How often should a port-A-cath be flushed?

While it is important during treatment to flush the port-A-cath (PAC) with heparin regularly, catheter maintenance needs to be evaluated in those patients who, after completion of therapy, retained their ports for extended periods of time. The manufacturer has recommended monthly accession to maintain catheter patency and function. Our objective is to demonstrate that a longer interval between maintenance accessions of PACs still may be medically safe, convenient, and more efficient. We performed a retrospective review of all patients who had undergone PAC insertion from 1988 to 1993 at the Albert Einstein College of Medicine, and from 1997 to 2002 at the New York Hospital Medical Center of Queens. An adequate maintenance time is defined as a period of at least 6 months without chemotherapy or total parenteral nutrition. Data collected included date and location of PAC insertion, date of PAC accessions, PAC complications, and results of attempts at flushing the catheters with no venous blood return. All data were entered into an Excel spreadsheet and analyzed. The difference in interval accessions in patients without any complication to patients with complication was calculated using the Mann-Whitney "U" test. A total of 73 patients were included in the study. Compliance with visits for PAC maintenance varied considerably with the individual median accession times varying between 28 and 262 days with an overall median of 42 days. The individual means ranged from 29.5 to 244 days with an overall mean of 53.6 days. Seven patients in the group had episodes where the provider was unable to draw blood from the port during routine accession. The average intervals between accessions for each of these patients ranged from 38 to 244 days. The average intervals of accession among those patients who had no blood return during PAC accession was 79 days, versus 63 days for those without any difficulty. The difference was not statistically significant (p>0.05). Monthly maintenance of PAC is excessive, inconvenient for the patients, and expensive. Extending the interval of PAC maintenance proves to be medically safe and beneficial to the patients, the physicians and the health care system. Our clinical experience suggests that less frequent accessions of PACs is safe and feasible. We strongly advocate future prospective investigation of alternative PAC maintenance protocols in gynecologic cancer patients.

Chemotherapy in metastatic gastric cancer: population-based perceptions and practice patterns of medical oncologists.

Although randomised trials in metastatic gastric cancer have shown a survival benefit from chemotherapy, a significant proportion of medical oncologists do not believe that it prolongs survival or improves quality of life, including those who routinely treat metastatic gastric cancer. There was wide variation in what was considered to be 'standard therapy' and a statistically significant difference between what medical oncologists consider 'standard therapy' and what they use in every day practice.

A randomized trial of exercise and quality of life in colorectal cancer survivors.

We conducted a randomized controlled trial to determine the effects of a home-based exercise intervention on change in quality of life (QOL) in recently resected colorectal cancer survivors, most of whom were receiving adjuvant therapy. Participants were randomly assigned in a 2:1 ratio to either an exercise (n = 69) or control (n = 33) group. The exercise group was asked to perform moderate intensity exercise 3-5 times per week for 20-30 min each time. The primary outcome was change in QOL as measured by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scale. Adherence in the exercise group was good (75.8%) but contamination in the control group was problematic (51.6%). Intention-to-treat analysis revealed no significant differences between groups for change in the FACT-C (mean difference, -1.3; 95% CI, -7.8 to 5.1; P = 0.679). In an 'on-treatment' ancillary analysis, we compared participants who decreased versus increased their cardiovascular fitness over the course of the intervention. This analysis revealed significant differences in favour of the increased fitness group for the FACT-C (mean difference, 6.5; 95% CI, 0.4-12.6; P = 0.038). These data suggest that increased cardiovascular fitness is associated with improvements in QOL in colorectal cancer survivors but better controlled trials are needed.

Allelotype of papillary serous peritoneal carcinomas.

OBJECTIVE: Papillary serous peritoneal carcinoma (PSPC) is histologically indistinguishable from papillary serous ovarian carcinoma (PSOC) with a similar clinical presentation, yet may differ in its carcinogenesis. The purpose of this study was to determine the incidence of allelic loss and the frequency of p53 mutation by p53 overexpression in PSPC compared to PSOC. METHODS: An allelotype analysis of 26 patients with PSPC was performed using 39 microsatellite markers from 25 chromosomal arms. Thirty-seven previously studied patients with PSOC served as the comparison. P53 mutations were detected by immunohistochemical protein overexpression. RESULTS: There was significantly less LOH in PSPC than PSOC. Both the number of chromosomes with LOH and the proportion of tumors with allelic loss were less frequent. Significant LOH, defined as >/=30% of informative tumors having loss at a chromosome locus, was seen on 4 chromosome arms in PSPC: 12p, 17p, 17q, and 18q, compared to 18 arms in PSOC: 4q, 5q, 6p, 6q, 9p, 9q, 12p, 12q, 13q, 15q, 16q, 17p, 17q, 18q, 19p, 19q, 22q, and Xq (P < 0.001). The median LOH frequency was higher in PSOC than PSPC, 43% versus 33%, respectively (P = 0.013), and more PSOC tumors had LOH than PSPC tumors, 91% versus 65% (P = 0.042). P53 overexpression was detected in 80% of PSPC tumors. CONCLUSIONS: LOH occurs less frequently in PSPC compared to PSOC. Chromosomal regions with high frequencies of LOH common to PSPC and PSOC, such as 12p, 17p, 17q, and 18q, may harbor tumor suppressor genes important in the carcinogenesis of both malignancies and likely include p53.

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.

Clinical survival predictors in patients with advanced cancer.

BACKGROUND: The clinical and epidemiological relevance of different prognostic factors for survival in patients with advanced or terminal cancer remains controversial. PURPOSES: To establish the survival of patients with cancer after diagnosis of terminal disease and to determine the predictors of survival. METHODS: An inception cohort of 227 consecutive patients aged 18 years or older with terminal cancer of the lung, breast, and gastrointestinal tract were observed from July 1, 1996, through December 31, 1998. Tumor- and treatment-specific, clinical, laboratory, demographic, and socioeconomic variables were recorded at baseline. The relationships between these characteristics and survival time were examined using univariate Kaplan-Meier and multivariate Cox regression analyses. RESULTS: At the time of data analysis, 208 patients (91.6%) had died; the overall median survival for the sample was 15.3 weeks. Shorter survival was independently associated (P< or =.05) with a primary tumor of the lung (vs breast and gastrointestinal tract combined), liver metastases, moderate to-severe comorbidity levels (vs absent-to-mild levels), weight loss of greater than 8.1 kg in the previous 6 months, serum albumin levels of less than 35 g/L, lymphocyte counts of less than 1 X 10(9)/L, serum lactate dehydrogenase levels of greater than 618 U/L, and clinical estimation of survival by the treating physician of less than 2 months (vs 2-6 and >6 months). Performance status, symptoms other than nausea and vomiting, tumor burden, and socioeconomic characteristics such as social support and education and income levels did not appear to be independently associated with survival after adjusting for the effect of prognostic factors. CONCLUSIONS: Simple clinical and laboratory assessments are useful aids in the prediction of survival in patients with solid malignant neoplasms at the onset of terminal stages. Methodological improvements in the design and implementation of survival studies may reduce prognostic uncertainty and ultimately provide better care for the terminally ill patients and their families.

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.

Screening for gynecologic malignancies: A continuing responsibility.

Screening for cervical cancer with the Papanicolaou cervical smear has resulted in a decline in incidence and mortality from cervical cancer. Targeting the unscreened population is the next challenge to reduce the incidence of this disease further. Currently, there are no available screening modalities for endometrial or ovarian cancer. Breakthroughs in molecular genetics may result in screening tests for ovarian cancer.

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.

Outpatient 5-fluorouracil, folinic acid and cisplatin in patients with advanced esophageal carcinoma.

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

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.

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.

Endometrioid adenocarcinoma of the ovary and long-term tamoxifen therapy: a coincidence or a cause for concern?

In recent years, the extensive usage of tamoxifen in patients with breast cancer has led us to acquire a great deal of knowledge of its effects on various organs in the gynecological system, especially the effect on the endometrium and the increased risk of endometrial cancer. Information on the possible potential carcinogenic effect of tamoxifen on the ovary, however, has been limited, mainly because of the overall low incidence of ovarian carcinoma. In addition, there is the confounding variable posed by the diverse here-ditary breast and ovarian cancer syndromes which tend to occur in a younger age group. Here, we present a case of a postmenopausal woman who was treated for six years with tamoxifen for breast cancer before being diagnosed with endometrioid carcinoma of the ovary. We believe that given the age of the patient and the duration of tamoxifen use, the occurrence of ovarian endometrioid carcinoma may be associated with long-term tamoxifen use.

Analysis of MDR1 expression in normal and malignant endometrium by reverse transcription-polymerase chain reaction and immunohistochemistry.

The purpose of this study was to quantitate the expression of human MDR1 mRNA levels in normal endometrium and in endometrial carcinoma and to determine the association of MDR1 levels with prognostic indicators. Endometrial samples from 43 postmenopausal patients with endometrial carcinoma and 38 patients (controls) with benign disease undergoing hysterectomy were snap-frozen. MDR1 levels were determined by quantitative reverse transcription-PCR (RT-PCR) and compared to sensitive and resistant cell lines. Immunohistochemistry was done with MM4.17, an anti-MDR1 antibody, on paraffin sections, and the results were compared to those obtained from RT-PCR. Data was analyzed using the Kruskal-Wallis and Bonferroni tests, setting the P value at 0.05. In both postmenopausal endometrial tissue and tumors, MDR1 expression was localized to the epithelial cell layer. Comparison of immunohistochemistry and RT-PCR results demonstrated a correlation of 80%. In control patients, MDR1 expression was significantly higher in postmenopausal endometrium (n = 15) than in the proliferative premenopausal endometrium (n = 15; P = 0.0024). MDR1 expression in all tumors was lower than that measured in the postmenopausal controls. Between each tumor group, there was no significant difference in the MDR1 levels observed. MDR1 expression was significantly lower in patients with high nuclear grade (n = 18) tumors when compared to patients with low nuclear grade (n = 14; P = 0.04) tumors. Comparison of MDR1 levels with multiple prognostic indicators for endometrial cancer was only significant for nuclear grade. The data indicate that MDR1 expression is not a major component of the drug resistance observed in primary endometrial tumors.

The genetics of ovarian cancer: an assessment of current screening protocols and recommendations for counseling families at risk.

Although the need for effective ovarian cancer screening is apparent, a highly sensitive and specific screening methodology has yet to be elucidated. 42-44 Given that there are more than 43 million women in the United States older than 45 years of age and that the average cost of a pelvic sonogram is $ 275 (and $ 45 for CA125 screening), the screening of this population is estimated to increase health care costs by $ 14 billion per year. 45 The additional cost of BRCA1 screening varies according to the level of diagnostic effort required to establish BRCA1 gene mutations in a particular family and ranges from $ 295 to $ 1,200 per sample. Assuming an average cost of $ 600 per sample, initial screening of these same women would likely increased costs in excess of $ 25 billion. Current knowledge and technology in ovarian cancer screening has not yet proved beneficial for the general population or for women with fewer than two affected family members. For women with two or more affected family members, there is a 3% chance of that patient being a proband in a hereditary cancer syndrome family. 11,46 In this group, who may be at increased risk for developing a malignancy, heightened surveillance is warranted, although there are still no data to confirm that screening even these high-risk women will reduce mortality. Nevertheless, annual bimanual examination, serum CA125, and transvaginal sonography are recommended among this particular subgroup of women at risk, and are likely to be recommended for young, asymptomatic, at-risk women who screen positive for the 185delAG BRCA1 deletion commonly found in persons of Ashkenazi Jewish ancestry. It is only through prospective, randomized trials that reliable data regarding the risk/benefit ratio of ovarian cancer screening among various populations at risk will be determined. The results of the prospective/randomized PLCO trial and the mature data from ongoing prospective, nonrandomized screening trials for women with a family history of cancer may provide this information and are eagerly awaited.

Mature results of a phase II trial of concomitant cisplatin/pelvic radiotherapy for locally advanced squamous cell carcinoma of the cervix.

PURPOSE: Patients with locally advanced squamous cell carcinoma of the cervix have a poor prognosis when treated by standard radiotherapy (RT) alone. Factors such as large tumor volume or nodal disease result in pelvic and distant treatment failures. Cisplatin (CDDP), a known radiosensitizer with documented activity in squamous cell carcinomas, was used in a phase II prospective study to evaluate the efficacy of combined chemo/radiotherapy in locally advanced squamous cell carcinomas of the cervix. METHOD: CDDP was administered (20 mg/m2) daily X 5 at 21-day intervals with concomitant external beam and intracavity RT. Standard RT was delivered at 1.8-2.0 Gy/day, 5 fractions per week for 5 weeks. Intracavitary cesium insertions were planned to treat point A to approximately 80 Gy. RESULTS: Fifty-nine patients were enrolled from March 1986 to July 1990. Four patients were voluntarily withdrawn, leaving 55 patients evaluable for response. Of these, 16 were Stage IB/IIA, 11 were Stage IIB, 24 were Stage III, and 4 were Stage IV. The median age of patients enrolled was 47 years (range 27-79). Median follow-up time was 65 months (range 60-113). Histopathologic confirmation of node status was available in 33 patients, of whom 45.5% (15/33) had nodal metastases. Overall response was 96% (CR = 87%, PR = 9.0%) and 3.6% had progressive disease during treatment. Forty-six patients were evaluable at 5 years for overall and disease-free survival. Calculations were based on Kaplan-Meier product limit estimates. The 5-year survival was 73% for Stage IB/IIA, 60% for Stage IIB, 67% for Stage III, and 25% for Stage IV. The disease-free survival at 5 years was 73% for Stage for IB/IIA, 50% for Stage IIB, 67% for Stage III, and 25% for Stage IV. Hematologic toxicity was severe but tolerable. No treatment-related deaths occurred. CONCLUSION: Concomitant CDDP/RT is a safe and tolerable method of treating patients with locally advanced squamous cell carcinoma of the cervix. Our data suggest a benefit in both disease-free and 5-year survival, particularly notable among patients with Stage III disease.

Altered expression of transforming growth factor-beta 1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix.

BACKGROUND: Transforming growth factor-beta 1 (TGF-beta 1) is a potent growth inhibitor of epithelial cell growth, but can also stimulate stromal cell growth. Loss of responsiveness to TGF-beta 1 or loss of TGF-beta 1 itself may be important in the progression of cervical intraepithelial neoplasia (CIN) to invasive cervical carcinoma. METHODS. To examine the expression of TGF-beta in early stages of malignant transformation of the uterine cervix, paraffin embedded tissue samples from 11 patients with normal cervical epithelium, 15 with CIN I-III, 12 with microinvasive, and 18 with invasive squamous cell carcinoma were examined using an immunohistochemical technique. Tissues were immunostained with polyclonal antibodies that react with intracellular and extracellular forms of TGF-beta 1. RESULTS: Percent positive staining for the intracellular form of TGF-beta 1 was 100% for normal epithelium, 73.3% for CIN, and 44.1% for invasive carcinomas, (P = 0.002). Percent positive staining for the extracellular form of TGF-beta 1 was 63.6% for stroma underlying normal epithelium, 60% for stroma associated with CIN, and 94.1% for stroma surrounding invasive cancer (P = 0.007). CONCLUSIONS: Decreased expression of intracellular TGF-beta 1 in neoplastic epithelium and increased expression of extracellular TGF-beta 1 in stroma associated with invasive cervical carcinoma suggest that an early event in the neoplastic transformation of cervical epithelia] cells may involve the loss of TGF-beta 1. Tumor progression may be indirectly promoted by TGF-beta 1 secreted into or produced by supporting stromal elements.