The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial.

Second primary tumors (SPTs) develop at an annual rate of 3-7% in patients with head and neck squamous cell cancer (HNSCC). In a previous Phase III study, we observed that high doses of 13-cis-retinoic acid reduced the SPT rate in this disease. In 1991, we launched an intergroup, placebo-controlled, double-blind study to evaluate the efficacy of low-dose 13-cis-retinoic acid in the prevention of SPTs in patients with stage I or II squamous cell carcinoma of the larynx, oral cavity, or pharynx who had been previously successfully treated with surgery, radiotherapy, or both, and whose diagnoses had been established within 36 months of study entry. As of September 16, 1999, the Retinoid Head and Neck Second Primary (HNSP) Trial had completed accrual with 1384 registered patients and 1191 patients randomized and eligible. All of the patients were followed for survival, SPT development, and index cancer recurrence. Smoking status was assessed at study entry and during study. Smoking cessation was confirmed biochemically by measurement of serum cotinine levels. The annual rate of SPT development was analyzed in terms of smoking status and tumor stage. As of May 1, 2000, SPTs have developed in 172 patients. Of these, 121 (70.3%) were tobacco-related SPTs, including 113 in the aerodigestive tract (57 lung SPTs, 50 HNSCC SPTs, and 6 esophageal SPTs) and 8 bladder SPTs. The remaining 51 cases included 23 prostate adenocarcinomas, 8 gastrointestinal malignancies, 6 breast cancers, 3 melanomas, and 11 other cancers. The annual rate of SPT development observed in our study has been 5.1%. SPT development related to smoking status was marginally significant (active versus never, 5.7% versus 3.5%; P = 0.053). Significantly different smoking-related SPT development rates were observed in current, former, and never smokers (annual rate = 4.2%, 3.2%, and 1.9%, respectively, overall P = 0.034; current versus never smokers, P = 0.018). Stage II HNSCC had a higher overall annual rate of SPT development (6.4%) than did stage I disease (4.3%; P = 0.004). When evaluating the development of smoking-related SPTs, stage was also highly significant (4.8% for stage II versus 2.7% for stage I; P = 0.001). Smoking-related SPT incidence was significant for site as well (larynx versus oral cavity, P = 0.015; larynx versus pharynx, P = 0.011). Primary tumors recurred at an annual rate of 2.8% in a total of 97 patients. The rate of recurrence was higher in patients with stage II disease (4.1% versus 2.2%, P = 0.004) as well as oral cavity site when compared with larynx (P = 0.002). This is the first large-scale prospective chemoprevention study evaluating smoking status and its impact on SPT development and recurrence rate in HNSCC. The results indicate significantly higher SPT rates in active smokers versus never smokers and significantly higher smoking-related SPT rates in active smokers versus never smokers, with intermediate rates for former smokers.

Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage I non-small-cell lung cancer.

BACKGROUND: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-small-cell lung cancer (NSCLC) patients. METHODS: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. RESULTS: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T(2) versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. CONCLUSIONS: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers.

The NCCN guidelines development process and infrastructure.

A major task of the National Comprehensive Cancer Network (NCCN) is to develop pathways reflecting the major step-by-step management decisions required to provide care for patients with cancer. The determination of what is appropriate care involves assessing the balance between the sum of the benefits compared to the sum of the risks. The guidelines are composed of recommendations based on the best evidence available at the time they are derived. Each guideline is reviewed annually and once revisions have been uniformly accepted, the new version becomes the official NCCN guideline for that year.

Phase II study of intravenous CI-958 in metastatic colorectal adenocarcinoma.

In a multicenter, phase II trial, CI-958, a benzothiopyranoindazole DNA intercalator, was administered to 18 patients who had not received prior chemotherapy for metastatic colorectal cancer. The drug was given by intravenous infusion at a dose of 700 mg/m2 every 21 days. There were no objective responses. Grades III and IV toxic effects were limited to granulocytopenia in 42% of courses and anemia in 5% of courses. There was one case of grade III increase in transaminases. Our results show that at this dose and schedule, CI-958 lacks activity against colorectal cancer.

Antibiotic treatment of gastric lymphoma of mucosa-associated lymphoid tissue. An uncontrolled trial.

BACKGROUND: Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is related to Helicobacter pylori infection and may depend on this infection for growth. OBJECTIVE: To determine the response of gastric MALT lymphoma to antibiotic treatment. DESIGN: Prospective, uncontrolled treatment trial. SETTING: University hospital referral center and three collaborating university and community hospitals. PATIENTS: 34 patients with stage I or stage II N1 gastric MALT lymphoma. INTERVENTION: Two of three oral antibiotic regimens--1) amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2)tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times daily--were administered sequentially (usually in the order written) for 21 days at baseline and at 8 weeks, along with a proton-pump inhibitor (lansoprazole or omeprazole) and bismuth subsalicylate. MEASUREMENTS: Complete remission was defined as the absence of histopathologic evidence of lymphoma on endoscopic biopsy. Partial remission was defined as a reduction in endoscopic tumor stage or 50% reduction in the size of large tumors. RESULTS: 34 patients were followed for a mean (+/-SD) of 41 +/- 16 months (range, 18 to 70 months) after antibiotic treatment. Of 28 H. pylori-positive patients, 14 (50% [95% CI, 31% to 69%]) achieved complete remission, 8 (29%) achieved partial remission (treatment eventually failed in 4 of the 8), and 10 (36% [CI, 19% to 56%]) did not respond to treatment. Treatment failed in all 6 (100% [CI, 54% to 100%]) H. pylori-negative patients. Patients with endoscopic appearance of gastritis (stage I T1 disease) were most likely to achieve complete remission within 18 months. Tumors in the distal stomach were associated with more favorable response than tumors in the proximal stomach. CONCLUSIONS: A subset of H. pylori-positive gastric MALT lymphomas, including infiltrative tumors, may respond to antibiotics. The likelihood of early complete remission seems to be greatest for superficial and distal tumors.

Reproducibility of guidelines. A comparison of the NCCN and ASCO lung cancer guidelines.

Clinical practice guidelines are reproducible if two groups of experts, presented with the same evidence and methods, derive similar recommendations. Reproducibility is an essential attribute in justifying the use of clinical practice guidelines to guide and monitor physicians' practices. This article will compare guidelines for the management of advanced non-small-cell lung cancer developed by the National Comprehensive Cancer Network (NCCN) with guidelines derived by the American Society of Clinical Oncology (ASCO). This comparison aims to determine whether the two guidelines are similar or whether there are major differences that pose significant problems for clinicians attempting to manage patients according to one oncology standard.

Clinical practice guidelines in the management of gynecologic malignancies.

The need for guidelines in managing gynecologic cancer is addressed in the first part of this article. Second, the guideline development process that enables the practitioner to judge the validity and usefulness of proffered guidelines is detailed. An important element in this discussion is an exploration of the shortcomings, either real or perceived, of the process. The last section focuses on issues relating to the implementation of guidelines and some of the obstacles that one may encounter as the programs evolve.

Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract.

BACKGROUND: Tobacco smoking is an established risk factor for cancers of the upper aerodigestive tract, and measurement of chromosomal aberrations, i.e., chromatid breaks, induced in lymphocytes in vitro by bleomycin has been shown to be a predictor of risk for these cancers. In a case-control study, we recruited case subjects who were previously treated with surgery and/or radiotherapy for stage I or stage II squamous cell carcinoma of the head and neck to test the hypothesis that lymphocytic chromatid breaks induced by benzo[a]pyrene diol epoxide (BPDE), a tobacco mutagen, may also be associated with risk of developing cancers of the upper aerodigestive tract. METHODS: Case subjects were matched to control subjects on the basis of age, sex, ethnicity, and smoking status. Primary lymphocytes from 67 case subjects and 81 control subjects were treated with 2 microM BPDE for 24 hours, and the frequency of induced chromatid breaks was determined. All statistical tests were two-sided. RESULTS: Lymphocytes from case subjects compared with lymphocytes from control subjects showed significantly more breaks per cell induced by BPDE (mean+/-standard deviation, 0.77+/-0.38 versus 0.49+/-0.25; P<.001). Lymphocytes from 64.2% of case subjects were sensitive to BPDE (using a cutoff value of > or =0.60 break per cell). Subjects in the highest quartile of chromatid breaks had an approximately 20-fold increased risk of cancer compared with those in the lowest quartile after adjustment for age, sex, ethnicity, and smoking status. The association between BPDE sensitivity and cancer risk was higher in former smokers than in current smokers and higher in younger patients than in older patients. Subjects with sensitivity to both BPDE and bleomycin were at a 19.2-fold increased risk of cancer compared with those who were not sensitive to either agent. CONCLUSIONS: Mutagen sensitivity assays may aid in identifying individuals at risk of cancer, and use of parallel assays with two mutagens may improve risk predictability.

Guidelines and disease management.

The four NCCN Guidelines that follow represent the initial deliberations of an institutionally diverse, multidisciplinary panel comprised of internationally recognized experts. These experts have attempted to address the broad range of clinical decisions that oncologists face as they attempt to manage a patient with a particular tumor. The goal of the NCCN guidelines program is to publish comprehensive pathways that will serve as a foundation for all cancer care providers to develop superior disease management programs.

Cost considerations as potential barriers to cancer treatment.

PURPOSE: An analytical cross-sectional survey was conducted to determine the prevalence of barriers to cancer treatment in Texas as perceived by diagnosed cancer patients. Results reported here address the role of insurance coverage, indirect costs (transportation, lodging, and work days lost), and direct costs of care as barriers to treatment for white, black, and Hispanic cancer patients. Specific objectives of the analyses undertaken here are to examine 1) racial/ethnic differences in insurance coverage; 2) barriers relating to insurance coverage experienced by cancer patients; and 3) role of treatment-related costs as barriers to cancer treatment. DESCRIPTION OF STUDY: A mail questionnaire was developed to assess the perceived barriers to cancer treatment in Texas for adult cancer patients, 17 years and older, who had been diagnosed with breast, colon, cervical, prostate, or lymphoma during the period of 1989 to 1993. The sampling frame for this study was obtained from a network of cancer treatment facilities throughout the state of Texas within the University of Texas M.D. Anderson Cancer Center Texas Community Oncology Network. A total of 593 cancer patients returned their surveys, yielding a 65.2% response rate. Weighting adjustments were then made to correct for differential sampling and response rates by racial groupings and type of cancer. All of the analyses used adjusted weights. RESULTS: The findings document the financial considerations (insurance, direct and indirect costs) as they relate to barriers to cancer treatment. Specific insurance premium-related barriers with regard to maintaining and affording coverage were more prevalent for blacks. Hispanics were less likely to have insurance coverage; however, more blacks reported being denied insurance coverage when they changed jobs compared with whites and Hispanics. Minorities, particularly Hispanics, were more likely to have experienced cost-related barriers associated with medications, diagnostic tests, and hospitalizations. In addition, Hispanics experienced significant out-of-pocket costs in paying for cancer treatment. CLINICAL IMPLICATIONS: This research shows the need for staff at cancer treatment facilities to be aware that there are nonclinical, financial factors that are important considerations in the treatment of cancer patients. Assessment of cancer patients during the diagnostic and treatment stages, possibly through case management, will provide information on potential barriers to treatment for individual patients. Hospital programs that reimburse out-of-pocket costs, transportation costs to obtain services, and lodging accommodations may be available. Additional services may be offered through cancer advocacy groups, such as the American Cancer Society and the National Coalition for Cancer Survivors, to assist patients with managing costs and overcoming barriers to care.

Information sources and barriers to cancer treatment by racial/ethnic minority status of patients.

BACKGROUND: This study examined the sources used by cancer patients to obtain helpful information regarding their treatment options and side effects and the major predictors that facilitated usage of information. METHODS: The survey was administered to a representative sample of cancer patients in Texas. The cancer treatment facilities from which the patients were sampled were part of the University of Texas M. D. Anderson Cancer Center's Texas Community Oncology Network. A total of 593 patients (65%) out of 910 contacted responded to the survey. RESULTS: The patients reported that providers such as physicians and nurses were the most helpful sources of information. White patients tended to use books and reference materials more heavily to gather additional information regarding their treatment, while black patients relied on pamphlets and television. Educational level appeared to have a major influence on the black patient's use of printed materials. CONCLUSIONS: The results document the important role that providers play in influencing patients' treatment decisions. Effective ways to communicate with cancer patients are different for patients with different racial backgrounds. Implications for the future development of patient education materials and cancer prevention initiatives targeting ethnic minorities are addressed.

The NCCN guideline program--1998.

In 1995, the National Comprehensive Cancer Network (NCCN) embarked on an ambitious project to develop comprehensive diagnostic and treatment algorithms for the broad spectrum of oncologic diseases and support modalities. To date, 28 NCCN guideline panels have developed guidelines covering an estimated 93% of tumors, and an additional 9 panels have guidelines under development. This article reviews the NCCN guideline infrastructure and development process. The process relies on the expertise of the 17 NCCN member institutions and follows a formal procedure for guideline development to ensure that the recommendations offer the cancer patient the best chance for a successful outcome.

Phase II trial of 9-aminocamptothecin (NSC 603071) administered as a 120-hr continuous infusion weekly for three weeks in metastatic colorectal carcinoma.

9-Aminocamptothecin (9-AC) is a camptothecin derivative with broad antitumor activity in preclinical studies. Prior investigations suggested that prolonged maintenance of 9-AC lactone plasma concentrations above 10 nmol/l and frequent administration of the drug are important determinants of antitumor activity. Our phase II study, therefore, examined a 5-day continuous infusion of 9-AC weekly for 3 weeks in patients with advanced colorectal cancer. Eighteen patients previously untreated for metastatic disease received 480 microg/m2/day of 9-AC. No responses were observed in 17 evaluable patients. Severe toxicities included granulocytopenia, nausea, vomiting and diarrhea. The median absolute granulocyte count (AGC) nadir was 2,300/microl (range 0-9,000/microl) and occurred on day 10. Eight patients received an escalated dose of 600 microg/m2/day. The median AGC nadir at the escalated dose was 1,500/microl (range: 300-2,700/microl) and occurred on day 22. The median number of courses given was 2 (range: 1-8); and the median time to disease progression was 8 weeks (range: 1-40 weeks). 9-AC administered by this schedule lacked antitumor activity in patients with advanced colorectal carcinomas.

Transportation as a barrier to cancer treatment.

PURPOSE: Patients with cancer must overcome many psychological, social, and economic barriers to obtain needed treatment. Because of the need for repeated visits for cancer treatment on either an outpatient or an inpatient basis, one of the major issues that patients with cancer must confront is that of arranging for transportation to care. METHODS: This study compares the distance and mode of transportation to radiotherapy and chemotherapy and perceptions of transportation as a barrier to care among white, black, and Hispanic cancer patients receiving treatment from a consortium of cancer treatment facilities in Texas. A mail questionnaire was developed to assess the perceived barriers to cancer treatment for patients who had been diagnosed clinically with breast, colon, cervical, or prostate cancer, or lymphoma between 1989 and 1993. A total of 910 surveys were mailed to prospective participants. Of the surveys mailed, 593 were returned, yielding a 65.2% response rate. By race, the respondents included whites (42%), blacks (40%), Hispanics (15%), and Asian-Pacific Islanders (3%). Two respondents were 17 years of age; the remaining respondents were 18 years or older. RESULTS: This study shows that some patients may forgo needed treatment because of problems with transportation. This was perceived as an issue more for minority patients than for white patients. Black and Hispanic patients consistently reported that barriers such as distance, access to an automobile, and availability of someone to drive them to the treatment center were potential major problems. The distance to the facilities was farther for whites than for blacks and Hispanics. Patients generally had to travel farther for chemotherapy than for radiotherapy. CLINICAL IMPLICATIONS: Patients, particularly minorities, may opt to forgo needed care in the absence of available and affordable means of transportation to treatment facilities. These findings demonstrate the need for healthcare providers to be aware of the transportation problems that patients with cancer experience in obtaining treatment. Healthcare providers must work with patients, their families, and volunteer agencies in the community to facilitate transportation to cancer treatment services.

Characterization and phylogenetic significance of rhinoceros luteinizing hormone beta (LHbeta) subunit messenger RNA structure, complementary DNA sequence and gene copy number.

The luteinizing hormone (LH) beta subunit gene is expressed in the pituitary glands of all mammals, whereas the closely related chorionic gonadotropin (CG) beta subunit genes have been identified only in primates and equids, and are expressed in placenta. In the case of horses, there is a single-copy equine (e) luteinizing hormone/chorionic gonadotropin hormone beta subunit gene (eLH/CGbeta) that (1) is expressed in both pituitary gland and placenta, (2) encodes a characteristic carboxyl terminal peptide (CTP) extension, and (3) transcribes an atypically elongated 5'-untranslated region (UTR) in both pituitary and placenta. However, it is not known whether similar expression patterns and gene locus characteristics may be exhibited by other members of the order Perissodactyla (equid, rhinoceros and tapir species). To begin to investigate these possibilities, we undertook analysis of the rhinoceros (rn or rhino) LH/(CG?)beta gene locus and the rnLHbeta cDNA. Total RNA isolated from the pituitary gland of a female white rhino was used as template for amplifying rnLHbeta cDNA by reverse transcription-polymerase chain reaction. Following cloning of the amplified cDNA, nucleotide (nt) and deduced amino acid sequences were determined. The first in-frame stop codon occurred at codon position +122, suggesting that the rnLHbeta subunit does not contain a CTP. To assess gene copy number, Southern blot analysis of Indian rhino genomic DNA was performed. The resulting simple hybridization pattern indicated that, as in the horse and donkey, there is a single-copy gene at the rnLH/(CG?)beta gene locus. Primer extension mapping of the pituitary transcriptional start site of the rnLHbeta subunit gene revealed an 8 nt 5'-UTR which is similar to that reported for the majority of mammalian LHbeta transcripts. Northern analysis was consistent with the transcriptional start site findings. We postulate from these data that rhinos diverged from equids prior to the occurrence of the mutations causing CTP expression and adoption of a non-consensus 5'-UTR/proximal promoter region. However, these findings do not rule out the possibility of expression of a placental CGbeta subunit lacking a CTP in rhinos.

The role of informal and formal social support networks for patients with cancer.

PURPOSE: In this study, the authors examined the role of informal and formal social support networks in mitigating barriers to cancer treatment among whites, blacks, and Hispanics, based on a representative sample of cancer patients in Texas. DESCRIPTION OF STUDY: The sample frame for this study was obtained from the University of Texas M. D. Anderson Cancer Center's Texas Community Oncology Network, a consortium of cancer treatment facilities in Texas. Of the 910 patients who were contacted, 593 (65%) responded to the survey. RESULTS: The results show the value of social support networks in assisting cancer patients with continuing treatment. An important finding indicated that health professionals do not provide information regarding social support groups to patients with cancer at the time of diagnosis. Fewer than half of the respondents were asked whether they would be interested in joining a formal social support group. Individuals of all racial/ethnic groups reported that the formal support groups provided emotional assistance. Minorities were more apt to report that the formal support groups helped with continuing treatment. In addition, informal social support networks, such as extended families and civic clubs, were seen as more helpful for blacks and Hispanics as compared with whites. CLINICAL IMPLICATIONS: The need for formal and informal networks is indicated by the results of this study, which show that networks, such as relationships with family, friends, and relatives, play an important role in assisting patients in coping with their cancer. These networks are part of the patient's total treatment experience and must be acknowledged by healthcare professionals. A large number of patients are not asked to join social support groups, suggesting a need for training healthcare professionals to provide information regarding the potential benefits of support groups for cancer patients.

Terminally ill cancer patients. Their most important concerns.

PURPOSE: When the goal of treatment is palliative, the most important outcome is improving patient quality of life. The authors describe the major concerns of terminally ill cancer patients with a prognosis of 6 months of less. OVERVIEW: In phase I of this three-part study, 74 terminally ill patients were interviewed to identify their major concerns. In phase II, interviews with 120 terminally ill cancer patients showed that their most important concerns encompass existential, spiritual, familial, physical, and emotional issues. Phase III will determine the validity and reliability of a quality-of-life scale based on these patients' most important concerns. The information presented here summarizes the results of interviews from phases I and II. CLINICAL IMPLICATIONS: Patients were receptive to being interviewed and remarked on the relevance and importance of these issues to their own experience. Several patients commented that although their disease was assessed and reassessed throughout their care, the existential, spiritual, familial, and emotional aspects of their illness rarely were a focus of their care. Healthcare professionals can create an atmosphere in which these patients feel comfortable exploring the quality-of-life issues that are most important to them. The systematic assessment of patient concerns about quality of life may complement disease assessment and facilitate referrals to appropriate members of the healthcare team. The wide range of concerns reported suggests that a team approach, including physicians, nurses, social workers, psychiatrists, psychologists, and chaplains, is the most effective way to meet the needs of terminally ill patients.

Evidence that endogenous relaxin promotes growth of the vagina and uterus during pregnancy in gilts.

Recently, it was demonstrated that endogenous relaxin promotes growth of the vagina during the second half of pregnancy in rats and that administration of porcine relaxin promotes growth of the uterus in nonpregnant or early pregnant gilts. This study examined the effects of circulating relaxin on growth of both the vagina and uterus during the last two thirds of the 114-day gestation period in gilts. Furthermore, this study employed an in vitro immunohistochemical localization technique to determine whether the vagina and uterus in pigs have specific relaxin-binding sites. Three groups of pregnant gilts were used: sham-ovariectomized controls (group C; n = 8), ovariectomized progesterone-treated (group OP; n = 6), and ovariectomized progesterone- plus relaxin-treated (group OPR; n = 7). Gilts were either sham ovariectomized or ovariectomized on day 40 of gestation. Hormone replacement therapy with progesterone (group OP), progesterone plus relaxin (group OPR), or hormone vehicles (group C) began on day 38 (progesterone) or day 40 (relaxin) and continued until day 110. On day 110, the vagina and uterus were collected, and wet weight, dry weight, and percent hydration were determined. Small pieces (2-3 cm3) of the vagina and uterus from groups C and OP were frozen and cryosectioned for the immunohistochemical localization of relaxin-binding sites. Relaxin promoted growth of both the vagina and uterus. The wet weights of both the vagina and uterus in relaxin-deficient gilts (group OP) were lower (P < 0.05) than those in controls (group C), and relaxin replacement therapy (group OPR) restored the wet weights of both tissues to values that did not differ from those in controls. The mean dry weights and percent hydrations in the vagina and uterus did not differ among treatments. Immunohistochemical localization studies in the vagina and uterus demonstrated that specific and saturable binding of relaxin was localized in the same cell types of both tissues, namely epithelial cells (luminal in vagina, and both luminal and glandular in uterus), smooth muscle cells (both circular and longitudinal in vagina, and myometrial in uterus), and cells associated with blood vessels. In conclusion, this study provides evidence that circulating relaxin promotes growth of both the vagina and uterus during pregnancy in the pig. Furthermore, this study provides evidence that both the vagina and uterus contain specific and saturable relaxin-binding sites in epithelial cells, smooth muscle cells, and cells associated with blood vessels. We conclude that these cells probably initiate relaxin's effects on the vagina and uterus of the pregnant pig.