Regulatory T Cells Suppress Natural Killer Cell Immunity in Patients With Human Cervical Carcinoma.

OBJECTIVE: To determine the functional attributes of CD4 CD25 regulatory T (Treg) cells by suppressing natural killer (NK) cell activity in human cervical cancer (CC). METHODS: Triple-color flow cytometry was used to study the phenotypic expression of CD4 CD25 Treg cells and NK cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs). In vitro coculture assays were performed to illustrate the cytokine immunoregulations between Treg cells and NK cells. RESULTS: Significantly lower expression ratio of NK cells and higher expression ratio of Treg cells in TILs than PBLs were found. The NK cells displayed significantly higher expression ratio of inhibitory NK receptors (CD158a, CD158b, and NKG2A) and lower expression ratio of activating NK receptors (NKG2D, NKp46, and NKp30) as well as perforin in TILs than PBLs, suggesting the suppressed cytotoxicity of the NK cells in the CC tumor milieu. The expression ratio of transforming growth factor-ß1 (TGF-ß1) on Treg cells as well as TGF-ßRII on Treg cells and NK cells was significantly higher in TILs than PBLs. Further functional in vitro assays demonstrated that NK cell function was suppressed by Treg cells, mimicking the inhibition of TGF-ß on NK cells, and interleukin-2/interleukin-15 stimulation was able to restore the NK cell activity. CONCLUSIONS: These findings indicate that Treg cells in TILs may abrogate NK cell cytotoxicity through TGF-ß pathway, and therefore, Treg cell elimination may enhance NK cell activity and be a novel therapeutic strategy for CC.

Recurrent endometrial stromal sarcoma in the cecum causing intussusception.

INTRODUCTION: Most endometrial stromal sarcomas (ESS) develop recurrent disease at pelvis and lung. Recurrent ESS in the cecum causing intussusception is a rare but emergent phenomenon. CASE REPORT: After initial surgical treatment in 1997, a 41-year-old female developed recurrent ESS in the cecum causing ileo-colic intussusception in 2008, which were operated with right hemicolectomy. The patient was then treated with progestin for 2 years to date. She has since been disease-free. CONCLUSION: This case report emphasizes the importance of long-term follow-up and initial surgical treatment of ESS and suggests systemic hormonal therapy in case of recurrence.

LOC550643, a Long Non-coding RNA, Acts as Novel Oncogene in Regulating Breast Cancer Growth and Metastasis.

Metastatic disease is responsible for over 90% of death in patients with breast cancer. Therefore, identifying the molecular mechanisms that regulate metastasis and developing useful therapies are crucial tasks. Long non-coding RNAs (lncRNAs), which are non-coding transcripts with >200 nucleotides, have recently been identified as critical molecules for monitoring cancer progression. This study examined the novel lncRNAs involved in the regulation of tumor progression in breast cancer. This study identified 73 metastasis-related lncRNA candidates from comparison of paired isogenic high and low human metastatic breast cancer cell lines, and their expression levels were verified in clinical tumor samples by using The Cancer Genome Atlas. Among the cell lines, a novel lncRNA, LOC550643, was highly expressed in breast cancer cells. Furthermore, the high expression of LOC550643 was significantly correlated with the poor prognosis of breast cancer patients, especially those with triple-negative breast cancer. Knockdown of LOC550643 inhibited cell proliferation of breast cancer cells by blocking cell cycle progression at S phase. LOC550643 promoted important in vitro metastatic traits such as cell migration and invasion. Furthermore, LOC550643 could inhibit miR-125b-2-3p expression to promote breast cancer cell growth and invasiveness. In addition, by using a xenograft mouse model, we demonstrated that depletion of LOC550643 suppressed the lung metastatic potential of breast cancer cells. Overall, our study shows that LOC550643 plays an important role in breast cancer cell metastasis and growth, and LOC550643 could be a potential diagnosis biomarker and therapeutic target for breast cancer.

Extracellular Signal-Regulated Kinase Mediates Ebastine-Induced Human Follicle Dermal Papilla Cell Proliferation.

Ebastine is a second-generation histamine H1 receptor antagonist that is used to attenuate allergic inflammation. Ebastine has also shown to affect hair loss; however, the immunoregulatory effect of ebastine cannot completely exclude the possibility of spontaneous hair regrowth in ebastine-treated mice. In this study, we examined the effects of ebastine on the growth of human follicle dermal papilla cells (HFDPC) using a WST-1 cell proliferation assay and a bromodeoxyuridine incorporation assay. Ebastine was shown to significantly increase the proliferation of HFDPC. The expression levels of cell-cycle regulatory proteins and an antiapoptotic protein were increased in ebastine-treated HFDPC. Furthermore, elevated expression levels of phospho-AKT and phospho-p44/42 extracellular signal-regulated kinase (ERK) were observed in ebastine-treated HFDPC. Ebastine-mediated HFDPC growth was completely reversed by blocking ERK kinase. The results from our present study suggest that the regulation of HFDPC proliferation by ebastine might be directly involved in hair regrowth through the ERK signaling pathway.

Spontaneous perforated pyometra with an intrauterine device in menopause: a case report.

Spontaneous perforation of the uterus is rare and only several cases have been reported in the English medical literature. Most of the patients had gynecological malignancy and almost all were associated with cervical occlusion. We report a case of diffuse peritonitis resulting from spontaneously perforated pyometra with an intrauterine device (IUD) inserted for more than two decades. This case differs from others in that the cervical canal was not occluded. In the absence of other possible causes of uterine perforation, the etiology in this case is mostly likely hemorrhagic necrosis related to the long-term IUD.

Epithelial-Mesenchymal Transition with Malignant Transformation Leading Multiple Metastasis from Disseminated Peritoneal Leiomyomatosis.

Disseminated peritoneal leiomyomatosis (DPL) is a rare condition that is characterized by the presence of multiple subperitoneal or peritoneal smooth muscle nodules of varying sizes on the omentum and peritoneal surfaces, grossly mimicking disseminated carcinoma. DPL usually develops in premenopausal women with a benign course, and it is often found incidentally during abdominal surgery. Malignant transformation is a rare clinical course of DPL. Only a few studies have focused on DPL transformation into a leiomyosarcoma. Herein, we describe the case of a 61-year-old woman with a history of recurrent leiomyoma of the uterus who presented with intermittent progressive abdominal pain. The imaging study revealed a huge heterogeneous density mass in the pelvic region with pulmonary and hepatic metastases. Exploratory laparotomy and debulking surgery were performed, and showed the coexistence of DPL and leiomyosarcoma. She died approximately one month after the diagnosis because of rapid progression of pleural effusion due to malignancy. This case highlights the clinical features of DPL and its malignant transformation and metastasis so physicians can make an early diagnosis and provide timely management.

Preservation of splenic vessels during laparoscopic spleen-preserving distal pancreatectomy via lateral approach.

INTRODUCTION: Preserving splenic vessels during laparoscopic distal pancreatectomy (SPDP-LA) is feasible and avoids unnecessary splenectomy. AIM: To present our outcomes for this unique technique. MATERIAL AND METHODS: Between January 1998 and January 2012, 6 patients who underwent SPDP-LA for benign or low malignancy tumors in the pancreatic tail were included. Clinical characteristics as well as perioperative data were retrospectively recorded. RESULTS: All procedures were successful, with an average operative time of 184 min (range: 88-277 min) and average blood loss of 401.7 ml (range: 10-900 ml). The mean hospital stay was 7 days. Pancreatic fistula occurred in 2 patients but was then cured by external drainage. There was no mortality. Follow-ups were available for all patients. CONCLUSIONS: Our experience was characterized by a lack of conversions and by acceptable rates of postoperative fistula and morbidity. The lateral approach showed beneficial results in patients without complications and short post-operative hospital stays.

Risk factors associated with intra-operative major blood loss in patients with hepatocellular carcinoma who underwent hepatic resection.

BACKGROUND: Minimizing intraoperative blood loss during hepatectomy for hepatocellular carcinoma (HCC) decreases the need for blood transfusion. The purpose of this study was to investigate the risk factors associated with major blood loss in performing liver resection for HCC. METHODS: A total of 643 consecutive patients who underwent hepatic resection for HCC were included in this retrospective study. Patients were divided into groups according to the intraoperative blood loss. Blood loss more than 1,000 mL was defined as major blood loss. Twenty-eight variables were analyzed. RESULTS: As compared with patients with blood loss < 1,000 mL, patients with major blood loss had worse disease-free and overall survival rates (p < 0.001). Patients with major blood loss had higher surgical morbidity, mortality and prolonged hospital stay (p < 0.001). Multivariate analysis shows that independent risk factors associated with major blood loss include: male gender, alanine aminotrasferase > 55U/dL, prothrombin time < 95%, resection more than 3 Couinaud segments, en bloc resection, surgeon with low case volume (< 65 cases) and tumor with central location. CONCLUSIONS: Hemorrhage control is the main problem in liver resection for HCC. In patients with risk factors of major bleeding, it is essential to take effective measure in order to minimize intraoperative blood loss in hepatectomy for patients with HCC.

Activation of regulatory T cells instigates functional down-regulation of cytotoxic T lymphocytes in human breast cancer.

Regulatory T (Treg) cells are a subpopulation of T cells with the ability to control the responses of both CD4+ and CD8+ T cells. A case-control study was conducted in order to determine the functional attributes of Treg cells within the breast cancer milieu. Triple-color flow cytometry was utilized to study the phenotype expression of CD4+CD25+ Treg cells and CD8+ T cells in autologous tumor-infiltrating lymphocytes (TILs) and peripheral blood lymphocytes (PBLs) derived from 33 patients with stage I-III breast cancer. The prevalence of CD4+CD25+ T cells was significantly higher in TILs than in PBLs. The expressions of FOXP3 and GITR in CD4+CD25+ Treg cells were lower in PBLs than in TILs. Functional studies showed that both granzyme B and perforin were barely expressed in peripheral Treg cells but were highly expressed in Treg cells in the tumor microenvironment. On the contrary, down-regulation of both granzyme B and perforin expressed in the CD8+ cytotoxic T lymphocytes was significantly lower in TILs than in PBLs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules were synchronously up-regulated in CD8+ cytotoxic T cells. The in vitro kinetic study showed that adequate activation of TILs derived from breast cancer tissue could restore the appropriate antitumor immune response.

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

BACKGROUND: A study was carried out to determine the functional attributes of CD4(+) CD25(+) regulatory T cells in cancer progression by suppressing antitumor immunity. METHODS: Triple-color flow cytometry was used to study the phenotype expression of CD4(+) CD25(+) regulatory T cells and CD8(+) T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters. RESULTS: The prevalence of CD4(+) CD25(+) T cells was significantly higher in the TILs than PBLs. The expression of CD4(+) CD25(+) regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4(+) CD25(+) regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8(+) T cells were CD28(-) CD45RA(-) CD45RO(+) CCR7(-) , suggesting good terminal differentiation. Most of them had an activated role with CD69(+) CD103(+) CD152(+) . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8(+) cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8(+) cytotoxic T cells. CONCLUSIONS: Regulatory T cells in the tumor microenvironment may abrogate CD8(+) T cell cytotoxicity in a granzyme B- and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression.