1,086, Okinawa = 402. other Asian countries - 450 P < .05. REPORTS Yol. 82, No. 12, June 20, 1990 10 ] s Military Working Dogs May Be A Sentinel for Human Cancer ' Military working dogs and their han dlers who served in Vietnam faced more risks than those from the enemy, a report in this issue indicates. (See page 1042). The dogs and their handlers were ex posed in Vietnam to Agent Orange and other phenoxy herbicides, chemical pes ticides, zoonotic infections, and "the ex tensive use of therapeutic drugs" to fight off bacterial infections. For exam ple, from 1965-1970, more than 11 mil lion gallons of Agent Orange were sprayed over Vietnam during "Opera tion Ranch Hand." Until now, few studies havebeen able to quantitate the health effects of the environ mental exposures associated with the Vietnam experience. Testicular Cancer But Howard M. Hayes, D.V.M., of the National Cancer Institute, and his coauthors be lieve that military working dogs who served in Vietnam may be a "sentinel" for the related health effects of the Vietnam experience in humans. In particular, Hayes said, the dogs may be a "useful indicator of carcinogenic risk" to the Vietnam war veteran. Hayes and his colleagues re port they found a two-fold ex cess of testicular tumors and independently, testicular dys function in military working dogs who served and died in Vietnam. Of the 96 male dogs that returned in tact and alive from Vietnam and died between 1974-1978,25 were diagnosed with testicular tumors, again a two-fold excess. According to Hayes, the mili tary dogs were exposed to herbicides and insecticides for longer periods of time than their soldier handlers who were usually rotated out of Vietnam within a year. In addition, high doses of tetracy cline were given to the dogs. The antibi otic has been shown in vitro to lead to reduced sperm quality in man and dog, and testicular atrophy has been re ported in the rat and the dog, the au thors said. The anatomic development of the male genital tract, testis descent and tu nica albuginea relationship in the dog closely parallel man, Hayes said. Histo logically, canine seminomas are identi cal to the classic testicular tumors found in man, except that in the dog they are usually benign. And the Vietnam Vets An ongoing study conducted by the U.S. Air Force on Air Force veterans involved in the spraying of herbicides during Operation Ranch Hand so far has identified three cases of testicular cancer among 995 veterans in the Ranch Hand group and no testicular cancers in 1,299 Air Force controls, Hayes said. Additionally, a mortality " study of West Virginia veterans by the West Virginia Health Department in 1986 "did find a significant increase in testicular cancer deaths (3 cases observed versus 0.6 expected) among Vietnam veterans compared to Vietnamera veterans who did not serve in Viet nam," Hayes added. Another study by the Veterans Ad ministration showed a nonsignificant 1002 Journal of the National Cancer Institute Age (yr) 3-4 5-6 7-8 9-10 11-12 13-14 Table 2. Frequency of testicular seminoma, by age, observed among MWDs by necropsy period; prevalence OR, adjusted for age, for seminoma in Vietnam MWDs MWDs, 1968- 1973 MWDs, 1974-1978 CONUS Vietnam CONUS Vietnam veteran No. of No. of No. of No. of OR No. of No. of No. of No. of cases necropsies* cases necropsies* cases necropsies'* cases necropsies* 1 135 6 313 2.6 1 30 0 0 1 126 17 317 7.1* 1 51 15 II 229 28 307 2.0 10 133 4 22 17 197 17 137 1.5 48 309 14 45 3 37 0 11 0 35 148 6 24 1 30 10 3 11 0 0 Summary OR = 1.9 Summary OR = 2.0 (95% Cl = l.:!. 3.0) (95% Cl = 1.2, 3.5) *Values represent total number of necropsies of unneutered male dogs. t95% Cl excludes I. OR _ 12.5 2.7 2.51 1.1 -- lar tumor risk. No evidence was seen for such a source o f bias, and the finding o f an increased risk o f testis tumor in Vietnam veteran MWDs dying in CONUS during 1974-1978 argued against such a bias. Given the strength o f the observed associ ations and the lack o f identifiable sources of bias, we conclude that some factor(s) or exposure(s) associated with service' in Vietnam had a deleterious effect on the testes o f MWDs and led to increased tes ticular tumor risk. The anatomic development of the male genital tract, testis descent, and tunic rela tionships in the dog closely parallel that in man {18). Man and dog also share most of the same epidemiologic features regarding tumor development, although they differ in cell type frequencies and overall fre quency o f occurrence. Embryonal carci nomas and teratomas predominate in chil dren and seminomas in adults, but Sertoli cell and interstitial cell tumors, which occur in equal proportion to seminoma in the dog, are very rare in man (19). Man and dog share many o f the known risk factors, including the strong association with cryptorchism and to a lesser extent inguinal hernia (19,20), and occasional familial tendencies (21). Histologically, canine seminoma is identical to the classic seminoma seen in man, except that in the dog it is usually benign, as are most canine testis tumors (22). Because o f a significant predisposition to seminoma development in the German shepherd (23), MWDs may be a particularly sensitive sentinel for ex posure^) leading to increased seminoma risk in man. MWDs that served in Vietnam were exposed to many infectious zoonotic have been observed in laboratory animals agents (1,2) and native parasites; harsh exposed to phenoxy herbicides used exten ambient working conditions; extensive sively in Vietnam. Feeding studies with therapeutic treatment with drugs, particu rats have shown chlorinated dibenzo-p- larly tetracyclines (24); and levels of man dioxin in the testis (37). Furthermore, made chemicals not experienced by their 2,3,7,8-tetrachIorodibenzo-p-dioxin in CONUS counterparts. It is unclear whether duces arylhydrocarbon hydroxylase activ any o f these factors affected the increased ity (35) and binds to receptor proteins in risk o f testicular dysfunction and semi the rat testis (39). Investigators (40-47) noma in Vietnam MWDs, but some of the have demonstrated testicular dysfunction exposures have been demonstrated to have in six laboratory animal species after expo adverse affects on sperm quality, sper sure to phenoxy herbicides or dioxin. Al matogenesis, and testicular tissue. though some have argued that these abnor Many Vietnam MWDs received exten malities are a secondary effect due to sive treatment with tetracyclines for ehrli wasting (42,43), abnormally reduced an chiosis, a parasitism caused by a tick- drogen levels (45), decreased steroidogen borne rickettsial organism. No immunity esis (49), and enhanced lipid mobilization was imparted following recovery (25), and and peroxidation (50) have been identified thus many Vietnam MWDs received regi in rats as likely being responsible for the mens of tetracycline two or more times testicular effects rather than nutritional during one duty tour. No mention was deprivation. made o f testis pathology with canine ehr Available evidence, although limited, lichiosis prior to the Vietnam era (26,27), shows that other chemicals sprayed exten and no association was observed in this sively in Vietnam [picloram (57), a com study between ehrlichiosis and testicular ponent o f the herbicide Agent White, and dysfunction or seminoma. malathion (52-54), an insecticide used to Tetracycline is known to be strongly control mosquitos] also cause testicular absorbed by mammalian spermatozoa in atrophy and damage to the seminiferous vivo and in vitro (25,29). Testicular atro tubules in laboratory animals. MWDs in phy has been reported in the tetracycline Vietnam and Okinawa received consider exposed rat and dog (30,37), as has im able direct exposure to malathion, as they paired spermatogenesis in in vivo rat stud were regularly dipped in a 0.5% solution ies (32-34). Furthermore, in vitro expo for tick control following the Ehrlichia sure to tetracycline has led to reduced epizootic in 1968-1969 (5,55). sperm quality in man and dog (35,36). Epidemiologic studies o f cancer risk in Thus extensive tetracycline exposure may Vietnam veterans have, for the most part, have contributed to the increased risk of assessed mortality. For the most part, mor testicular problems observed in Vietnam. tality has been assessed in epidemiologic service MWDs. studies of cancer risk in Vietnam veterans. Testicular involvement and dysfunction However, high survival rates of testicular 1044 Journal of the National Cancer Institute cancer patients (56) limits the power o f mortality studies to detect increased testis cancer risk in Vietnam veterans. A mortal ity study in West Virginia did reveal a significant increase in testicular cancer deaths (three cases observed vs. 0.6 ex pected) among Vietnam veterans com pared with Vietnam-era veterans who did not serve there (57). Another such study conducted by the Veterans Administration reported nonsignificant elevated relative risks o f 1.1 for US Army personnel and 1.3 for US Marines who served in Vietnam (58). Other mortality studies have shown no difference in testicular cancer death rates between veterans of Vietnam and those who did not serve there (59,60) or have not addressed the issue (61-63). One ongoing study (64) o f cancer inci dence in Vietnam veterans is the prospec tive investigation of US Air Force veterans involved in the spraying o f herbicides in Operation Ranch Hand (RH). A recent update from the RH incidence study notes three confirmed cases of testicular cancer in 995 individuals in the RH group and none in 1,299 US Air Force controls (Michalek J: unpublished results). The recent Vietnam Experience Study o f the Centers for Disease Control that evaluated veteran physical health by medical exami nation (65) noted unexplained differences in semen quality of veterans 15+ years after leaving that country, including a de crease in sperm motility and significant decreases in sperm concentration and the average proportion o f morphologically "normal" sperm cells. Semen evaluation o f the RH cohorts, however, showed no difference in sperm count or percentage of abnormal sperm between RH members and their matched controls (66). However, a decrease in sperm concentration, al though not significant, has been reported among selected Vietnam veterans from Texas, thought to have received high ex posures to Agent Orange (67). Low sperm counts also have been reported in a selfselected group o f Vietnam veterans claim ing exposure to this herbicide (68). At present, we have no convincing evi dence that service in Vietnam led to in creased risk of testicular cancer in veter ans. However, the magnitude of the observed excess risk o f testicular semi noma and dysfunction in MWDs serving in Vietnam strongly suggests that military service in Vietnam be considered a risk factor for testicular cancer. References (/) Pryor WH. Irving GS. K undin WD. et al: A serologic survey of military personnel and dogs inThailand and South Vietnam for antibodies to arboviruses, Rickettsia isuisugamushi and Pseudomonas pseudomaUei. Am J Vet Res 33:2091-2095. 1972 (2) Alexander AD. Binn LN. E lisberg B. et al: Zoonotic infections in military scout and tracker docs in Vietnam. Infect Immun 5:745-749,^972 (J) Hleper WC. Wiley FH. Wolfe HD: Experi mental production of bladder tumors in dogs by administration of beta-naphthylamine. J Indust Hyg Toxicol 20:46-84. 1938 (4) Hayes HM Jr. Hoover RN.TaroneRE: Blad der cancer in pel dogs: A sentinel for environ mental cancer? Am J Epidemiol 114:229-233, 1981 (5) Guckman LT, Domanski LM, Maguire TG, et al: Mesothelioma in pet dogs associated with exposure of their owners to asbestos. Environ Res 32:305-313. 1983 (6) Olson RC: Physical evaluation and selection of military dogs. J Am Vet Med Assoc 159:1444-1446. 1971 (7) US Air Force Sentry Dog Program. Fed Regis ter 37:24823-24825, 1972 (fi) Ntsis RM, Ferguson JA, Walker JL, et al: Epizootiology of tropical canine pancytopenia in Southeast Asia. I Am Vet Med Assoc 158:53-63, 1971 (9) Editorial News: Medical care of Vietnam war dogs. 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Jennings PB, Moe JB, et al: Glossitis of military working dogs in South Misset, Moshe Itzhaki, Ren Vietnam: History and clinical characteristics. J ,Am Vet Med Assoc 163:272-274,1973 Adam, Grard Milano Bernard (56) Fraley EE. Lange PH, Kennedy BJ: Germ Hecquet, Georges Math cell testicular cancer in adults (second of two parts). N Engl J Med 301:1420-1426,1979 (57) Bailey C, Baron RC, Bosanac E, et al: West Virginia Vietnam Era Veteran Mortality Study, The toxic effects and tissue uptake of West Virginia Residents 1968-1983, Prelimi nary Report. Charleston, WV: West Virginia Health Dept. 1986. p 23 both cisplatin and oxaliplatin-- [(17?, 2/?)-l,2-cycIohexanediam ine-?V,iV'] (58) Breslin P. Kang HK, Lee Y. et al: Propor [oxalato(2-)-Oi O']platinum-- were pre tionate mortality study of US Army and US Marine Corps veterans of the Vietnam War. J Occup Med 30:412-419,1988 (59) Anderson HA, Hanrahan LP, Jensen M, viously shown to vary similarly accord ing to dosing time in mice. A 4-hour infusion of cisplatin resulted in fewer et al: Wisconsin Vietnam Veteran Mortality Study. Madison. WI: Wisconsin Div Health, 1985 (60) C enters for Disease Control: The Centers side effects and allowed administration of higher doses at 16 hours than at 4 hours in patients with cancer. W e hy for Disease Control Vietnam Experience Study: Postservice Mortality Among Vietnam Veter ans. Atlanta. GA: DHHS. 1987, p 43 (6!) Kogan MD. Clapp RW: Mortality Among Vietnam Veterans in Massachusetts. 1972- pothesized that the continuous venous infusion of oxaliplatin for 5 days would be less toxic and would deliver a higher dose to the patient if the drug were infused at a circadian rhythm-modu lated rate (peak at 16 hr; schedule B) rather than at a constant rate (schedule* A). We tested this hypothesis in a ran domized phase I trial. We escalated the dose of oxaliplatin to the patient by 25 mg/m2 per course. Courses were re peated every 3 weeks. An external, mul tichannel, progranimable-in-tinic pump was used for the infusions. Toxicity was assessable for 94 courses in 23 patients (12 patients with breast carcinoma, nine with hepatocellular carcinoma, and two with cholangiocarcinoma). The inci dence of neutropenia of World Health Organization grades Il-IV and the inci dence of distal paresthesias were 10 or more times higher (P < .05) with sched ule A than with schedule B. In addition, vomiting was 55% higher (P = .15) with schedule A than with schedule B. Fur thermore, with schedule B, the mean dose of oxaliplatin (P < .001) and Its maximum tolerated dose (P = .06 could be increased by 15% over thosi doses with schedule A. An objective response was achieved in two of the li patients with previously treated breas cancer. We recommend that the dose o oxaliplatin for phase U trials be 17: mg/m2, delivered according to the circa dian rhythm-modulated rate. [J Nat Cancer Inst 82:1046-1050,1990] Received March 26,1990; accepted April 3 , 199< Supported in part by gram 6180 from the Associ; tion pour la Recherche sur le Cancer, Aguetta Laboratories, and Debiopharm. J.-P. Caussanel, F. Lvi, Unit de Recherd Associe, Centre National de la Recherche Scie tifique, Chronobiologie-Chronophannacoiogie, Fa dation A. de Rothschild, Paris, France. J.-P. Caussanel, F. Lvi.S. Brienza, J.-L. Misst M. Itzhaki, G. Math, Service des Maladies Sa guines Immunitaires et Tumorales, Institut du Cane et d'immunogntique. Association Clauc Bernard, Hpital Paul-Brousse, Villejuif, France. R. Adam. Surgery Department, Hpital Pat Brousse, Villejuif, France. G. Milano, Laboraiorie d'Oncophannacotog Centre A. Lacassagne, Nice, France. B. Hecquet. Laboratoire de Pharmacodynam Centre O. Lambret, Lille, France. We thank Elisabeth Couv and Sylvie Rech J editorial assistance. ^Correspondence to: Francis Lvi, M.D., Ph.I Unit de Recherche Associe, Centre National de Recherche Scientifique, Chronobiologi-Chroi pharmacologie, Service des Maladies Sanguines I munitaires et Tumorales, Institut du Cancer d'immunogntique. Hpital Paul-Brousse. 16. i Paul-Vaillant-Couturier, 94804 Villejuif Cd France. 1046 Journal of the National Cancer Institi