Ho-Hsiung Lin

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.

Transplacental leakage ofHBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus

Thirty-two HBeAg-positive carrier mothers and their 32 babies were investigatedto elucidate the mechanism involved in intrauterine infection with HBV. Five mothers had symptoms and signs of threatened abortion and/or threatened preterm labor. Three mothers gave birth more than 6 weeks after the episodes, and their babies were those infected in utero. The other two gave birth within 1 week after the episodes, and the two babies were treated with HBIG immediately after birth; HBV infection was successfully prevented. Therefore we suggest that transplacental leakage of HBeAg-positive maternal blood, which is induced by uterine contractions during pregnancy and the disruption of placental barriers, is the most likely route to cause HBV intrauterine infection.

Hepatitis B surface antigenemia at birth: A long-term follow-up study

OBJECTIVE To investigate the prevalence and outcome of hepatitis B surface antigenemia in newborns of hepatitis B e antigen (HBeAg)-positive hepatitis B surface antigen (HBsAg) carrier mothers under the current immunoprophylaxis program. STUDY DESIGN From 1984 to 1993, 665 high-risk newborns born to HBeAg-positive HBsAg carrier mothers were prospectively recruited. The newborns were tested for HBsAg soon after birth, before hepatitis B immune globulin administration. All newborns received hepatitis B immune globulin within 24 hours after birth plus subsequent hepatitis B vaccination. Those who were seropositive for HBsAg at birth were regularly followed up for their hepatitis B virus (HBV) markers, liver function profiles, and alpha-fetoprotein levels from 1984 to 1996. RESULTS Sixteen (2.4%) of the 665 subjects were found to be seropositive for HBsAg at birth, and all remained HBsAg-positive at 6 months of age. Twelve of the 16 received long-term follow-up care, and all were confirmed to have chronic HBV infection. Of the 12, 2 had HBeAg seroconversion, and 1 had alanine aminotransferase flares without HBeAg seroconversion. Delayed appearance of hepatitis B core antibody (anti-HBc) occurred in 2 without alanine aminotransferase elevation. CONCLUSIONS Current immunoprophylaxis strategy does not protect newborns with surface antigenemia, apparently acquired in utero, from becoming HBV carriers. Immunologic attempts to eliminate HBV may occur in carrier children infected in utero, despite their profound immune tolerance to HBV.

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.

Least microtransfusion from mother to fetus in elective cesarean delivery

Objective To examine the variability of maternal-fetal microtransfusion in different modes of delivery, as measured by hepatitis B surface antigen (HBsAg) and placental alkaline phosphatase. Methods We recruited 97 HBsAg-positive pregnant women. The mode of delivery included elective cesarean in 16, normal spontaneous vaginal delivery in 56, vacuum or forceps delivery in 12, and emergency cesarean after labor in 13. We measured HBsAg and placental alkaline phosphatase levels in 97 pairs of maternal and fetal blood samples collected at delivery. Results The mean maternal placental alkaline phosphatase levels did not differ among these four groups. The mean cord placental alkaline phosphatase level of the elective cesarean group was the lowest (P ≤ .05). All samples of cord sera for this group were negative for HBsAg, compared with 38 of 56, eight of 12, and seven of 13 in the spontaneous vaginal, vacuum or forceps, and emergency cesarean groups, respectively (P ≤ .05). Conclusion The level of mother-to-fetus microtransfusion was least in the elective cesarean group, as revealed by both the lowest cord placental alkaline phosphatase and HBsAg levels. These observations may have implications for reducing perinatal transmission of blood-borne viruses.

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.

An alternative intervention for urinary incontinence: Retraining diaphragmatic, deep abdominal and pelvic floor muscle coordinated function

This study was a randomized controlled trial to investigate the effect of treating women with stress or mixed urinary incontinence (SUI or MUI) by diaphragmatic, deep abdominal and pelvic floor muscle (PFM) retraining. Seventy women were randomly allocated to the training (n = 35) or control group (n = 35). Women in the training group received 8 individual clinical visits and followed a specific exercise program. Women in the control group performed self-monitored PFM exercises at home. The primary outcome measure was self-reported improvement. Secondary outcome measures were 20-min pad test, 3-day voiding diary, maximal vaginal squeeze pressure, holding time and quality of life. After a 4-month intervention period, more participants in the training group reported that they were cured or improved (p < 0.01). The cure/improved rate was above 90%. Both amount of leakage and number of leaks were significantly lower in the training group (p < 0.05) but not in the control group. More aspects of quality of life improved significantly in the training group than in the control group. Maximal vaginal squeeze pressure, however, decreased slightly in both groups. Coordinated retraining diaphragmatic, deep abdominal and PFM function could improve symptoms and quality of life. It may be an alternative management for women with SUI or MUI.

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.