Wen-Hsun Chang

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.

Nonsteroidal Anti-Inflammatory Drugs for Wounds: Pain Relief or Excessive Scar Formation?

The inflammatory process has direct effects on normal and abnormal wound healing. Hypertrophic scar formation is an aberrant form of wound healing and is an indication of an exaggerated function of fibroblasts and excess accumulation of extracellular matrix during wound healing. Two cytokines—transforming growth factor-β (TGF-β) and prostaglandin E2 (PGE2)—are lipid mediators of inflammation involving wound healing. Overproduction of TGF-β and suppression of PGE2 are found in excessive wound scarring compared with normal wound healing. Nonsteroidal anti-inflammatory drugs (NSAIDs) or their selective cyclooxygenase-2 (COX-2) inhibitors are frequently used as a pain-killer. However, both NSAIDs and COX-2 inhibitors inhibit PGE2 production, which might exacerbate excessive scar formation, especially when used during the later proliferative phase. Therefore, a balance between cytokines and medication in the pathogenesis of wound healing is needed. This report is a literature review pertaining to wound healing and is focused on TGF-β and PGE2.

Extracellular matrix proteases - cytokine regulation role in cancer and pregnancy.

The extracellular matrix proteases act in diverse physiological and pathological processes involving tumor growth, angiogenesis, and pregnancy through the cleavage of extracellular matrix (ECM) and non-matrix proteinaceous substrates. Matrix metalloproteinases (MMPs) constitute a main family among the ECM proteases. Endogenous tissue inhibitors of metalloproteinases (TIMPs), as one kind of MMPs inhibitors (MMPIs), reduce the excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in cancer tumorigenesis, angiogenesis, as well as embryo implantation and trophoblastic invasion during pregnancy. A variety of literature concerns the correlated changes in MMPs and MMPIs during the formation of cancer and pregnancy-related complications. Importantly, MMPs and TIMPs may act as regulators of signaling pathways through the cleavage of non-matrix substrates, including cytokines, chemokines, and growth factors. In this review, we concentrate on mutual interactions between ECM proteases and cytokines during cancer development and pregnancy. The current knowledge in the field of identified ECM proteases will be contributive to the innovative therapeutic intervention in both cancer and pregnancy-related processes.

An overview of a 30-year experience with amniocentesis in a single tertiary medical center in Taiwan.

OBJECTIVE Amniocentesis is a popular and effective prenatal diagnostic tool for chromosomal disorders. It is well-established that the risk of chromosomal abnormalities increases with maternal age; however, other related indications are seldom reported. Herein, we report our 30-year experience with amniocentesis from a single medical center, focusing on the indications and rates of abnormality. MATERIAL AND METHODS A retrospective review of 16,749 pregnant women in the mid-trimester between January 1981 and December 2010 was conducted. The medical records were analyzed. RESULTS The indications for amniocentesis were advanced maternal age (≥ 34 years old) (n=10,970, 65.5%), increasing-risk maternal triple-marker Downs screening test (≥ 1/270) (n=2090, 12.5%), history of abnormal offspring birth (n=792, 4.7%), abnormal ultrasound findings (n=484, 2.9%), parent with abnormal karyotype (n=252, 1.5%), family history of chromosomal abnormality (n=183, 1.1%), drug and radiation exposure (n=165), abnormal chorionic villus sampling (CVS) results (n=25), intrauterine fetal death (n=50), and other non-specific causes (n=1662, 9.9%). The rate of abnormality for each indication was 16% in the abnormal CVS group, 12% in the intrauterine fetal death group, 11.5% for parental chromosomal abnormality, 8.7% in the abnormal ultrasound finding group, 3.0% in the increasing-risk maternal triple-marker Downs screening test group, 2.5% in the advanced maternal age group, 1.5% for other non-specific causes, 1.4% for history of abnormal offspring birth, and 1.1% for family history of chromosomal abnormality. CONCLUSIONS Both parents with abnormal karyotype and abnormal ultrasound findings are indications for which consideration of further amniocentesis is highly recommended.

Rupture of a pregnant unscarred uterus in an early secondary trimester: A case report and brief review

Rupture of a pregnant uterus in early pregnancy and an unscarred uterus are extremely rare, and some non‐specific symptoms might appear before this occurrence. We report the case of a multiparous woman (gravida 3, para 2) with uterine fundal rupture in her early second trimester (17+ weeks of gestational age), who presented upper abdominal discomfort and vomiting for 3 days, and progressed into sudden acute abdomen and shock. During emergent laparotomy, the entire amniotic sac was found in the peritoneal cavity with a rupture of the uterine fundus. Although we could not confirm that the appearance of upper gastrointestinal symptoms and severe vomiting was associated with uterine rupture in this pregnant woman, abdominal symptoms or signs might be a hint or cause of severe catastrophic pregnancy‐related complications.

The Risk of Epithelial Ovarian Cancer of Women With Endometriosis May be Varied Greatly if Diagnostic Criteria Are Different: A Nationwide Population-Based Cohort Study

AbstractThis article aims to test the hypothesis that the risk of epithelial ovarian cancer (EOC) in women with endometriosis might be changed by enrolling different population.A nationwide 14-year historic cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan and the Registry for Catastrophic Illness Patients was conducted. A total of 239,385 women aged between 20 and 51 years, with at least 1 gynecologic visit after 2000, were analyzed. Cases included women with a diagnosed endometriosis, which was established along a spectrum from at least 1 medical record of endometriosis (recalled endometriosis) to tissue-proved ovarian endometriosis (n = X). Controls included women without any diagnosis of endometriosis (n = 239,385 – X). We used Cox regression, and computed hazard ratios (HRs) with 95% confidence intervals (95% CI) to determine the risk of EOC in patients.The EOC incidence rates (IRs, per 10,000 person-years) of women with endometriosis ranged from 1.90 in women with recalled endometriosis to 18.70 in women with tissue-proved ovarian endometrioma, compared with those women without any diagnosis of endometriosis (0.77–0.89), contributing to crude HRs ranging from 2.59 (95% CI, 2.09–3.21; P < 0.001) to 24.04 (95% CI, 17.48–33.05; P < 0.001). After adjustment for pelvic inflammatory disease, infertility, Charlson co-morbidity index, and age, adjusted HRs were ranged from the lowest of 1.90 (95% CI, 1.51–2.37; P < 0.001) in recalled endometriosis to the highest of 18.57 (95% CI, 13.37–25.79; P < 0.001) in tissue-proved ovarian endometrioma, which was inversely related to the prevalence rate of endometriosis (from the highest of 30.80% in recalled endometriosis to the lowest of 1.54% in tissue-proved ovarian endometrioma).The risk of EOC in women with endometriosis varied greatly by different criteria used. Women with endometriosis might have a more apparently higher risk than those reported by systematic review and meta-analysis.

Prevalence of maternal group B streptococcus colonization and vertical transmission in low-risk women in a single institute

Background: Intrapartum administration of antibiotics lowers the risk of neonatal group B streptococcus (GBS) infection based on recommended guidelines (a risk‐based approach and a culture‐based screening approach). However, many pregnant women do not undergo culture‐based screening, nor treatment with prophylactic antibiotics after a GBS risk‐based approach. Therefore, the value of GBS detection in asymptomatic low‐risk pregnant women is controversial. Methods: A cohort study of 354 asymptomatic pregnant women at more than 37 weeks’ gestation who were planning to undergo vaginal delivery, and 118 neonates (107 paired samples of both mother and newborn), was conducted to evaluate the GBS colonization rate of these pregnant women and the subsequent vertical transmission rate, using a culture method. Results: The positive rate for GBS culture was 6.2% (22/354). Among 107 paired samples, six maternal samples and one neonatal sample were positive for GBS culture, with an estimated vertical transmission rate of 16.7% (1/6). Conclusion: Although the positive rate of GBS culture was lower in asymptomatic low‐risk pregnant women, the possibility of vertical transmission might be high. This finding is worthy of further investigation.

Double-balloon cervical ripening catheter works well as an intrauterine balloon tamponade in post-abortion massive hemorrhage

OBJECTIVE Clinical experience in the management of post-abortion hemorrhage is limited. CASE REPORTS Two women with severe post-abortion hemorrhage were reported. One case occurred after methotrexate treatment of Cesarean scar pregnancy and the other occurred after abortion surgery. Both patients were successfully treated with a double-balloon cervical ripening catheter inducing intrauterine balloon tamponade. CONCLUSION Use of a double-balloon cervical ripening catheter either before or after systemic methotrexate treatment is one of the choices in the management of severe post-abortion hemorrhage and can prevent the use of more invasive and/or destructive procedures.

Management of adnexal masses during pregnancy

We read the report by Balci et al. Management and outcomes of adnexal masses during pregnancy: A 6-year experience with interest. Because either surgical or medical illness might complicate pregnancy in any one of the pregnancy periods, the dilemmas and challenges of these complications might bother both physicians and pregnant women. Any management method used should not have a negative impact on the well-being of either the mother or the fetus. The authors retrospectively analyzed 36 pregnancies with adnexal masses during a 6-year period and found a high rate of surgical intervention for adnexal masses during pregnancy (94%, 34/36) and an acceptable complication rate (9%, 3/34) at their tertiary referral center. The following comments do not dispute the excellent results in the article; however, some controversial opinions are worthy of attention. First, although we know that the surgical management of adnexal masses during pregnancy cannot be completely avoided, especially when a pregnant woman is complicated with rupture, torsion, or a high level of suspicion of malignancy or any urgent condition without acceptable explanation, the decision to perform an operation should be made with caution. In addition, the questions of how or when to treat these patients and who should be treated with surgical intervention for adnexal masses during pregnancy are always present. For example, did the report by Balci et al. really show strong indications to perform an operation on these women? Up to 41% of the final pathological diagnoses after operation in their article were functional ovarian cysts, a rate significantly higher than that of the general population or even pregnant women. We evaluated 174 women who underwent adnexal surgery during pregnancy at our institute and only 11% had functional ovarian cysts. Even when we included simple ovarian cysts in the category of functional ovarian cysts, the incidence was only 21%. Although the real reason for this discrepancy in the final pathological diagnosis in our and the report by Balci et al. is unknown, one explanation might be that the rate of emergency surgery was higher in their group (65%, 22/34) compared to our group (18%, 32/174). In our previous study, we also found that the diagnosis of ovarian functional cyst in emergency surgery was higher than in elective surgery (19 vs 9%), although this was without a statistically significant difference. Therefore, we should not neglect the potential risk of functional cysts during pregnancy, even though the absolute risk is considered to be minimal. Second, the authors mentioned in the Discussion section that approximately half of all adnexal masses were smaller than 5 cm, a quarter were between 5 and 10 cm, and the remainder were larger than 10 cm, and of the masses observed, 95% were unilateral and 2–5% were malignant in character. Then the authors used the report by Ueda and Ueki to mention that 90.3% of tumor-like lesions and 78.8% of benign tumors would be detected before the 10th gestational week. This results in confusion. In addition, because tumor size might be one of the most important parameters predicting the future outcome of a patient, especially for tumors greater than 10 cm in diameter during pregnancy, it would be better to know the mean tumor size in Balci’s group. Third, we completely agree with the authors that the most frequently seen and serious complication of benign ovarian tumor during pregnancy is torsion. Although the authors addressed the important issue that torsion often occurs during the first trimester, they failed to provide other important information. For example, the diagnosis of mature teratoma during pregnancy should be emphasized based on the following: the diagnosis of mature teratoma is easy to make using high resolution ultrasound in early pregnancy, and this type tumor teratoma is prone to torsion in the first trimester. Furthermore, torsion during the first trimester might contribute to a high risk of severe complication, such as abortion or fetal loss. Based on the previous study, we found the following which may be associated with spontaneous fetal loss in women with adnexal surgery during pregnancy: (i) no fetal loss occurred after the eighth week of gestation in selective surgery; and (ii) an urgent operation might increase the risk of fetal loss before the tenth week of gestation, especially in cases of mature teratoma. Therefore, we recommend that a prophylactic doi:10.1111/j.1447-0756.2009.01048.x J. Obstet. Gynaecol. Res. Vol. 35, No. 3: 597–598, June 2009

Clinical presentation and outcome of adult-type granulosa cell tumors: A retrospective study of 30 patients in a single institute

Background: Ovarian adult‐type granulosa cell tumors (GCTs) are characterized as low‐malignant and late‐recurrent ovarian tumors. Although some clinical and pathological prognostic factors have been reported, other factors have yet to be sufficiently investigated for necessary confirmation. The aim of this study was to test the correlation between clinical factors and outcome, based on patients seen in a single institute. Methods: Thirty patients with pathologically confirmed adult‐type GCTs between 1984 and 2010 were reviewed retrospectively. Among them, eight (26.7%) had recurrence, which subsequently contributed to two mortalities. Results: In a comparison of the clinical characteristics of the premenopausal and postmenopausal women with GCT, all of the postmenopausal women had symptoms (100% vs. 63.6%, p = 0.01). With regard to disease recurrence, only abnormal preoperative serum cancer antigen 125 level (≥35 U/mL) was significant (50% vs. 11%, p = 0.03), and residual tumor showed a borderline trend (100% vs. 21.4%, p = 0.06). Other factors, including International Federation of Gynecology and Obstetrics stage, tumor size, tumor rupture prior to or during operation, body mass index, parity, serum estrogen level, and adjuvant therapy, were not statistically significant. Conclusion: Physicians should be alert to the difference in the symptom presentation of GCTs between pre‐ and postmenopausal women, giving particular attention to the usefulness of the preoperative serum level of cancer antigen 125 in patients with GCTs. More evidence is needed to confirm this observation.