Racial disparities in the treatment of endometrial intraepithelial neoplasia in postmenopausal women.

Disparities in endometrial cancer has increased during the past decade with Black women more likely to be diagnosed at a later stage and have higher mortality. The majority of research has been focused on cultural barriers, socioeconomic status, lack of access to care, comorbidities, and tumor histology to explain these disparities. Limited studies have been conducted on the disparity in the treatment of endometrial intraepithelial neoplasia(EIN). We sought to analyze the differences in treatment used in the management of postmenopausal women with EIN to evaluate whether race/ethnicity is a contributing factor. An IRB approved retrospective study was conducted amongst women at a single institution diagnosed with EIN. Ethnicity/race was defined as non-Hispanic White, non-Hispanic Black, Hispanic, and Asian. Demographic and clinical data was extracted. Multivariable logistic regression was used to examine the association between ethnicity/race and treatment, adjusted for age, BMI, and underlying medical conditions such as cardiovascular disease and diabetes. In total, 254 patients were analyzed. A significant association between ethnicity/race and treatment with non-Hispanic Black women less likely to be treated with surgical management compared to non-Hispanic White women (OR = 0.326, 95 %CI 0.129-0.827, p = 0.026). Importantly, after adjusting for clinical risk factors(age, BMI, CVD, diabetes), non-Hispanic Black women remained at an increased risk of not undergoing surgical intervention (OR = 0.333, 95 % CI 0.125-0.882, p = 0.027). Future research is imperative to evaluate the root cause of this disparity in the healthcare system.

Use of aromatase inhibitors in menopausal deep endometriosis: a case report and literature review.

We report and review the clinical effectiveness of aromatase inhibitors in a patient with refractory, recurrent and infiltrating endometriosis. We demonstrate excellent clinical, radiological and endoscopic responses after failure of multiple other modalities. Our case and the literature show that single-agent letrozole is capable to treat deep infiltrative endometriosis involving the rectum and the urinary tract. The use of aromatase inhibitor treatment of endometriosis in postmenopausal women makes sense, is safe and is well tolerated. Difficult cases of deep infiltrative endometriosis might require use of combined surgical and medical treatment modalities. Multidisciplinary involvement of the gynecologist, bowel surgeon, urologist and invasive radiologist might be needed. Aromatase inhibitors should be considered to be an integral part of the armamentarium in the management of women with endometriosis, especially in refractory cases that have failed conventional therapeutic modalities.

Long-term outcome of postmenopausal women with non-atypical endometrial hyperplasia on endometrial sampling.

OBJECTIVE: To assess the long-term outcome of postmenopausal women diagnosed with non-atypical endometrial hyperplasia (NEH). METHODS: This was a retrospective study of women aged 55 or older who underwent endometrial sampling in our academic medical center between 1997 and 2008. Women who had a current or recent (< 2 years) histological diagnosis of NEH were included in the study group and were compared with those diagnosed with atrophic endometrium (AE). Outcome data were obtained until February 2018. The main outcomes were risk of progression to endometrial carcinoma and risk of persistence, recurrence or new development of endometrial hyperplasia (EH) ('persistent EH'). Logistic regression analysis was used to identify covariates that were independent risk factors for progression to endometrial cancer or persistent EH. RESULTS: During the study period, 1808 women aged 55 or older underwent endometrial sampling. The median surveillance time was 10.0 years. Seventy-two women were found to have a current or recent diagnosis of NEH and were compared with 722 women with AE. When compared to women with AE, women with NEH had significantly higher body mass index (33.9 kg/m2 vs 30.6 kg/m2 ; P = 0.01), greater endometrial thickness (10.00 mm vs 6.00 mm; P = 0.01) and higher rates of progression to type-1 endometrial cancer (8.3% vs 0.8%; P = 0.0003) and persistent NEH (22.2% vs 0.7%; P < 0.0001). They also had a higher rate of progression to any type of uterine cancer or persistent EH (33.3% vs 3.5%; P < 0.0001). Women with NEH had a significantly higher rate of future surgical intervention (51.4% vs 15.8%; P < 0.0001), including future hysterectomy (34.7% vs 9.8%; P < 0.0001). On multivariable logistic regression analysis, only NEH remained a significant risk factor for progression to endometrial cancer or persistence of EH. CONCLUSIONS: Postmenopausal women with NEH are at significant risk for persistent EH and progression to endometrial cancer, at rates higher than those reported previously. Guidelines for the appropriate management of postmenopausal women with NEH are needed in order to decrease the rate of persistent disease or progression to cancer. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

The association of sexual dysfunction with race in women with gynecologic malignancies.

Gynecologic cancer survivors report sexual health among their highest concerns. The aim of this study was to identify the prevalence of sexual dysfunction (SD) in survivors of gynecologic malignancies and to evaluate the association of sexual function with race, ethnicity and treatment modality. In this study, survivors of endometrial, cervical, vaginal, and vulvar cancer who presented to the gynecologic oncology practice were asked to self-administer the Female Sexual Function Index (FSFI) survey to evaluate their sexual function. The prevalence of SD was estimated and its association with demographic and clinical co-variates was analyzed. Of the 155 participants, the prevalence of SD was 44.5% (95%CI: 36.7-52.7). Patients were significantly more likely to report SD if they did not currently have a partner (69% vs 22% p < .01). Abstinence within six months of their cancer diagnosis was also associated with SD (72% vs 26% p < .01). Patients who self-identified as black race compared to white race were three times more likely to have SD (OR = 3.9, 95% CI 1.1-14.3). Patients who received adjuvant chemotherapy and radiation therapy compared to those who did not among the entire cohort had an increased risk of SD (OR = 3.4, 95% CI 1.2-9.6). In our diverse population, almost half of our patients were identified to have SD. Black as compared to white race reported significantly higher sexual dysfunction. An increased risk for sexual dysfunction was observed among those women who received chemotherapy and radiation with or without surgery. PRECIS: Survivorship is an important issue for women with gynecologic malignancies. This study addresses the high rates of sexual dysfunction in a racially diverse patient population.

Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer.

BACKGROUND: In spite of profound reduction in incidence, cervical cancer claims >275,000 lives annually. Previously we demonstrated efficacy and safety of radioimmunotherapy directed at HPV16 E6 oncoprotein in experimental cervical cancer. MATERIALS & METHODS: We undertook a direct comparison of targeting E7 and E6 oncoproteins with specific (188)Rhenium-labeled monoclonal antibodies in CasKi subcutaneous xenografts of cervical cancer cells in mice. RESULTS: The most significant tumor inhibition was seen in radioimmunotherapy-treated mice, followed by the unlabeled monoclonal antibodies to E6 and E7. No hematological toxicity was observed. Immunohistochemistry suggests that the effect of unlabeled antibodies is C3 complement mediated. CONCLUSION: We have demonstrated for the first time that radioimmunotherapy directed toward E7 oncoprotein inhibits experimental tumors growth, decreases E7 expression and may offer a novel approach to cervical cancer therapy.

Combined treatment of the experimental human papilloma virus-16-positive cervical and head and neck cancers with cisplatin and radioimmunotherapy targeting viral E6 oncoprotein.

BACKGROUND: Human papilloma virus (HPV) is implicated in >99% of cervical cancers and ∼40% of head and neck squamous cell carcinoma (HNSCC). We previously targeted E6 oncogene with (188)Rhenium-labelled monoclonal antibody (mAb) C1P5 to HPV16 E6 in cervical cancer and HNSCC. Intranuclear E6 can be accessed by mAbs in non-viable cells with leaky membranes. As radioimmunotherapy (RIT) efficacy depends on the availability of target protein-we hypothesised that pretreatment with cisplatin will kill some tumour cells and increase E6 availability for RIT. METHODS: Mice with subcutaneous HPV16+ cervical (CasKi) and HNSCC (2A3) tumours were pretreated with 0-7.5 mg kg(-1) per day cisplatin for 3 days followed by (188)Re-C1P5 and biodistribution was performed 24 h later. For RIT, the animals were treated with: 5 mg kg(-1) per day cisplatin for 3 days; or 5 mg kg(-1) per day cisplatin for 3 days followed 200 or 400µCi (188)Re-C1P5 mAb; or 200 or 400µCi (188)Re-C1P5 mAb; or left untreated, and observed for tumour growth for 24 days. RESULTS: Pretreatment with cisplatin increased the uptake of (188)Re-C1P5 in the tumours 2.5 to 3.5-fold and caused significant retardation in tumour growth for CasKi and 2A3 tumours in both RIT alone and cisplatin, and RIT groups in comparison with the untreated control and cisplatin alone groups (P<0.05). The combined treatment was more effective than either modality alone (P<0.05). CONCLUSION: Our study demonstrates that preceding RIT targeting E6 oncogene with chemotherapy is effective in suppressing tumour growth in mouse models of HPV16+ cancers.

Phase I trial of ixabepilone plus pegylated liposomal doxorubicin in patients with adenocarcinoma of breast or ovary.

BACKGROUND: Ixabepilone is a semisynthetic epothilone B analogue that is active in taxane-resistant cell lines and has shown activity in patients with refractory breast and ovarian cancer. We carried out a phase I trial of ixabepilone plus pegylated liposomal doxorubicin (PLD) in patients with advanced taxane-pretreated ovarian and breast cancer. METHODS: Patients with recurrent ovarian or breast carcinoma received PLD every 3 or 4 weeks plus five different dose schemas of ixabepilone in cohorts of three to six patients. RESULTS: Thirty patients received a total of 142 treatment cycles of the PLD-ixabepilone combination. The recommended phase II dose and schedule of ixabepilone was 16 mg/m(2) on days 1, 8, and 15 plus PLD 30 mg/m(2) given on day 1, repeated every 4 weeks. Hand-foot syndrome and mucositis were dose limiting when both ixabepilone and PLD were given every 3 or 4 weeks. Objective responses were observed in 3 of 13 patients (23%) with breast cancer and 5 of 17 patients (29%) with ovarian cancer. CONCLUSION: Ixabepilone may be safely combined with PLD, but tolerability is highly dependent upon the scheduling of both agents. This combination demonstrated efficacy in patients with breast and ovarian cancer and merits further evaluation in these settings.

Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone.

BACKGROUND: We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS: Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS: Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION: The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

Concomitant cisplatin and extended field radiation therapy in patients with cervical and endometrial cancer.

The purpose of this study is to evaluate the toxicity and safety of concomitant cisplatin (CDDP) and extended field radiation therapy (EFRT) in patients with cervical cancer (CxCA) and endometrial cancer (EnCA). Twenty-five patients were analyzed retrospectively for treatment-related morbidity from 1989 to 1998. Fourteen patients had CxCA and 11 patients had EnCA. Eighteen patients (72%) had surgery prior to radiotherapy and chemotherapy. EFRT was delivered by a four-field technique to the pelvis and para-aortic regions. CDDP at 100 mg/m2 was given over 5 days during 1st and 4th week of EFRT. EFRT dose for EnCA and CxCA was 45 Gy. Toxicity was analyzed using the RTOG toxicity criteria. Twenty-four (96%) of the 25 patients completed the prescribed therapy. Of the 14 patients with CxCA, three (21%) had no toxicity, three (21%) had grade 1-2, and eight (58%) had grade 3-4 hematologic toxicities. Overall six (24%) had grade 3-4 acute gastrointestinal toxicities, three (21%) of these patients were treated for cervix cancer and three (27%) patients were treated for endometrial cancer. The worst (Grade 3-4) toxicities in 15 patients occurred after the 4th week of radiotherapy. In six of 25 (24%) patients radiation treatments had to be delayed due to toxicities. The median delay of treatment was 10.5 days (range 7-31 days). Of the six patients who had grade 3-4 acute gastrointestinal toxicities, four (66%) had undergone exploratory laparotomy and lymph node sampling prior to start of chemoradiation. We conclude that concomitant EFRT and CDDP appears to be safe with moderate but manageable toxicity. Toxicity is most severe after the 4th week of treatment. Morbidity may be worse in patients with prior laparotomy.

Pattern of lymph node metastases in clinically unilateral stage I invasive epithelial ovarian carcinomas.

PURPOSE: There is controversy regarding the pattern of lymphatic spread in unilateral stage I invasive ovarian carcinomas. The purpose of this study is to describe the incidence and distribution of lymph node (LN) metastases in ovarian carcinomas clinically confined to one ovary. METHODS: Ninety-six patients with disease visibly confined to one ovary were identified. Pathology reports were reviewed to identify metastatic LN involvement, number of involved nodes, and their locations. Patients with gross disease in the pelvis or abdomen or those who had grossly positive LNs removed for debulking were excluded from this review. RESULTS: Fourteen of ninety-six patients (15%) had microscopically positive LNs on pathologic review. All of these 14 patients had grade 3 tumors. Grade 3 tumors were more commonly seen in LN-positive versus LN-negative patients (P < 0.001). Pelvic nodes were positive in 7 patients (50%), paraaortic nodes in 5 patients (36%), and both in 2 patients (14%). Forty-two patients had LN sampling only on the side ipsilateral to the neoplastic ovary, 4 of whom (10%) had LN metastases. Fifty-four patients had bilateral sampling performed, 10 of whom (19%) had LN metastases. Of these 10 patients, isolated ipsilateral LN metastases were seen in 5 (50%) cases. Isolated contralateral LN metastases were seen in 3 (30%) cases, and bilateral metastases were seen in 2 (20%). CONCLUSIONS: In this cohort of patients with clinical stage I ovarian carcinoma with disease limited to one ovary, bilateral LN sampling increased the identification of nodal metastases. Ipsilateral sampling may result in the understaging of patients. Bilateral pelvic and paraaortic LN sampling is recommended to accurately stage ovarian carcinoma.

Ovarian carcinoid: management of primary and recurrent tumors.

We present a case of Stage I ovarian carcinoid tumor recurrent in the peritoneal cavity and review the pertinent literature concerning the management of this disease. Based on the data in the gynecologic and general surgery literature, it appears that primary complete cytoreductive surgery usually affords a high cure rate. Reexploration and attempt at complete resection of this slow-growing tumor appears to provide significant and prolonged palliation and is indicated for recurrent disease.

Malignant Brenner tumor mimicking a primary squamous cell carcinoma of the cervix.

An 86-year-old female presented with a necrotic cervical mass that was biopsy-proven squamous cell carcinoma. She had an elevated CA-125 and a pelvic mass. At surgery, this mass was found to be of adnexal origin and contiguous with the cervix. Histology showed a malignant Brenner tumor with abundant squamous differentiation eroding the cervix and simulating a primary cervical malignancy. We describe this case and review the literature on metastatic tumors to the cervix.

Colony-stimulating factor-1 and its receptor do not have a role in the pathogenesis of uterine sarcomas.

OBJECTIVE: Several studies have demonstrated overexpression of the mononuclear phagocytic growth factor colony-stimulating factor-1 (CSF-1) and its receptor (CSF-1R) in breast, ovarian, and endometrial adenocarcinomas, and their expression in each of these cancers is strongly correlated with poor prognosis. In addition to adenocarcinomas, sarcomas that are highly malignant arise at much lower frequency in the uterus. Given the common organ of origin and hormonal environment of the adenocarcinomas, we evaluated the potential role of CSF-1 and CSF-1R in the genesis of these tumors using immunohistochemical methods. RESULTS: Immunohistochemical analysis was performed on 19 archival uterine sarcoma samples. Affinity-purified rabbit anti-CSF-1 antiserum (R52) and human cross-reactive murine anti-c-fms antibody were used. In the 19 cases evaluated for CSF-1 immunoreactivity, 42.1% had staining in less than 25% of the tumor, 36.9% had staining in 25-50% of the tumor, and only 21% had staining in greater than 50% of the tumor. When present, the majority of the CSF-1 immunostaining was associated with the extracellular matrix. There was variable intensity in CSF-1 expression: 52.6% had negative to mild staining, and 47.4% had moderate to strong staining. Immunostaining for the CSF-1R revealed that 52.6% of tumors had expression in less than 25% of cells, 21.0% had expression in 25-50% of the tumor, and 26.4% had staining in greater than 50% of the tumor. There was variable intensity of CSF-1R staining. Slight staining was found in 31.6% of the cases, moderate staining was found in 47.4% of the tumors, and 21.0% of the cases had strong expression. There was no statistically significant correlation between CSF-1 and CSF-1R expression and stage, estrogen/progesterone receptor status, number of mitoses per 10 high-power fields, or disease outcome. In addition, overall expression and intensity of CSF-1 and CSF-1R did not predict tumor virulence or disease outcome. CONCLUSION: In contradistinction to endometrial adenocarcinomas, in which CSF-1/CSF-1R is strongly correlated with tumor progression, CSF-1 and CSF-1R overexpression does not appear to play a role in the growth and differentiation of uterine sarcomas.

Compliance with Papanicolaou smear screening following tubal ligation in women with cervical cancer.

To evaluate patient compliance with Papanicolaou (Pap) smear screening after tubal ligation compared with other methods of birth control in patients who develop cervical cancer, a retrospective review of 262 women with cervical cancer diagnosed at age < or = 70 years was undertaken at the Albert Einstein College of Medicine from January 1987 to December 1995. Demographic data, stage of the disease, histologic type, history of smoking, history of sexually transmitted disease (STD), and birth control use were recorded. The Pap screening history was obtained from all the patients. Women who had a bilateral tubal ligation (BTL) were compared with those who did not have this form of birth control. The date and result of their last Pap test prior to their diagnosis of cervical cancer was noted. Two hundred fourteen women with cervical cancer were evaluable. The clinical stage, mean age, history of smoking, and history of STD were similar for both groups. Gravidity among the BTL group was higher than in the non-BTL group (p < 0.01). Forty-eight (22.4%) women had a previous BTL. Twenty-seven of these 48 patients (56.3%) did not have a Pap smear within 3 years prior to the diagnosis of cervical cancer. Of the 166 patients, 61 (36.7%) did not have a Pap test within 3 years (p < 0.05). Fourteen women (29.2%) in the tubal ligation group never returned for a Pap test following the BTL. An average of 6.2+/-5.9 years elapsed since the last Pap test in the BTL group, with 4.0+/-5.1 years in the nontubal ligation group (p < 0.05). There was a correlation between the number of years since BTL (14.2+/-7.7) to the number of years since the last Pap test (6.2+/-5.9) (p < 0.05). Women who have had a BTL should be considered high risk because of poor screening compliance. A Pap test every 3 years is not adequate in this high-risk population group. We advocate improved counseling regarding the importance of continued annual Pap screening for women who are considering tubal ligation.

Dermatofibrosarcoma protuberans of the vulva: a rare tumor presenting during pregnancy in a teenager.

OBJECTIVES: We report a case of a young patient with dermatofibrosarcoma protuberans of the vulva diagnosed during pregnancy. We also provide a review of the literature on this topic. MATERIALS AND METHODS: This patient's case was reviewed retrospectively. A current literature search was performed and findings were reported. RESULTS: This rare malignancy was diagnosed during pregnancy in a teenager. CONCLUSIONS: Dermatofibrosarcoma protuberans of the vulva, a rare vulvar neoplasm mostly associated with older patients and never before reported during pregnancy, should be considered as part of the differential diagnosis for any vulvar mass and cannot be excluded on the basis of the patient's age or pregnancy status.

The rectus abdominis myocutaneous flap: modifications, complications, and sexual function.

BACKGROUND: Vaginal, perineal, and pelvic floor reconstruction is being performed with increasing frequency in conjunction with radical pelvic surgery. Although the vertical rectus abdominis myocutaneous flap is ideally suited to such procedures, little information exists regarding risks or complications associated with it. METHODS: A chart review of all patients who underwent this procedure at two institutions was performed, and the results were compared with existing series. Surviving patients were asked to describe their satisfaction with the procedure and their sexual function. RESULTS: Between 1990 and 1997, 22 patients underwent placement of a rectus abdominis myocutaneous flap for vaginal/pelvic floor reconstruction, 21 (95.5%) at the time of pelvic exenteration. Attachment of the graft was complete in 20 patients (90.9%) and partial in 1 (4.5%), and 1 patient experienced complete loss that resulted in total vaginal stenosis. Four patients (18.2%) developed mild vaginal stenosis that was corrected with dilators. Donor site complications included wound separation (above the fascia) in three patients and one delayed abdominal closure. There were no cases of bowel obstruction, dehiscence, hernia, or death. The only statistically significant identifiable risk factors for graft necrosis included prior abdominal surgery and operative time. Thirteen of 22 (59.1%) of the patients are cancer free (median progression free interval, 42.2 months), 11 (84.6%) of whom reported having had vaginal intercourse since surgery. CONCLUSIONS: The rectus abdominis myocutaneous flap can be safely used with excellent results and acceptable morbidity, and in this series it restored sexual function in the majority of cancer survivors. Because previous abdominal surgery (transverse incisions or colostomy) may compromise blood supply to the flap, alternative sites should be considered in such cases.

Pelvic exenteration for cervix cancer: would additional intraoperative interstitial brachytherapy improve survival?

OBJECTIVE: Improved local control with the addition of brachytherapy to pelvic exenteration for recurrent cervical cancer has been reported to improve survival. We examined the sites of recurrence after pelvic exenteration to determine if these patients might have been salvaged by the improved local control promised by interstitial brachytherapy. We sought to identify risk factors available intraoperatively or perioperatively which might predict decreased local control. METHODS: A retrospective review of 26 patients with recurrent cervical cancer who underwent total pelvic exenteration since 1988 at our institution was performed. RESULTS: Overall, the mean follow-up was 29.5 months (range 6.1-81.6). Of the 26 patients, 14 had no evidence of disease (NED), 1 was alive with disease (AWD), 9 were dead of disease (DOD), and 2 died of unrelated causes (DOC). Seven of 26 patients (27%) had margins < or = 5 mm, of whom 2 were NED, 4 DOD, and 1 AWD. Seven of 26 (27%) patients had lymphovascular involvement (LVI) or perineural invasion (PNI) with clear margins. Three of the seven with LVI or PNI and clear margins were NED, and four DOD. Of the 10 failures, 9 (90%) had close margins, PNI, or LVI. CONCLUSION: Our data reveal that 9 of 14 (64%) patients with close margins, LVI, or PNI were DOD or AWD, and 6 of 9 of those patients suffered local regional failure alone. Brachytherapy has the potential to cure 6 of 14 (43%) patients with these risk factors. Further study of brachytherapy at the time of pelvic extenteration is warranted.

Continuous low-dose combined hormone replacement therapy and the risk of endometrial cancer.

Hormone replacement therapy (HRT) provides relief of menopausal symptoms, reverses atrophic urogenital changes, prevents osteoporosis, and produces favorable lipoprotein effects. Continuous combined HRT using 2.5 mg of medroxyprogesterone was designed to increase patient compliance by eliminating withdrawal bleeding while at the same time retaining the beneficial effects of HRT. There are limited long-term data, however, regarding the safety of continuous combined HRT. Of concern are reports of endometrial carcinoma arising in women receiving continuous HRT with low-dose progestin. Eight cases of women who developed endometrial carcinoma while on this regimen are presented. The possible increased risk of endometrial cancer associated with this regimen may be related to inadequate progestin dose, prior use of unopposed estrogen, poor patient compliance, use of less effective progestins, less efficient reversal of hyperplasia, and the use of progestin continuously.

Induction of transforming growth factor beta-1 in cervical intraepithelial neoplasia in vivo after treatment with beta-carotene.

Transforming growth factor (TGF) beta1 is a potent growth inhibitor of epithelial cells. Loss of responsiveness to TGF-beta1 and/or loss of TGF-beta1 itself may be important in the progression of cervical intraepithelial neoplasia to invasive cervical cancer. Retinoids have antiproliferative effects on epithelial cells and have been used as chemopreventive and chemotherapeutic agents for several human cancers. There is evidence that retinoids exert their effects by promoting the induction of TGF-beta. The aim of this study was to determine whether the expression of TGF-beta1 was altered in patients enrolled in a clinical trial designed to test the therapeutic efficacy of beta-carotene, a carotenoid metabolized to retinol, in cervical intraepithelial neoplasia. Using an immunohistochemical technique, tissues were stained with two types of antisera that react with the intracellular and extracellular forms of TGF-beta1. Matched cervical biopsies taken from 10 patients before and after treatment with beta-carotene were immunostained simultaneously to allow direct comparison of relative staining intensity. A significant increase in intracellular TGF-beta1 immunoreactivity was noted in cervical epithelial cells in patients with cervical intraepithelial neoplasia after treatment with beta-carotene (P = 0.003). These results demonstrate regulation of a TGF-beta isoform in vivo in humans in response to beta-carotene administered as a chemopreventive agent.