Bor-Ching Sheu

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.

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.

Cytokine regulation networks in the cancer microenvironment.

During carcinoma formation, cancer cells release various cytokines and growth factors into their surroundings and recruit and reprogram many other types of cells in order to establish a tumor microenvironment. Consequently, the tumor tissues almost always contain a large number of endothelial cells, fibroblasts, and infiltrating inflammatory cells that in turn produce a variety of cytokines. The cytokines produced by these cells have been posited as key factors in modulating immune response either against or in favor of tumorigenesis in the microenvironment. The interactions that take place between immune and cancer cells are complex, involving multiple cascades of cytokines, chemokines, and/or growth factors. In this review, we address the essential pro- and anti-tumorigenic roles of cytokines in the tumor microenvironment. As the interaction of cytokines, growth factors, and cancer cells forms a comprehensive network at the tumor site that is then responsible for the overall progression or rejection of the tumor, the current review links the microenvironment-derived cytokines and growth factors to a number of different kinds of human carcinogenesis models. Multifunctional cytokines, extracellular matrix mediators, and regulatory cytokines in the cancer environment are all shown to be key factors in the different cancer immune-editing systems. The characterization of cytokine networks in various types of cancer cells may yield important information for understanding the immune-related mechanisms of cancer development, and this knowledge may have subsequent application in cancer immunotherapy.

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.

Down-Regulation of CD25 Expression on the Surface of Activated Tumor-Infiltrating Lymphocytes in Human Cervical Carcinoma

To investigate the activation status of tumor-infiltrating lymphocytes (TILs) within the tumor milieu of human cervical carcinoma, we quantitatively measured and compared the activation markers on lymphocyte subpopulations which infiltrating normal and neoplastic cervix. A total of 20 patients with stage IA to IIA cervical cancer (cancer group) and 10 women with normal cervix (control group) were enrolled in this study. Mononuclear cells were isolated from tissue specimens by mechanical dispersal technique and three-color flow cytometry was utilized for the quantification of activation markers on lymphocyte subsets. Compared with control group, lymphocytes isolated from cancer tissue consisted of higher proportions of B cells (7.23% +/- 4.49% vs. 3.67% +/- 3.19%, P = 0.016) and T cells (72.33% +/- 8.70% vs. 53.15% +/- 17.36%, P = 0.004), but an inverted CD4:CD8 ratio (0.74 +/- 0.27 vs. 1.14 +/- 0.28, P = 0.002) and decreased NK cells (7.53% +/- 4.33% vs. 16.00% +/- 11.82%, P = 0.035). Low expression of CD25, but not CD69 and HLA-DR was observed on both CD4+CD3+ and CD8+CD3+ T cells derived from cervical cancer (P < 0.0001). Further dual activation marker analysis demonstrated that the expression of CD25 was dissociated from CD69 and HLA-DR on the same TILs in cancer tissue (P < 0.001). TILs in the tumor microenvironment can be functionally inhibited and lose the ability of clonal proliferation due to depressed expression of CD25.

Synchronous primary carcinomas of the endometrium and ovary

Objectives: Synchronous carcinomas of the endometrium and ovary may indicate either independently developing neoplasms or metastatic disease. The clinical implications and prognosis of these two categories are quite different. The objectives of this study were to identify and evaluate the empirical criteria and significant therapeutic implications. Method: The National Taiwan University Hospital Cancer Registry records and pathological reports from 1977 to 1994 were reviewed. Empirical criteria were used to identify synchronous primary cancers. Results: A total of 322 patients had endometrial cancer and 421 patients had ovarian cancer in our Cancer Registry records. Eleven patients had simultaneous cancer involvement of both the endometrium and ovary. Six cases fulfilled the criteria of synchronous primary carcinomas of the endometrium and ovary. Of these, five were alive and free of disease for 35–144 months (median 94.2 months). The disease‐free survival rates between patients with synchronous primary and metastatic cancers of different histologic types showed a statistically significant difference (P = 0.013). No statistical significance was noted for different histologic types (P > 0.5). Conclusions: The empirical criteria used here were useful in identifying synchronous primary cancers of the endometrium and ovary. The favorable clinical outcome may relate to early detection of early‐stage disease and low‐grade malignancy with an indolent growth rate. Surgical management with or without adjuvant therapy has a satisfactory outcome in our experience.

Limb defects after chorionic villus sampling

Objective To clarify the association between limb defects and chorionic villus sampling (CVS) Methods Questionnaires were sent to 165 major obstetric units in Taiwan to survey the incidence of limb defects with and without CVS exposure during 1991. Limb defects with CVS exposure from September 1990 to June 1992 were also surveyed. The spectrum of limb defects in CVS-exposed and general populations were compared by the Poisson test. Results The incidence of limb defects in the surveyed general population in 1991 was 0.032% and that with CVS exposure was 0.294%, a statistically significant difference (P < .001). The incidence of severe limb defects in the general population was 0.0026% and that with CVS exposure was 0.22%, also statistically significant (P < .001). Twentynine cases of limb defects after CVS were reported from September 1990 until June 1992:19 cases with transverse limb reduction, two with mid-palm reduction, seven with adactyly or hypodactyly, and one with syndactyly. Four cases also had oromandibular-limb hypogenesis syndrome. Conclusions The incidence of limb defects, especially the severe types, was increased after CVS. The spectrum of limb defects with CVS exposure was more severe than the limb defects seen in the general population and showed a specific pattern ranging from hypodactyly, adactyly, and transverse limb reduction, to oromandibular-limb hypogenesis. A correlation between the severity of limb defects and the timing of CVS was suggested.

Adenomyosis and its variance: adenomyoma and female fertility.

Extensive adenomyosis (adenomyosis) or its variance, localized adenomyosis (adenomyoma) of the uterus, is often described as scattered, widely-distributed endometrial glands or stromal tissue found throughout the myometrium layer of the uterus. By definition, adenomyosis consists of epithelial as well as stromal elements, and is situated at least 2.5 mm below the endometrialmyometrial junction. However, the diagnosis and clinical significance of uterine adenomyosis and/or adenomyoma remain somewhat enigmatic. The relationship between infertility and uterine adenomyosis and/or adenomyoma is still uncertain, but severe endometriosis impairs the chances of successful pregnancy when using artificial reproductive techniques. To date, there is no uniform agreement on the most appropriate therapeutic methods for managing women with uterine adenomyosis and/or adenomyoma who want to preserve their fertility. Fertility has been restored after successful treatment of adenomyosis using multiple modalities, including hormonal therapy and conservative surgical therapy via laparoscopy or exploratory laparotomy, uterine artery embolization, and other methods, including a potential but under-investigated procedure, magnetic resonance-guided focused ultrasound. This review will explore recent publications that have addressed the use of different approaches in the management of subfertile women with uterine adenomyosis and adenomyoma.

Prognosis and Treatment of Squamous Cell Carcinoma from a Mature Cystic Teratoma of the Ovary

BACKGROUND/PURPOSE Squamous cell carcinoma (SCC) arising from a mature cystic teratoma of the ovary is rare and only reported sporadically. Clinical information on the disease is limited. This study assesses the clinical characteristics, treatment, outcome and prognostic factors of reported cases. METHODS Two hundred and twenty cases from 1976 through to 2005 in MEDLINE were analyzed for patient age, clinical and laboratory data, extent of disease, tumor markers, treatment and survival rates. Only the 188 cases with surgical staging were included in the survival analysis. RESULTS The disease occurred most often in elderly women (mean, 55.0 +/- 14.4 years) and cysts were large (mean, 13.7 +/- 5.7 cm). Abdominal pain (71.6%) was the most common symptom. Preoperative serum SCC antigen level had a high positive rate (81.3%). Overall 5-year survival rate for all stages was 48.4%. For Stage I, the 5-year survival rate was 75.7%; stage II, 33.8%; stage III, 20.6%; and stage IV, 0% (p < 0.0001). Univariate analysis revealed that tumor stage, patient age, tumor size, preoperative SCC antigen and CA125 levels, and optimal debulking were significant prognostic factors. Further investigation into treatments for all stages revealed that postoperative adjuvant chemotherapy may produce a better survival rate for both stage III and stage IV cases. However, postoperative radiotherapy did not show a similar effect. Multivariate analysis indicated that stage and optimal debulking were significant factors that influenced survival. CONCLUSION A mature cystic teratoma should be treated as early as possible. Tumor stage and optimal debulking are critical to survival. Unlike SCCs of the uterine cervix, postoperative adjuvant chemotherapy may produce a better result than adjuvant radiotherapy for advanced-stage cases.