Fibroblast growth factor receptor is a mechanistic link between visceral adiposity and cancer.

Epidemiological evidence implicates excess adipose tissue in increasing cancer risk. Despite a steeply rising global prevalence of obesity, how adiposity contributes to transformation (stage a non-tumorigenic cell undergoes to become malignant) is unknown. To determine the factors in adipose tissue that stimulate transformation, we used a novel ex vivo system of visceral adipose tissue (VAT)-condition medium-stimulated epithelial cell growth in soft agar. To extend this system in vivo, we used a murine lipectomy model of ultraviolet light B-induced, VAT-promoted skin tumor formation. We found that VAT from mice and obese human donors stimulated growth in soft agar of non-tumorigenic epithelial cells. The difference in VAT activity was associated with fibroblast growth factor-2 (FGF2) levels. Moreover, human and mouse VAT failed to stimulate growth in soft of agar in cells deficient in FGFR-1 (FGF2 receptor). We also demonstrated that circulating levels of FGF2 were associated with non-melanoma tumor formation in vivo. These data implicate FGF2 as a major factor VAT releases to transform epithelial cells-a novel, potential pathway of VAT-enhanced tumorigenesis. Strategies designed to deplete VAT stores of FGF2 or inhibit FGFR-1 in abdominally obese individuals may be important cancer prevention strategies as well as adjuvant therapies for improving outcomes.

The CD44 receptor is a molecular predictor of survival in ovarian cancer.

PURPOSE: CD44 is a cell surface receptor implicated in cancer progression and metastases. Malignant tumors may show a loss of CD44 splice control mechanisms. We investigated the role of CD44 splice variant expression in ovarian tumors and metastases, and its association with survival. EXPERIMENTAL DESIGN: We tested CD44 expression in 142 cases of epithelial carcinoma of the ovary and 265 metastatic sites by immunohistochemistry. RESULTS: Survival analysis showed that the expression of CD44s, CD44-v4, -v5, -v6, -v9, and -v10 are significant predictors for survival in univariate analysis. After stage, the expression of CD44-v10 in metastases was the strongest predictor of decreased survival in multivariate analysis (p = 0.0009). Conversely, CD44-v10 expression in the primary tumor was an independent predictor of improved survival in multivariate analysis (p = 0.0002). The expression of CD44s in the tumor/stroma interface of the primary tumor was associated with improved survival (p < 0.0001). CONCLUSIONS: CD44 variant expression is a molecular prognostic maker for epithelial ovarian carcinomas. CD44-v10 expression is an independent prognostic indicator and the site of expression determines a positive or negative influence in survival. Our results also indicate that CD44 may be involved in important tumor/stroma interactions.

Clear cell carcinoma of the ovary: characterization of its CD44 isoform repertoire.

OBJECTIVE: CD44 is a cell surface receptor implicated in tumor metastases. We have previously shown that there is a loss of CD44 splice control in clear cell carcinoma (CCCa) of the ovary. Our aim is to characterize the expression of CD44-3v, -5v, -7v, and -10v in clear cell ovarian tumors and to determine their prognostic value. METHODS: Twenty-two cases of ovarian CCCa were studied for CD44-3v, -5v, -7v, and -10v expression by immunocytochemistry. RESULTS: The primary tumors showed expression of CD44-3v, -5v, -7v, and -10v in 44, 55, 61, and 39% of the cases, respectively. We were able to compare the expression of CD44 in the primary tumor and metastatic sites from the same patient in 7 cases (metastatic sites n = 16). We observed decreased immunoreactivity of CD44-3v, -5v, -7v, and -10v in 67, 100, 93, and 92% of the sites, respectively. CD44-3v and -10v expression was absent in 100% of the nonaffected contralateral ovaries while -7v and -10v were expressed in 1/11 (9%) of them. When CD44-10v was not expressed in the primary tumor, only 18% of the women recurred or died of disease; in contrast, of the cases where it was present, 71% of the women recurred or died of disease (P = 0.049). CONCLUSIONS: There is aberrant alternative mRNA splicing in the development of CCCa of the ovary when compared to the contralateral nonaffected ovary. The expression of CD44-10v correlates with survival. Larger series are needed to further understand the role of CD44 isoforms in ovarian cancer metastases.

CD44-9v and CD44-10v are potential molecular markers for squamous cell carcinoma of the vulva.

OBJECTIVE: CD44 is a cell surface glycoprotein widely distributed in the extracellular matrix. CD44 isoforms arising from alternative mRNA splicing are implicated in tumor metastases. The aim of this study is to investigate the expression of CD44s and two splice variants, CD44-9v and CD44-10v, in squamous cell carcinoma (SCC) of the vulva as well as its correlation with lymph node (LN) metastases and disease-free survival. METHODS: Thirty-five SCC vulvar tumors were evaluated for CD44s, CD44-9v, and CD44-10v expression by immunocytochemistry. One nonmetastatic LN was studied also. In cases with LN metastases, the metastatic LN as well as a nonmetastatic LN from the same patient were evaluated. RESULTS: CD44s and CD44-9v were expressed in all epithelia--normal, dysplastic, and SCC. However, intensity and distribution of expression of 9v isoforms changed within the tissue containing invasive cancer. CD44-9v expression was downregulated in the most differentiated cells within the carcinoma, mainly in patients who had disease recurrence or eventually died of disease (P = .031). All metastatic tumor to LNs was immunoreactive also for CD44-9v. CD44-10v expression was present in 78% of tumors and 56% of normal epithelium. Interestingly, CD44-10v membrane expression, but not cytoplasmic expression, correlated with disease recurrence (P = .035). CONCLUSION: Our findings warrant larger multi-institutional studies to determine the potential of CD44-9v and CD44-10v as molecular markers of disease recurrence in vulvar carcinoma. We propose to test the use of anti-CD44-9v monoclonal antibody for radioimmunoimaging of occult LN metastases.

Prognostic value of CD44 expression in invasive squamous cell carcinoma of the vulva.

OBJECTIVE: CD44 is a cell adhesion molecule that binds extracellular matrix. CD44 isoforms arising from alternative mRNA splicing are implicated in tumor metastases. The aim of our study is to investigate the expression of CD44 splice variants and its correlation to lymph node metastases and disease-free survival in squamous cell carcinoma (SCC) of the vulva. METHODS: Thirty-five cases of SCC of the vulva were evaluated for CD44 splice variants -3v, -4v, -5v, and -7v expression by immunocytochemistry. When available one nonmetastatic lymph node (LN) was also studied. In cases with LN metastases, the metastatic LN as well as a nonmetastatic LN from the same patient were evaluated. RESULTS: All CD44 variants studied were expressed in all epithelium: normal, dysplastic, and SCC. CD44 variants showed decreased immunostaining in the tumor cells when compared to normal epithelium. Furthermore, intensity of expression of the CD44 isoforms changed within the tissue containing invasive cancer. Interestingly, CD44-4v expression was downregulated in the most differentiated cells within the carcinoma, mainly in patients who had disease recurrence or died of disease (P = 0.004). Confirming prior publications, CD44-5v and -7v expression did not correlate with survival. One hundred percent of metastatic tumors to LNs were immunoreactive with CD44-3v and only 1/30 normal LN had CD44-3v expression. Eighty percent of metastatic tumors to LNs were immunoreactive for CD44-4v. However, 3 LNs without tumor were also immunoreactive with CD44-4v. CONCLUSION: CD44-4v is a potential molecular marker of disease recurrence in vulvar carcinoma. A larger multiinstitutional study is needed to evaluate the specificity of CD44-3v expression in LN metastasis. If a larger scale study confirms our findings, a CD44-3v antibody could be used for radioimmunoimaging of occult lymph node metastases in patients with vulvar cancer.

CD44 splice variant expression in clear cell carcinoma of the ovary.

OBJECTIVE: CD44 is a surface glycoprotein widely distributed among different tissues. Malignant tumors may show a more complex pattern of CD44 expression, indicating a loss of splice control. The aim of our study is to investigate the expression of CD44 splice variants (CD44v) and its metastatic potential in clear cell carcinoma of the ovary. METHODS: Twenty-two cases of clear cell carcinoma of the ovary were evaluated for CD44 standard form (CD44s) and splice variants: -4v, -6v, and -9v expression by immunocytochemistry. RESULTS: Twenty-one primary ovarian tumors and 23 metastatic sites were available for evaluation. Eighteen of 21 (86%) of ovarian sections studied expressed CD44s; 15/21 (71%) expressed CD44-4v; 14/21 (67%) expressed CD44-6v; and 12/21 (57%) expressed CD44-9v. Of 23 metastatic sites evaluated, 87% expressed CD44s. In contrast, only 5 (22%) metastases had CD44-4v and CD44-6v expression and 8 (35%) had CD44-9v immunoreactivity. None of 10 normal contralateral ovaries expressed CD44s or any splice variants. In 2 cases we had tumor available from the primary surgery, and subsequent recurrences. Both recurrences showed decreased expression of CD44-4v and CD44-6v. CONCLUSIONS: Clear cell carcinoma of the ovary shows an abnormal pattern of CD44s expression and mRNA splicing when compared to the contralateral normal ovary in the same patient. Metastases of clear cell carcinoma show a downregulation in expression of some splice variants. Furthermore, we have data that suggest that as the tumors recur, CD44s and its isoforms are downregulated. Our results suggest that alternative mRNA splicing of CD44 may be important in the development of metastases from clear cell carcinoma of the ovary.

Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women.

OBJECTIVE: To investigate the significance of race and histologic type as prognostic factors in endometrial carcinoma. METHODS: We conducted a retrospective review of the medical records of all patients diagnosed with endometrial cancer from 1982 to 1995. Patients' clinical and pathologic characteristics were analyzed. RESULTS: The sample consisted of 401 patients, 59.9% (N = 229) were blacks and 40.1% (N = 153) were non-blacks. The mean age was 63.7 +/- 11.6 years. The histologic subtypes of endometrial carcinoma included 346 endometrioid (86.3%), 42 papillary serous (10.5%), and 13 clear cell (3.2%) adenocarcinomas. We found 79% of endometrioid adenocarcinomas were stage I or II compared to 26% of papillary serous tumors and 58% of clear cell carcinomas (P < 0.01). Eighty-eight percent of patients with papillary serous and 77% of patients with clear cell cancers were black (P < 0.01). Within each stage, patients were treated similarly irrespective of cell type or race. Five-year survival for endometrioid, papillary serous and clear cell adenocarcinomas was 69, 18, and 25%, respectively (P < 0.01). Black women had poorer 5-year survival (56%) than non-black women (71%). In multivariate analyses using age, stage, race, and histology, only stage and histology were independent risk factors for survival. CONCLUSIONS: Patients with papillary serous and clear cell endometrial cancer were more likely to be black, present at an advanced stage of disease, and have poor survival compared to patients with endometrioid adenocarcinoma. This may help to explain the poorer survival reported in blacks with endometrial cancer.

CD4 lymphocytes in women with invasive and preinvasive cervical neoplasia.

OBJECTIVE: To assess the relationship between CD4 lymphocyte population and stage of disease in cervical neoplasia. METHODS: Study population was 107 women with invasive cervical cancer, 116 women with cervical intraepithelial neoplasia (CIN), and 32 women without neoplasia diagnosed in 1988-1994. All women under age 50 were seronegative for the human immunodeficiency virus (HIV). All women over age 50 with CD4:CD8 ratio below normal were HIV-negative. Stage was defined by FIGO criteria using clinical findings. CD4 and CD8 lymphocyte populations were enumerated by flow cytometry prior to treatment. The normal range of CD4 counts was defined as 537-1571 cells/mm3. RESULTS: Distribution of CD4 count was similar in stages I (n = 40), II (n = 24), and III (n = 32), with 31% below normal and 9% above normal (mean CD4 count = 881). However, in stage IV (n = 11), 64% were below normal and 18% above normal (mean CD4 = 591). The difference in distribution between stages I-III and stage IV was statistically significant. Among 116 CIN patients, 10% had CD4 counts below normal and 3% above normal (mean CD4 = 910). Among 32 women without cervical neoplasia, 0% had CD4 counts below normal and 3% above normal. The difference between CIN and invasive cancer in the distribution of CD4 counts and CD8 counts was significant (P < 0.01). There was no difference in the CD4 count distribution by CIN severity. Forty-five percent of patients with below-normal CD4 counts at diagnosis developed recurrent cancer compared to 43% of patients with normal or above-normal CD4 counts. CONCLUSION: Women with invasive cervical cancer have lower CD4 counts and a broader distribution compared to women with preinvasive or no neoplasia. Metastatic cancer at diagnosis was associated with severely depressed CD4 count.

Age, substance abuse, and survival of patients with cervical carcinoma.

BACKGROUND: The poor survival of young patients with cervical cancer in a low income, disadvantaged community stimulated an investigation of pathologic and behavioral risk factors. METHODS: The records of 1173 patients with cervical cancer diagnosed in 1967-1988 were evaluated with respect to age, stage, histology, and presenting symptoms. Histopathologic risk factors were evaluated in 196 patients with Stage IB disease treated by initial hysterectomy. Substance abuse behaviors were evaluated for 332 symptomatic patients with Stages IB-III disease diagnosed from 1976 to 1988. RESULTS: There were no significant age-related differences in survival for patients without squamous cell carcinoma or those with Stage IA and asymptomatic Stage IB squamous cell carcinoma. Women age 70 years and older had a poorer survival rate than did younger women with Stages IB-III disease. Symptomatic patients with squamous cell carcinoma younger than age 50 years had a poorer survival than did patients age 50-69 years with Stages IB/IIA, IIB, and III disease. For patients with symptomatic Stage IB tumors, poor prognostic histopathologic factors were distributed equally among women younger than age 50 and those aged 50-69 years. Substance abuse was significantly more prevalent among younger patients, and patients who smoked or abused alcohol or drugs had significantly poorer survival than did nonsubstance abusers. However, in a multivariate analysis of age, stage, and substance abuse, young age remained a significantly poor prognostic factor. CONCLUSIONS: Substance abuse may contribute to poor outcome of young patients with symptomatic squamous cell carcinoma but does not explain adequately their poor survival.

Clinical impact of chemotherapy-induced thrombocytopenia in patients with gynecologic cancer.

PURPOSE AND METHODS: This retrospective analysis of 501 patients with gynecologic cancer treated with chemotherapy evaluates the relationship between platelet count and clinical bleeding, as well as the clinical effects of platelet transfusion therapy. Thrombocytopenic patients were divided into six groups according to platelet counts, and major or minor bleeding manifestations were documented. Thrombocytopenia was defined as a platelet count less than 100,000/microL. RESULTS: Thrombocytopenia occurred in 182 (36.3%) patients over 808 of 1,546 chemotherapy cycles (52%). No intracranial or life-threatening bleeding occurred in any patient. The majority of patients (139 [76.4%]) had no clinical bleeding. Minor bleeding, such as purpura, occurred in 34 patients (18.7%) and 44 cycles (5.4%). Major bleeding occurred in nine patients (4.9%) and 10 cycles (1.3%). Five major bleeding events occurred in 49 patients with platelet counts between 0 and 10,000/microL. Forty-three of these patients received platelet transfusions. Thirty-eight of 43 transfused patients (88.3%) had no bleeding. Of the remaining five patients, two were transfused prophylactically with no effect. Three major bleeding events occurred in patients with platelet counts that ranged from 11,000 to 20,000/microL, but these were due to chronic instrumentation or trauma. In patients with platelet counts more than 20,000/microL, major bleeding occurred only from necrotic metastatic lesions. Random-donor platelet transfusions provided inconsistent increments in platelet counts. Overall, 27.5% of patients achieved the expected increase in platelet number based on units of platelet concentrate transfused. The use of single-donor or human leukocyte antigen (HLA)-matched platelets did not provide greater increments in those patients who were refractory to random-donor platelets. CONCLUSION: Platelet counts > or = 10,000/microL are not associated with spontaneous major bleeding. Prophylactic platelet transfusions in patients with gynecologic malignancies and chemotherapy-induced thrombocytopenia should be limited to those with platelet counts < or = 10,000/microL, provided they are not bleeding and have no major anatomic or pathophysiologic precursors of bleeding.

Kaolmite layer structure: relaxation by dehydroxylation.

Single-crystal electron-diffraction data reveal features of metakaolin. The basal plane parameters increase 2.2 percent in formation of metakaolin produced by heating kaolinite in air at 700 degrees C for 12 hours. This increase results from removal of the distortion of sheet structure (relaxation).