Daw-Yuan 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.

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.

Lysophosphatidic Acid Mediates Interleukin-8 Expression in Human Endometrial Stromal Cells through Its Receptor and Nuclear Factor-κB-Dependent Pathway: A Possible Role in Angiogenesis of Endometrium and Placenta

Lysophosphatidic acid (LPA) is a pleiotropic phospholipid molecule involved in inflammation, angiogenesis, would healing, and cancer invasion. Whereas serum lysophospholipase D activity increases in women with pregnancy, the role of LPA in pregnancy remains unclear. We investigated the expression of LPA receptors and function of LPA in endometrial stromal cells. Histologically normal endometrium was obtained from surgical specimens of women undergoing hysterectomy for leiomyoma. First-trimester decidua was obtained from women receiving elective termination of pregnancy. We examined the expressions of LPA1, LPA2, and LPA3 receptors in endometrial stromal cells. The effects of LPA on the expression of vascular endothelial growth factor, IL-6, and IL-8 were examined. Signal pathways of LPA were delineated. Functions of secretory angiogenic factors were tested using human endometrial microvascular endothelial cells. Immunoreactivity and mRNA of LPA1 receptors were identified in endometrial stromal cells. LPA enhanced IL-8 expression in a dose- and time-dependent manner, whereas vascular endothelial growth factor or IL-6 expression was not affected by LPA treatment. Mechanistic dissection disclosed that LPA functioned via the Gi protein, MAPK/p38 and nuclear factor-kappaB pathway. LPA-induced IL-8 enhanced migration, permeability, capillary tube formation, and proliferation of human endometrial microvascular endothelial cells. Endometrial stromal cells express LPA1 receptors. Through the LPA1 receptor, LPA induces IL-8 expression via a nuclear factor-kappaB-dependent signal pathway. These results could suggest that LPA may play a role in angiogenesis of endometrium and placenta through induction of IL-8 in endometrial stromal cells during pregnancy.

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma.

A study was carried out to determine the functional attributes of CD4+ CD25+ regulatory T cells in cancer progression by suppressing antitumor immunity.

Transvaginal hysterectomy or laparoscopically assisted vaginal hysterectomy for nonprolapsed uteri.

Background: To define a rational guideline for the use of either laparoscopically assisted vaginal hysterectomy (LAVH) or transvaginal hysterectomy in dealing with a nonprolapsed uterus. Methods: A total of 452 patients receiving LAVH or transvaginal hysterectomy were retrospectively studied between October 2002 and October 2004. The operative time, estimated blood loss, uterine weight, and complications were all recorded for analysis. Results: Significant linear correlations of uterine weight with operative time and estimated blood loss could be seen only in the transvaginal hysterectomy group. Transvaginal hysterectomy required significantly shorter operative time, but longer duration when the uterine weight exceeded 350 g. These 452 patients were stratified into 4 subgroups according to the uterine weight and hysterectomy procedure. Data are expressed as the mean ± standard deviation. For uterine weight less than 350 g, transvaginal hysterectomy had significantly shorter operative time than LAVH (80 ± 27 minutes compared with 118 ± 21 minutes, P < .05) but similar blood loss (70 mL compared with 74 mL). For uterine weight 350 g or less, transvaginal hysterectomy had not only significantly longer operative time (139 ± 30 minutes compared with 118 ± 17 minutes, P < .05) but also more blood loss (242 ± 162 mL compared with 66 ± 51 mL, P < .05) than LAVH. Conclusion: In view of the shorter operative time and less blood loss, LAVH is preferable for uterine weight 350 g or more, whereas transvaginal hysterectomy is better in dealing with uteri weighing less than 350 g. Level of Evidence: II-2

Increased Interleukin-6 Messenger RNA Expression in Macrophage-Cocultured Endometrial Stromal Cells in Adenomyosis

To determine the effects of macrophage on endometrial stromal cells (ESCs) in women with adenomyosis.

LAVH for large uteri by various strategies.

Background. To study if there are specific problems in laparoscopically assisted vaginal hysterectomy (LAVH) for a certain weight of bulky uteri and the strategies to overcome such problems. Methods. One hundred and eighty‐one women with myoma or adenomyosis, weighing 350‐1,590 g, underwent LAVH between August 2002 and December 2005. Key surgical strategies were special sites for trocar insertion, uterine artery or adnexal collateral pre‐ligation, laparoscopic and transvaginal volume reduction technique. The basic clinical and operative parameters were recorded for analysis. Results. Based on significant differences in the operative time and estimated blood loss, the patients were divided into medium uteri weighing 350–749 g, n = 138 (76%), and large uteri weighing ≥750 g, n = 43 (24%). There was no significant difference in terms of age, body mass index, preoperative diagnoses, complications and duration of hospital stay among groups. The operative time and estimated blood loss increased with larger uterine size (p<0.001). The operative time (196±53, 115–395 min), estimated blood loss (234±200, 50–1,000 ml) and frequency of excessive bleeding (14%) or transfusion (5%) were significantly greater, but in acceptable ranges, for those with large uteri. Conversion to laparotomy was required in a patient (2%) with a large uterus, and the overall conversion rate was 0.6%. There was no re‐operation or surgical mortality. Conclusion. Using various combinations of special strategies, most experienced gynecologic surgeons can conduct LAVH for most large uteri with minimal rates of complications and conversion to laparotomy.

Use of three-dimensional ultrasonography in the evaluation of uterine perfusion and healing after laparoscopic myomectomy

OBJECTIVE To evaluate vascular perfusion and uterine healing after laparoscopic myomectomy using three-dimensional power Doppler ultrasound (3D-PDU). DESIGN Prospective study. SETTING University-affiliated hospital. PATIENT(S) Ninety-seven women with symptomatic myomas warranting laparoscopic myomectomy. INTERVENTION(S) Three-dimensional PDU obtained preoperatively and 1 week and 3 months postoperatively. MAIN OUTCOME MEASURE(S) Resistance index, pulsatility index, and peak systolic velocity of the uterine artery; vascularization index, flow index, and vascularization flow index of the uterine tissue, nonoperative area, and healing myometrial area. RESULT(S) The median age was 39 years. More than half of the patients were nulliparous, and one third desired fertility. The median myoma size was 8 cm, and median weight of the extirpated myomas was 250 g. The median myoma volume was 262 cm(3), and median uterine volume was 380 cm(3). On the 7th postoperative day all laparoscopic myomectomy healing sites appeared as highly echogenic areas with profuse blood flow at the periphery and reduced resistance index and pulsatility index of the uterine artery. Nonoperated areas had significantly more blood flow than healing areas. Two patients had hematomas, which appeared as hypoechoic areas that were almost avascular. By the 3rd postoperative month the blood flow and uterine volume decreased significantly. However, an 11-cm(3) hypoechoic hematoma with poor tissue perfusion was still seen in 1 patient with a 720-cm(3) myoma. CONCLUSION(S) Healing of a laparoscopic myomectomy scar can be evaluated by 3D-PDU. Adequate perfusion demonstrated by 3D-PDU might suggest good wound healing and dissolving of hematomas.

Laparoscopic-Assisted Vaginal Hysterectomy with In Situ Morcellation for Large Uteri

STUDY OBJECTIVE To estimate whether laparoscopic in situ morcellation (LISM) can facilitate laparoscopic-assisted vaginal hysterectomy (LAVH) for large uteri. DESIGN Prospective study (Canadian Task Force classification II-1). SETTING University-affiliated hospital. PATIENTS In all, 147 women with myoma or adenomyosis weighing more than 500 g from January 2004 through December 2007 were enrolled. The patients were divided into 4 subgroups: patients with uteri weighing 500 to 749 g who had traditional LAVH without LISM (group 1A, n=69) or with LISM (group 1B, n=16); and patients with uteri weighing 750 g or more who were treated by traditional LAVH without LISM (group 2A, n=38) or with LISM (group 2B, n=24). INTERVENTIONS Laparoscopic-assisted vaginal hysterectomy with or without LISM. MEASUREMENT AND MAIN RESULTS No significant differences existed in age, body mass index, preoperative diagnoses, complications, or duration of hospital stay among groups. The mean uterine weights were 608+/-75, 597+/-66, 989+/-179, and 935+/-226 g for groups 1A, 1B, 2A, and 2B, respectively. The operative time (120+/-16 vs 157+/-36 minutes, p<.001; 140+/-19 vs 224+/-57 minutes, p<.001) were significantly shorter in patients with LISM than without in both groups 1 and 2. The estimated blood loss was highest in group 2A. Six (16%) patients lost more than 500 mL of blood and 3 (8%) of them needed blood transfusions. Conversion to laparotomy occurred in 1 (2.6%) of 38 patients in group 2A. No repeated surgery or surgical mortality occurred. CONCLUSION Laparoscopic-assisted vaginal hysterectomy with LISM was an efficient and safe procedure for removal of large uteri during LAVH.

Visceral Sliding Technique Is Useful for Detecting Abdominal Adhesion and Preventing Laparoscopic Surgical Complications

Study Objective: Introduce a non-invasive method preoperatively to prevent bowel injury by the Veres needle and trocar during laparoscopy. Design: Case-controlled study. Setting: A hospital-based study. Patients: Five hundred and twelve patients who underwent laparoscopic surgery were prospectively enrolled. Intervention: A simple and non-invasive method to detect bowel adhesions preoperatively. Results: A total of 512 patients who underwent operative laparoscopy were prospectively enrolled for ultrasonographic visceral sliding evaluation. They were subdivided into two groups as follows: group I, 332 patients without previous abdominal surgery; group II, 180 patients with previous abdominal surgery. No bowel adhesion to the umbilicus was present in group I. In group II, only two cases with bowel adhered to the periumbilical area were found by visceral sliding technique. No patients suffered any bowel injury. Conclusion: The proposed technique is useful and highly effective in guiding the insertion of the Veres needle and trocar to prevent bowel injury in laparoscopy.