Song-Nan Chow

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.

Effects of menopause and obesity on lipid profiles in middle-aged Taiwanese women: the Chin-Shan Community Cardiovascular Cohort Study

In this cross-sectional study, we examined the associations between lipid profiles and menopausal status, age, and obesity in Taiwanese women. The study population, established in 1990-91, consisted of 671 premenopausal and 872 postmenopausal women from the Chin-Shan Community Cardiovascular Cohort (CCCC). The associations of age, body mass index (BMI), and menopausal status with serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apoproteins (Apo) A-1 and B, and lipoprotein (a) [Lp (a)] were evaluated. The results showed that menopause was associated with significant increases in TC, LDL-C, TG, and Apo B levels (all P < 0.001). Total cholesterol, LDL-C, TG, and Apo B levels increased consistently with BMI in middle-aged women, regardless of menopausal status. Among women aged 45-49, menopausal women had significantly higher levels of TC and LDL-C than premenopausal women (P < 0.01). However, TG and Apo B levels were higher in postmenopausal than in premenopausal women aged 50-54 years (P < 0.05). Standardized regression analyses showed all lipid variables, except those of Apo A1 and Lp (a) before menopause and TC, LDL-C, and Lp (a) after menopause, were significantly associated with BMI (all P < 0.01). We conclude serum lipid levels in Taiwanese women are no more strongly associated with menopause and BMI than with age.

Correlation of Prenatal Ultrasound and Postnatal Outcome in Meconium Peritonitis

Objectives: To study the relationship between prenatal ultrasound features and postnatal course of meconium peritonitis. Methods: Meconium peritonitis was diagnosed by prenatal ultrasound. Fetuses were treated by intrauterine paracentesis of ascites when indicated, and symptomatic newborns received surgery. Results: Totally 17 cases were enrolled. Prenatal ultrasound findings include abdominal calcification (16/17), fetal ascites (12/17), hydramnios (9/17), pseudocyst (7/17) and dilated bowel loop (6/17). Persistent ascites, pseudocyst or dilated bowel loop are most sensitive (92%) to predict postnatal surgery (p = 0.022). The survivors have a higher gestational age at birth (36.4 vs. 33.3 weeks, p = 0.008). Persistent ascites and postnatal persistent pulmonary hypertension of the newborns significantly correlate with neonatal mortality (p = 0.029 and 0.022). Conclusion: Prenatal ultrasound can predict the neonatal outcome in meconium peritonitis.

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.

Clinical significance of tumor-infiltrating lymphocytes in neoplastic progression and lymph node metastasis of human breast cancer.

To investigate the clinical significance of tumor-infiltrating lymphocytes (TILs) within the tumor milieu, we quantitatively measured and compared the subpopulations of TILs in 24 patients with stage I-III breast carcinoma. Peripheral blood mononuclear cells (PBMCs), normal breast parenchyma-infiltrating lymphocytes (NILs), and TILs were isolated from tissue specimens and quantified by flow cytometry. The results showed that increased proportion of CD8(+) T cells, with decreased proportion of CD4(+) T cells, was significant in gated CD3(+) TILs as compared to autologous NILs or PBMCs (P<0.001). The tumor-infiltrating CD8(+) T cells significantly increased with stage progression, reflected in a more strongly decreased CD4/CD8 percentage (P=0.003). The CD4/CD8 percentage of TILs was strongly correlated with lymphovascular permeation and subsequent lymph node metastasis (P<0.001). Increased percentages of tumor-infiltrating CD8(+) T cells with decreased CD4/CD8 percentages are of prognostic importance for cancer progression in human breast cancer.

Immune concept of human papillomaviruses and related antigens in local cancer milieu of human cervical neoplasia

It is presently the right time for clarifying human papillomavirus (HPV)‐associated cellular immunity and clinical implications before global HPV vaccination programs begin. Infection with oncogenic HPV associates with the progression of cervical neoplasia. Both cellular and humoral immune responses are essential for the clearance of HPV‐associated cervical lesions. There is increasing evidence that the immune system plays a pivotal role in determining the outcome of HPV infection. Viruses and associated neoplastic cells are proposed to have evolved mechanisms to avoid immune attack. T‐cell‐mediated immune responses against oncogenic HPV are believed to play a central role in cervical carcinogenesis. The presence of HPV‐specific cytotoxic T lymphocytes (CTL) in a majority of human cervical cancer patients provides an approach for further study of their functional role in modulating this malignancy. Tumor‐infiltrating lymphocytes (TIL) develop as manifestations of the recognition and defense against malignant cells by the host immune system. Cancer cells may overcome immune surveillance, either by downregulating the proliferation of HPV‐specific CTL, or altering the effector compositions of immune cells against HPV infections. TIL in the tumor microenvironment can be functionally inhibited and lose the ability of clonal proliferation as a result of depressed expression of IL‐2Rα. The upregulation of inhibitory signaling relates to the modulation of the virus‐ and/or tumor‐specific immune responses. Alteration of host genetic susceptibility may also lead to abnormal immune response as a general genomic instability resulting from virus persistence. Induction of HPV‐specific immune responses is anticipated as an intimate point for the treatment of cervical neoplasia.

Age of menopause of Chinese women in Taiwan

Menopause has been studied in the West for about 30 years [1,2]. However recent papers show that different ethnic groups produce different findings [2]. Numerous studies have highlighted the features of menopausal age in different populations and countries, but there have been few on Chinese women [3]. Our study was conducted to determine the mean age of natural menopause of Chinese women in Taiwan and to examine some relevant factors affecting the age of menopause. During July to November 1991, face-to-face interview studies were conducted with 771 Chinese women between the ages of 40 and 60 years, who were randomly sampled from a community in Taipei, Taiwan. According to the criteria of menopause [2], only 124 women who ceased menstruation naturally at least 12 months prior to the interview and with no experience of hormone use were the subjects of this report. The current mean

Malignant ovarian germ cell tumors

Objectives: Fifty patients with malignant ovarian germ cell tumors, which accounts for 10.8% of all ovarian malignancies, were treated from 1977 through 1994. Their cases are reviewed. Methods: The histology includes endodermal sinus tumor (EST) in 15 patients, immature teratoma in 14, dysgerminoma in 13, and mixed germ cell tumor in eight. The mean age at presentation was 21.5 years and mean primary tumor diameter was 16 cm. All patients underwent surgery as the initial treatment, and 10 received more than one operation. Postoperative adjuvant chemotherapy was not given to cases with stage Ia immature teratoma and dysgerminoma. VAC (vincristine, actinomycin D, cyclophosphamide) and BVP (bleomycin, vinblastine, cisplatin) regimens were utilized in early 1980s for EST and advanced‐stage tumors of immature teratoma and dysgerminoma. BEP (bleomycin, etoposide, cisplatin) and EP (etoposide, cisplatin) regimens were applied in advanced‐stage disease and some stage I disease since 1990. VIP (VP‐16, ifosfamide, cisplatin) regimen was employed as salvage regimen in cases where other combinations failed. Results: α‐Fetoprotein (AFP) was elevated in every tumor containing endodermal sinus element, and AFP served as a good indicator for prediction of tumor recurrence. The follow‐up time ranged from 5 to 144 months with the mean of 54.5 months. Conclusions: The survival rate for EST was 54%, that for immature teratoma and dysgerminoma was 85% and 90%, respectively.

THE PRESENCE OF HYDROPS FETALIS IN A FETUS WITH CONGENITAL MESOBLASTIC NEPHROMA

We report the first prenatal diagnosis of a case of congenital mesoblastic nephroma complicated by hydrops fetalis. Congenital mesoblastic nephroma is generally thought to be a benign disease but when complicated by hydrops fetalis it may be a potentially lethal condition.