Su-Cheng Huang

Predominant Th2/Tc2 Polarity of Tumor-Infiltrating Lymphocytes in Human Cervical Cancer

Cytotoxic T lymphocytes (Tc) play a central role in cellular immunity against cancers. The cytotoxic potential of freshly isolated tumor-infiltrating lymphocytes (TILs) is usually not expressed. This suggests the possible existence of as yet unspecified and perhaps complex immunosuppressive factors or cytokines that affect the anti-tumor capacity of these TILs in the tumor milieu. In the present study, we demonstrated for the first time that TILs derived from human cervical cancer tissue consist mainly of Th2/Tc2 phenotypes. In vitro kinetic assays further revealed that cancer cells could direct the tumor-encountered T cells toward the Th2/Tc2 polarity. Cancer cells promote the production of IL-4 and down-regulate the production of IFN-γ in cancer-encountered T cells. The regulatory effects of cervical cancer cells are mediated mainly by IL-10, and TGF-β plays only a synergistic role. The cancer-derived effects can be reversed by neutralizing anti-IL-10 and anti-TGF-β Abs. IL-10 and TGF-β are present in cancer tissue and weakly expressed in precancerous tissue, but not in normal cervical epithelial cells. Our study strongly suggests important regulatory roles of IL-10 and TGF-β in cancer-mediated immunosuppression.

Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers

The role of breast-feeding in perinatal transmission of hepatitis C virus (HCV) was explored in 15 HCV-infected mothers and their infants. The 15 carrier mothers had anti-HCV titers ranging from 1:80 to 1:40,000 and also had HCV-ribonucleic acid with concentrations ranging from 10(4) to 2.5 x 10(8) copies/ml. Both anti-HCV antibody and HCV-ribonucleic acid were present in colostral samples in much lower levels, but none of the 11 breast-fed infants had evidence of HCV infection for up to 1 year of age. Thus breast-feeding seems safe for these infants.

Activation status of T and NK cells in the endometrium throughout menstrual cycle and normal and abnormal early pregnancy

Endometrial lymphocytes were studied at all stages throughout the menstrual cycle and early pregnancy by flow cytometry to examine different lymphocyte subpopulations and the expression of the T- and NK-cell activation markers. After pregnancy, CD8+CD3+ lymphocytes were decreased in the decidua. In both endometrium and decidua, more T cells expressed CD69, CD71, HLA-DR, and CD38 antigens than in peripheral blood. After pregnancy, CD71+CD3+ lymphocytes were further increased. CD25+CD3+ lymphocytes decreased significantly in the endometrium and decidua of ectopic pregnancies, but not in the decidua of normal pregnancies. These findings indicate that T cells are regionally activated in the first trimester, and it may be the result of the stimulation by fetal antigens. NK cells were the most abundant cell type in the decidua, which expressed the phenotype CD16- CD56+, and CD57-CD56+. The proportion of activated decidual NK cells was increased in anembryonic pregnancies more than in normal pregnancies, although the total NK subpopulation was similar in both groups. This might result in increased NK cytotoxicity in anembryonic pregnancies. In conclusion, T cells are activated, but NK cytotoxicity is decreased in the decidua of early normal pregnancies. This might be important in the control of trophoblast growth and placental development.

Up-regulation of Inhibitory Natural Killer Receptors CD94/NKG2A with Suppressed Intracellular Perforin Expression of Tumor-Infiltrating CD8+ T Lymphocytes in Human Cervical Carcinoma

Inhibitory signals that govern the cytolytic functions of CD8(+) T lymphocytes have been linked to the expression of natural killer cell receptors (NKRs) on CTLs. There is limited knowledge about the induction of inhibitory NKR (iNKR) expression in vivo. Up-regulation of iNKRs has been linked to the modulation of the virus- and/or tumor-specific immune responses in animal models. In the present study, we directly examined the expression of various NKRs on tumor-infiltrating lymphocytes (TILs) derived from human cervical cancer. We found that in human cervical cancer, the percentage expression of immunoglobulin-like NKR(+)CD8(+) T lymphocytes were similar in gated CD8(+)-autologous TILs and peripheral blood mononuclear cells. On the contrary, cervical cancer-infiltrating CD8(+) T lymphocytes expressed up-regulated C-type lectin NKRs CD94/NKG2A compared with either peripheral blood CD8(+) T cells or normal cervix-infiltrating CD8(+) T lymphocytes. Dual NKR coexpression analyses showed that CD94 and NKG2A were mainly expressed on CD56(-)CD161(-)CD8(+) TILs within the cancer milieu. Immunohistochemical study showed that cervical cancer cells expressed abundant interleukin 15 (IL-15) and transforming growth factor-beta (TGF-beta). In kinetic coculture assay, cervical cancer cells can promote the expression of CD94/NKG2A on CD8(+) T lymphocytes. The cancer-derived effects can be reversed by addition of rIL-15Ralpha/Fc and anti-TGF-beta antibody. Functional analyses illustrated that intracellular perforin expression of CD8(+) T cells was minimal upon up-regulation of CD94/NKG2A. Kinetic cytotoxicity assays showed that up-regulated expressions of CD94/NKG2A restrain CD8(+) T lymphocyte cytotoxicity. Our study strongly indicated that cervical cancer cells could promote the expression of iNKRs via an IL-15- and possibly TGF-beta-mediated mechanism and abrogate the antitumor cytotoxicity of TILs.

Effects of menopause on intraindividual changes in serum lipids, blood pressure, and body weight—the Chin-Shan community cardiovascular cohort study

In Taiwan, the Chin-Shan Community Cardiovascular Cohort (CCCC) was assessed prospectively to determine whether the changes in cardiovascular risk factors for women age 45--54 years are due to menopause. The average paired percentage changes that occurred between baseline (1990-1991) and follow-up (4 years later) in fasting serum lipids were compared in three groups of women including groups of 59 and 224 who were pre- and postmenopausal, respectively, and a group of 118 who had spontaneously stopped menstruating. Postmenopausal women had the least gain in body mass index (BMI), whereas, mainly premenopausal women had increased systolic blood pressure (P<0.05). All women had elevated total cholesterol (TC) levels, with the greatest elevation in women transitioning into menopause (P<0.001). Low-density lipoprotein cholesterol (LDL-C) levels increased before and during the transition to menopause, but decreased after menopause (P<0.01). Age had significant association with changes in TC, triglyceride (TG) and LDL-C levels, whereas BMI had significant association with changes in TG, LDL-C, and high-density lipoprotein cholesterol (HDL-C) levels (P<0.05). After controlling for age and BMI, only differences in TC remained significant, with the greatest gain in women who stopped menstruating (12.9%) followed by pre- (6.5%) and postmenopausal women (4.8%). Changes in both systolic and diastolic blood pressures, and TG and HDL-C levels were not significantly different, but HDL-C levels declined between 11.5 and 14.7% in all groups. This study suggests an unfavorable effect of menopause on lipid metabolism, especially on the TC level, which was predominantly elevated during the transition to menopause. The decline of HDL-C is of concern.

Decidual Natural Killer Cytotoxicity Decreased in Normal Pregnancy but Not in Anembryonic Pregnancy and Recurrent Spontaneous Abortion

PROBLEM: The natural killer (NK) cell activity is depressed in the decidua of early normal pregnancy. Recently Morii et al. (Am J Reprod Immunol 1993;29:1–4) found that all early intradecidual CD3+ T cells expressed either T cell receptor (TCR) α/β or γ/δ but that the expression of the CD3+/TCR complex was down‐regulated.

Risk factors for recurrence in patients with stage IB, IIA, and IIB cervical carcinoma after radical hysterectomy and postoperative pelvic irradiation

Objective To identify risk factors for cancer recurrence in patients with stage IB, IIA, and IIB cervical carcinoma after abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation. Methods One hundred and eighty-seven patients with cervical carcinoma stage IB (n = 63), IIA (n = 43), and IIB (n = 81) disease who received abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation were followed-up for 2–10 years. The histologic type, grade, lymphovascular tumor emboli, tumor size, invasion sites, deep cervical stromal invasion, and pelvic lymph node metastases were assessed for correlation with cancer recurrence. Results Recurrence occurred in 45 cases (24%), of whom 40 had died of the disease at the 5-year follow-up period. Univariate proportional hazards analysis revealed that the significant risk factors were adenocarcinoma, bulky tumor size (4 cm or greater), lymphovascular tumor emboli, deep cervical stromal invasion, and lymph node metastases, especially iliac nodal metastases and bilateral nodal metastases. Multivariate proportional hazards analysis showed that bulky tumor size (hazard ratio 2.34), tumor emboli (hazard ratio 2.74) and iliac nodal metastases (hazard ratio 5.31) remained significant risk factors. In contrast, no deaths occurred in the other 142 cases who did not have recurrence. Conclusion This retrospective study suggests that stage IB, IIA, and IIB cervical carcinoma cases with the above-mentioned pathologic factors are at higher risk of recurrence after abdominal radical hysterectomy with pelvic lymph node dissection and postoperative pelvic irradiation.

Insulin-like growth factor binding protein-3 (IGFBP-3) acts as an invasion-metastasis suppressor in ovarian endometrioid carcinoma.

Metastasis and invasion occur in the majority of epithelial ovarian carcinoma at diagnosis. To delineate the molecular signature in ovarian cancer invasion, we established and characterized a human ovarian endometrioid carcinoma (EC) cell line OVTW59-P0 and its invasion-related sublines (P1–P4, in the order of increasing invasive activity). P4 showed faster migration and larger xenograft formation with metastasis than P0. By microarray analysis of different gene expression among P0–P4 sublines, one group of gene was found negatively correlated with cancer invasion. Among these genes, IGFBP-3 was identified as one of the most remarkably suppressed gene that showed lower gene expression in P4 than P0. Re-expression of IGFBP-3 in P4 effectively inhibited cell migration, invasion and metastasis, but did not affect cell proliferation. In 35 patients with EC tumors, low IGFBP-3 expression correlated clinically with higher tumor grade, advanced stage and poor survival. Our results provide evidence and indicate that IGFBP-3 plays an important role as an invasion-metastasis suppressor in ovarian EC.

Abnormal urodynamic findings after radical hysterectomy or pelvic irradiation for cervical cancer

Objective: To assess urodynamic study results in patients with cervical cancer who had received radical hysterectomy or pelvic irradiation or radical hysterectomy with pelvic irradiation. Methods: Forty‐two patients with stage IB cervical cancer after radical hysterectomy (group A), 11 patients at stage IB or IIA after pelvic irradiation (group B), 15 patients at stage IB or IIA after both radical hysterectomy and pelvic irradiation (group C) and 17 patients at stage IB before treatment (group D) as control were recruited for urodynamic examination. The evaluations for each case included a 20‐min pad test, uroflowmetry, both filling and voiding cystometry, and stress urethral pressure profile. ANOVA method with Bonferroni test and Pearson χ2‐test were utilized for statistical analysis. Results: The mean ages in sequential groups A, B, C and D were 52.9±10.2, 62.5±13.5, 49.8±11.7 and 49.4±12.5 years (P=0.02), respectively. The occurring frequency of either detrusor instability or low bladder compliance was 57%, 45%, 80% and 24%, respectively. Each group revealed decreased bladder capacity as 268.4±102.8, 164.1±62.9, 233.5±73.9 and 293.0±47.2 ml (P<0.0001). However, the frequency of abdominal strain voiding was 100% in groups A, B and C as compared to 0% in group D (P<0.01), and the frequency of abnormal residual urine (>50 ml) was 41%, 27%, 40% and 24%. Although each case showed a poor pressure transmission ratio (<100%), the frequency of positive pad test in each group was 81%, 46%, 100% and 18% (P<0.001). The functional urethral length decreased in each group and was 2.6±0.8, 2.3±0.8, 2.5±0.8 and 2.9±0.6 cm, but there were no significant differences in maximal urethral pressure or urethral closure pressure among the four groups. Conclusions: Our data show that abnormal urodynamic findings pre‐exist in patients with cervical cancer before treatment especially in bladder storing function, and that these findings may worsen, or that new abnormal findings may happen after radical hysterectomy or pelvic irradiation, or both.

Comparison of treatment outcomes of imipramine for female genuine stress incontinence

Objective To assess the efficacy of imipramine as a treatment of genuine stress incontinence and to explore the possible determining factors for treatment success and failure.