Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer.

BACKGROUNDAdoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here, we explored the safety, feasibility, and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous TILs (auto-TILs) following concurrent chemoradiotherapy (CCRT) in patients with CC who had locally advanced disease.METHODSTwenty-seven patients with CC with stage III-IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practice (GMP) conditions and then infused after CCRT plus i.m. IL-2 injections.RESULTSTILs from 20 of the 27 patients were successfully expanded, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there were no treatment-related mortalities. Nine of 12 patients (75.0%) attained a complete response, with a disease control duration of 9-22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of patients with CC at baseline were correlated with the clinical response.CONCLUSIONTIL-based ACT following CCRT was safe in an academic center setting, with potentially effective responses in patients with locally advanced CC. "Hot" inflammatory immune environments were beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT04443296.FUNDINGNational Key R&D Program; Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Province Sci-Tech International Key Program; the National Natural Science Foundation of China.

Effectiveness of Sequential Chemoradiation vs Concurrent Chemoradiation or Radiation Alone in Adjuvant Treatment After Hysterectomy for Cervical Cancer: The STARS Phase 3 Randomized Clinical Trial.

IMPORTANCE: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. OBJECTIVE: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. DESIGN, SETTING, AND PARTICIPANTS: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. INTERVENTIONS: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of disease-free survival (DFS) at 3 years. RESULTS: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00806117.

Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study.

BACKGROUND: Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simon's two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. FINDINGS: Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. INTERPRETATION: The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. FUNDING: None.

Resveratrol prevents osteoporosis by upregulating FoxO1 transcriptional activity.

Resveratrol (3,5,4-trihydroxystilbene, RES), a natural antioxidant, prevents bone loss by attenuating damage caused by oxidative stress. Our previous research revealed that the forkhead box O1 (FoxO1)/ß-catenin signaling pathway affected the proliferation and differentiation of osteoblasts through its regulation of redox balance, and RES regulated the expression of FoxO1 to control white adipose tissue and then ameliorate an overweight condition. Based on previous research, we hypothesized that RES regulates FoxO1 transcriptional activity through the phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway to achieve an antioxidative effect on osteoporosis and then we confirmed this hypothesis in the present study. An ovariectomized (OVX) rat model of osteoporosis and a H2O2­induced oxidative cell injury model in RAW 264.7 cells were established to explore the underlying molecular mechanisms of how RES confers an antioxidant effect and prevents bone loss. The obtained results demonstrated that RES strongly prevented bone loss induced by oxidative stress in vivo. More specifically, RES effectively decreased the receptor activator of nuclear factor-κB ligand (RANKL) together with the tartrate-resistant acid phosphatase­5b (TRAP­5b) level, but elevated the osteoproprotegrin (OPG) level and attenuated bone microarchitecture damage. Notably, RES, due to its antioxidant effect, suppressed RANKL production and then inhibited osteoclastogenesis in the OVX rats. In vitro, RES improved the oxidative stress status of cells and thus inhibited the mRNA expression of osteoclast-specific enzymes. These data indicate that RES has a significant bone protective effect by antagonizing oxidative stress to suppress osteoclast activity, function and formation both in vivo and in vitro. Moreover, at the molecular level, we confirmed, for the first time, that RES upregulated FoxO1 transcriptional activity by inhibiting the PI3K/AKT signaling pathway, and hence promoted resistance to oxidative damage and restrained osteoclastogenesis. Inhibition of the PI3K/AKT signaling pathway may be induced by RANKL. FoxO1 is a major action target of RES to confer anti-osteoporosis function, and whose effect stems from its power to improve redox balance.

The Bidirectional Regulation between MYL5 and HIF-1α Promotes Cervical Carcinoma Metastasis.

Myosin light chains (MLC) serve important regulatory functions in a wide range of cellular and physiological processes. Recent research found that MLC are also chromatin-associated nuclear proteins which regulate gene transcription. In this study, the MLC member myosin regulatory light chain 5 (MYL5) expression was upregulated in late stage cervical cancer patients, positively correlated with pelvic lymph node metastasis, and identified as a poor survival indicator. MYL5 overexpression promoted metastasis in cervical cancer in vitro and in vivo models, whereas MYL5 silencing had the converse effect. We demonstrated a bidirectional regulation between MYL5 and hypoxia inducible factor-1α (HIF-1α). HIF-1α activates MYL5 via binding to the hypoxia response element (HRE) in the promoter of MYL5, and MYL5 could sustain HIF-1α expression by tethering to recognition sequence AGCTCC in the HIF-1α promoter region. Clinical data confirmed a positive correlation between MYL5 and HIF-1α. In summary, our data show that MYL5 may act as a prognosis predictive factor in cervical carcinoma, and strategies that inhibit the interaction of MYL5 and HIF-1α may benefit the cervical carcinoma patients with metastasis.

Betulinic acid promotes TRAIL function on liver cancer progression inhibition through p53/Caspase-3 signaling activation.

Betulinic acid (BA), isolated from the tree bark, is a pentacyclic triterpenoid, showing inhibitory role in cancer cells. However, the effects of BA treatment on liver cancer have little to be known. Thus, the study is conducted to explore the in vitro and in vivo role of BA in liver cancer. And the interactions between BA and tumor necrosis factor-related apoptosis-inducing ligand of APO2, also known as TRAIL, were investigated in liver cancer cells. A synergistic effect of BA and APO2 combination on apoptosis induction in liver cancer cells was observed. The cancer cells were insensitive to APO2 single therapy. However, liver cancer cells receiving BA were sensitive to APO2-triggered apoptotic response by enhancing Caspases cleavage, due to elevation of decoy receptor 1 and 2 (DcR1 and DcR2) dependent on p53. Bcl-2 family members of Bcl-2 and Mcl-1, belonging to anti-apoptosis, were decreased, whereas Bad and Bak, as pro-apoptotic members, were increased for BA and APO2 combined treatment. Additionally, the mouse xenograft model suggested that BA and APO2 in combination markedly inhibited liver cancer growth in comparison to BA or APO2 monotherapy without toxicity. The present study revealed a dramatically therapeutic strategy for promoting APO2-induced anti-cancer effects on liver cancer cells via BA combination.

[Immunological balance of CD8+CD28+/CD8+CD28- T lymphocytes can predict gastrointestinal hemorrhage in patients with inflammatory bowel disease].

OBJECTIVE: To evaluate the sensitivity and specificity of CD8+CD28+/CD8+CD28- T lymphocyte balance in predicting the gastrointestinal hemorrhage (GH) in patients with inflammatory bowel disease (IBD). METHODS: Forty-nine IBD patients, including 30 with ulcerous colitis (UC) and 19 with Crohn's disease (CD), were enrolled to test peripheral blood CD8+CD28+ and CD8+CD28- T cells using flow cytometry. All the patients were followed up for one year. The receiver-operating characteristic (ROC) curves were used to test the efficiency of CD8+CD28+/CD8+CD28- T lymphocyte balance to predict GH. The differences in lasting time of remission (LTR) under different factors were compared using Kaplan-Meier survival analysis, and the correlation between CD8+ T lymphocytes and the factors were analyzed. RESULTS: The utilization rates of immunosuppressant, steroids, and biological agent (BA) were significantly higher in CD patients than in UC patients (P=0.003, 0.043 and 0.002, respectively). The frequencies of CD8+CD28+T cells were obviously higher in UC patients than those in CD patients (t=3.022, P=0.004). CD8+CD28+T cells, CD8+CD28- T cells, and especially CD8+CD28+/CD8+CD28- ratio (area under curve of 0.977, P=0.000; cut-off value of 1.14 [13.95%/12.24%] with a sensitivity of 93.3% and a specificity of 91.2%) showed good efficiencies in predicting GH (P<0.01). The mean and median of LTR of IBD patients who did not receive BA or surgical treatment were significantly longer (Χ2=9.730, P=0.002; Χ2=15.981, P=0.000). CD8+CD28+/CD8+CD28- ratio was significantly related to both BA (P=0.009) and surgery (P=0.038). CONCLUSION: Both decreased CD8+CD28+T cells and elevated CD8+CD28-T cells are closely correlated with GH, and their ratio can predict the occurrence of GH with a high sensitivity and specificity and is correlated with BA and surgery at the cut-off value of 1.14.

Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits.

OBJECTIVE: To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status. METHODS: Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining. RESULTS: Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant. CONCLUSION: Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.

Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma.

DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.

Hydrogen gas protects against serum and glucose deprivation­induced myocardial injury in H9c2 cells through activation of the NF­E2­related factor 2/heme oxygenase 1 signaling pathway.

Ischemia or hypoxia­induced myocardial injury is closely associated with oxidative stress. Scavenging free radicals and/or enhancing endogenous antioxidative defense systems may be beneficial for the impediment of myocardial ischemic injury. Hydrogen (H2) gas, as a water­ and lipid­soluble small molecule, is not only able to selectively eliminate hydroxyl (·OH) free radicals, but also to enhance endogenous antioxidative defense systems in rat lungs and arabidopsis plants. However, thus far, it has remained elusive whether H2 gas protects cardiomyocytes through enhancement of endogenous antioxidative defense systems. In the present study, the cardioprotective effect of H2 gas against ischemic or hypoxic injury was investigated, along with the underlying molecular mechanisms. H9c2 cardiomyoblasts (H9c2 cells) were treated in vitro with a chemical hypoxia inducer, cobalt chloride (CoCl2), to imitate hypoxia, or by serum and glucose deprivation (SGD) to imitate ischemia. Cell viability and intracellular ·OH free radicals were assessed. The role of an endogenous antioxidative defense system, the NF­E2­related factor 2 (Nrf2)/heme oxygenase 1 (HO­1) signaling pathway, was evaluated. The findings revealed that treatment with CoCl2 or SGD markedly reduced cell viability in H9c2 cells. H2 gas­rich medium protected against cell injury induced by SGD, but not that induced by CoCl2. When the cells were exposed to SGD, levels of intracellular ·OH free radicals were markedly increased; this was mitigated by H2 gas­rich medium. Exposure of the cells to SGD also resulted in significant increases in HO­1 expression and nuclear Nrf2 levels, and the HO­1 inhibitor ZnPP IX and the Nrf2 inhibitor brusatol aggravated SGD­induced cellular injury. H2 gas­rich medium enhanced SGD­induced upregulation of HO­1 and Nrf2, and the HO­1 or Nrf2 inhibition partially suppressed H2 gas­induced cardioprotection. Furthermore, following genetic silencing of Nrf2 by RNA interference, the effects of H2 gas on the induction of HO­1 and cardioprotection were markedly reduced. In conclusion, H2 gas protected cardiomyocytes from ischemia­induced myocardial injury through elimination of ·OH free radicals and also through activation of the Nrf2/HO­1 signaling pathway.

Effect of glucocorticoid-induced oxidative stress on the expression of Cbfa1.

Glucocorticoids therapy is strongly limited since extended glucocorticoids can cause serious side effects, including increased susceptibility to develop the bone disease osteoporosis. Despite its side effects recognized importance to clinicians, seldom is known about how glucocorticoids directly impact bone-forming osteoblasts. Previous studies showed that dexamethasone (DEX) induces excessive production of reactive oxygen species (ROS), and causes oxidative stress in rat hippocampal slice cultures. To assess the implications and investigate the mechanisms of glucocorticoid-elicited osteoporosis, we hypothesize that DEX exposure induces oxidative stress which leads to decreased Cbfa1 mRNA expression, and predict that the antioxidant N-acetylcysteine (NAC) mitigates the damaging effects of DEX. Oxidative stress is implicated in osteoporosis. Furthermore, the osteoblast transcriptional factor Cbfa1 is reported to play a protective role against osteoporosis in postmenopausal women. Cells treated with (0.1, 1, 10µM) DEX exhibited signs of oxidative damages including depletion in total antioxidant capacity (T-AOC), increased ROS formation, and enhanced lipid peroxidation. Cbfa1 mRNA expression, by RT-PCR, was significantly reduced after exposure to (0.1, 1, 10µM) DEX. Pretreatment with the antioxidant NAC (2mM) prevented DEX-induced decrease in Cbfa1 mRNA. This study provides insight into the underlying mechanisms of high dose DEX-induced osteotoxicity. DEX (0.1, 1, 10µM) decreases the expression of Cbfa1 mRNA and inhibits differentiation and function of osteoblasts by inducing oxidative stress. The antioxidant NAC can mitigate the oxidative stress damaging effects of DEX. In addition, this study distinguishes itself by identifying Cbfa1 as a target for high dose DEX-induced osteotoxicity.

[Treatment and prognostic analysis of ovarian cancer patients with isolated region of lymph node recurrence].

OBJECTIVE: To evaluate the management and survival of lymph node region recurrence of epithelial ovarian cancer (EOC), and discuss its suitable therapeutic strategy. METHODS: Thirty-eight patients with the recurrence of lymph node region were extracted from 1945 patients who were diagnosed EOC and treated in Sun Yat-sen University Cancer Center from January 1995 to December 2008. The clinical characteristics, therapy methods and survival of them were retrospectively analyzed. Patient age at initial diagnosis was > 50 years old in 24 patients and ≤ 50 years old in 14 patients. There were 15 cases with stage II and 23 cases with stage III in terms of initial International Federation of Gynecology and Obstetrics (FIGO, 1987) staging. Classified with histological grade, 7 cases were in G(1), 14 cases were in G(2), 17 cases were in G(3); according to the histological types, 19 cases were with serous adenocarcinomas, and 19 cases were with non-serous adenocarcinomas (including 9 endometrioid adenocarcinoma, 1 mucinous adenocarcinoma and 9 unclassified adenocarcinoma). The median follow-up time was 59 months (ranged 16 to 124 months). RESULTS: (1) Feature of recurrences: the median interval of last treatment to recurrence was 18 months (range 9 to 96 months). Most of them were absence of symptoms. The serum level of CA(125) was elevated in 15 patients (39%, 15/38). (2) Treatment of recurrences:of the 38 patients, 19 underwent lymphadnectomy for recurrence regions and received adjuvant chemotherapy (surgery + chemotherapy group), 14 received local radiotherapy and adjuvant chemotherapy (radiotherapy + chemotherapy group), 5 received chemoherapy only (chemotherapy group). There were 35 cases achieved complete response (CR), including 19 patients underwent secondary debulking surgery in surgery + chemotherapy group, 14 cases in radiotherapy + chemotherapy group (12 of them treated by radiotherapy, the other 2 cases reached CR after adjuvant chemotherapy) and 2 cases in chemotherapy group. While only 3 patients reached partial response in chemotherapy group. (3) Survival and second recurrences: during follow-up, 14 cases died of tumor, 4 cases survival with tumor while 20 cases survival without evidence of tumor. The 5-year post-recurrence survival rate of 38 cases was 66.5%, with 71.8%, 68.8% and 40.0% in surgery + chemotherapy, radiotherapy + chemotherapy, and chemotherapy group, respectively, and there was no significant difference in survival rate between them (P > 0.05). A total of 15 patients experienced second recurrences, including 7 cases with peritoneal and 8 cases with lymph node region recurrences. (4) Prognosis factors: the univariate analysis shown that survival after recurrence was significantly related to patient age, tumor-free interval and number of recurrence disease (P < 0.05), while not to FIGO stage, histological type, histological grade, and lymphadnectomy during primary surgery (P > 0.05). The multivariate analysis showed that patient age and tumor-free interval were independent prognostic variables for survival after recurrence (P < 0.05). CONCLUSIONS: The lymph node region recurrence of EOC may be have good prognosis and distinctive clinical process. Local treatment strategies including secondary surgery and radiotherapy should be considered, which may significantly improve survival in ovarian cancer patients with lymph node region recurrence.

Baicalin down-regulates the expression of macrophage migration inhibitory factor (MIF) effectively for rats with ulcerative colitis.

The purpose of this study was to investigate whether baicalin, a Chinese herbal extract, down-regulates the expression of macrophage migration inhibitory factor (MIF), an inflammatory factor that regulates the function of macrophages (MΦ), in rats with trinitrobenzene sulphonic acid (TNBS)-induced ulcerative colitis (UC). The results showed that baicalin simultaneously down-regulated the expression of MIF, the quantity of MΦs and the amount of MΦ-related cytokines, including macrophage chemotactic factor-1 (MCP-1, CCL2) and macrophage inflammatory protein-3α (MIP-3α, CCL20), in rats with UC. There was no statistical difference between baicailin and mesalazine in down-regulating the expression of MIF. Our study demonstrated that baicalin, an inexpensive but effective monomer, could be a new and alternative pharmaceutical for UC.

A clinicopathological aspect of primary small-cell carcinoma of the uterine cervix: a single-centre study of 25 cases.

AIMS: Small-cell carcinoma is a variant of poorly differentiated neuroendocrine carcinoma. Primary small-cell carcinoma of the cervix (SCCC) is recognised as a rare and aggressive malignant tumour with poor prognosis. In this study, the authors report 25 Chinese cases of SCCC, with a particular focus on their clinical and pathological characteristics. MATERIAL AND METHODS: The records of 25 patients from 4075 Chinese patients with cervical cancer were collected and reviewed, including the patients' age, initial symptoms, cervical tumour size, International Federation of Gynaecology and Obstetrics clinical stage, lymph-node metastasis, treatments and follow-up results. Immunohistochemical detection was performed for cytokeratin, epithelial membrane antigen, neuron-specific enolase (NSE), synaptophysin (Syn), chromogranin A (CgA), neuronal cell adhesion molecules (CD56), thyroid transcriptional factor-1 and S100 protein (S100). RESULTS: The median age of 25 patients with SCCC was 43.7 years. The most common symptom was abnormal vaginal bleeding. Histologically, there were 19 'homogenous' SCCC samples and six samples of SCCC mixed with adenocarcinoma. The proportion of SCCC samples with positive immunoreactivity were 100.0% for NSE, 96.0% for Syn, 68.0% for CD56, 76.0% for CgA, 40.0% for thyroid transcriptional factor-1, 84.0% for epithelial membrane antigen, 68.0% for cytokeratin and 8.0% for S100, respectively. Every patient received one to three types of treatments, including surgery, chemotherapy and radiotherapy. The median survival time of patients was 20.9 months after diagnosis. CONCLUSION: The higher proportion of positive labelling of Syn, CD56, CgA, and NSE in SCCC implicated that they are valuably applied in a differential diagnosis of the malignancy. The patients with SCCC receive one to three types of therapies, including surgery, chemotherapy and radiotherapy, and have a poor prognosis.

[Clinical analysis of 12 cases of ovarian carcinosarcoma].

OBJECTIVE: To evaluate the clinical pathological characteristics, treatment and prognosis of ovarian carcinosarcoma. METHODS: The clinical, pathological and follow-up data of 12 cases of ovarian carcinosarcoma treated in Cancer Center of Sun Yat-sen University from May, 2002 to May, 2009 were analyzed retrospectively. RESULTS: The 12 patients with ovarian carcinosarcoma had a median age of 55 years at diagnosis, among whom 10 were postmenopausal women. The patients sought medical attention for such symptoms as pelvic and/or abdominal pain, abdominal distention and ascites. Ten patients showed elevated serum CA125 level ad admission, and postoperative chemotherapy resulted in lowered CA125 level within normal range in 7 of them; in 8 cases, CA125 level increased with disease recurrence. Pelvic mass was found by such imaging examinations as CT, MRI and ultrasound in all cases. A definite diagnosis was obtained by postoperative pathological examination. All the patients received surgical resection and platinum-based adjuvant chemotherapy. Two patients achieved disease-free survival after the treatment. Disease relapse occurred in 10 cases within 2 years after surgery, among whom 2 showed disease remission after a secondary surgery and/or chemotherapy, and 1 was receiving chemotherapy; death occurred in 5 cases, and 2 cases were lost to the follow-up. CONCLUSIONS: Ovarian carcinosarcoma has a poor prognosis. Primary surgery and platinum-based postoperative adjuvant chemotherapy is the main treatment for ovarian carcinosarcoma. The prognosis of ovarian carcinosarcoma is associated with the residual disease after surgery. The patients with disease recurrence may obtain remission and survival through a secondary surgery and/or chemotherapy. Serum CA125 can be used as a marker for monitoring the chemotherapeutic effect in clinical observation and follow-up visits.

[Response to neoadjuvant chemotherapy on locally advanced cervical cancer and long-term follow-up outcome].

OBJECTIVE: to assess the efficacy of neoadjuvant chemotherapy and the prognostic factors in patients with locally advanced cervical cancer. METHODS: from January 2005 to December 2006, 139 patients with stage Ib - IIa bulky cervical cancer (tumor diameter ≥ 4 cm) treated at our department were enrolled into this retrospective study. The patients were divided into two groups of neoadjuvant chemotherapy (NAC) (n = 117) and director operation (DOR) (n = 22). In NAC group, 84 with stage Ib and 33 with stage IIa disease received radical hysterectomy and lymphadenectomy after 1 - 3 cycles of neoadjuvant chemotherapy. In DOR group, 18 with stage Ib and 4 with stage IIa disease underwent radical hysterectomy directly after diagnosis. The high-risk patients in both groups received chemotherapy and/or radiotherapy according to the post-operative pathological results. All patients were followed up routinely to assess the prognosis. RESULTS: eighty-four patients achieved complete remission (CR) or partial remission (PR) after NAC administration. And the response rate for NAC was 71.8%. The death risk in PR cases was 28.82 times higher than that in CR cases. None of 12 patients with a pathologically complete remission developed recurrence or death. The median follow-up duration was 50 months for all cases. In NAC group, the disease-free survival time was (55.36 ± 2.16) months and the 3-year survival rate was 82.1%. The recurrent rate was 26.5% while the average recurrent time of (11.06 ± 9.50) months. In DOR group, the above parameters were (61.64 ± 3.63) months, 90.9%, 9.1% and (12.50 ± 7.78) months respectively. There were no significant difference between two groups in these prognosis parameters (all P > 0.05). Univariate analysis revealed that histological grade, deep cervical invasion, response to neoadjuvant chemotherapy and lymph node metastasis were the risk factors for prognosis in patients on NAC. The COX hazard analysis indicated that lymph node metastasis was only independent prognostic factor. CONCLUSION: neoadjuvant chemotherapy appears not to offer any advantage of improving the prognosis in locally advanced cervical cancer. The lymph node metastasis is an important prognostic factor. The patients with a pathological complete remission after NAC may have a good prognosis.

Establishing a Th17 based mouse model for preclinical assessment of the toxicity of candidate microbicides.

BACKGROUND: To effectively block the invasion of human immunodeficiency virus (HIV)-1 on mucosal surface, vaginal anti-HIV-1 microbicides should avoid inflammatory responses and disruption of mucosa integrity because these will facilitate transepithelial viral penetration and replication. However, existing models fail to predict and evaluate vaginal mucosal toxicity induced by microbicides, and most importantly, they are unable to identify subtle or subclinical inflammatory reactions. This study was designed to develop a cost-effective in vivo model to evaluate microbicide safety in a preclinical study which can recapitulate the mucosal topical reaction. METHODS: A murine model was employed with nonoxynol-9 (N-9) as the topical stimulant within the vagina. Different concentrations of N-9 (1%, 3%, and 4%) were topically applied to the vagina for five consecutive days. A panel of inflammatory cytokines including interleukine-2 (IL-2), IL-4, IL-6, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and immuno-regulatory IL-10 were assayed in vaginal lavage. Cytokines were quantified by using cytometric bead array (CBA) and reverse transcript (RT) real-time PCR. Histopathological evaluation of vaginal tissues was conducted on hematoxylin-eosin stained slides and scored with a semi-quantitative system according to the severity of epithelial disruption, leucocyte infiltration, edema, and vascular injection. The association between the cytokines and histopathological scores was assessed by linear regression analysis. RESULTS: All three concentrations of N-9 induced inflammatory cytokine production. The 4% N-9 application resulted in a consistent production of cytokines in a time-dependent manner. The cytokines reached peak expression on day three with the exception of IL-4 which reached its peak on day one. Histopathological examination of 4% N-9 treated cervicovaginal tissues on day three showed intensive damage in four mice (sores: 10 - 13) and moderate damage in one mouse (score: 8), which were significantly associated with both inflammatory cytokines IL-17A and IL-6 and anti-inflammatory cytokines IL-4 and IL-10. Interestingly, IL-17A showed significant positive association with inflammatory cytokine TNF-α (r = 0.739; P < 0.05), anti-inflammatory cytokines IL-10 (r = 0.804; P < 0.01) and IL-4 (r = 0.668; P < 0.05). CONCLUSIONS: Our data demonstrate that a panel of cytokines (IL-17A, IL-6, IL-4 and IL-10) could be used as surrogate biomarkers to predict the histopathological damage. Th17 may play a central role in orchestrating inflammatory cytokine responses. This Th17 based mouse model is cost-effective and suitable to assess the toxicity of candidate microbicides in preclinical studies.

Pulmonary miliary tuberculosis and intestinal tuberculosis co-infected with AIDS.

Infections with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis account for 25 million patients worldwide. Tuberculosis is the most common opportunistic infectious disease in HIV-infected subjects, and HIV infection is a high-risk factor for tuberculosis. The convergence of HIV and tuberculosis is a disaster practically unequalled in medical history. This is a rare case report on the topic of pulmonary miliary tuberculosis and intestinal tuberculosis with AIDS.

Noninvasive assessment of liver fibrosis with combined serum aminotransferase/platelet ratio index and hyaluronic acid in patients with chronic hepatitis B.

AIM: To construct a noninvasive assessment model consisting of routine laboratory data to predict significant fibrosis and cirrhosis in patients with chronic hepatitis B (CHB). METHODS: A total of 137 consecutive patients with CHB who underwent percutaneous liver biopsy were retrospectively analyzed. These patients were divided into two groups according to their aminotransferase (ALT) level. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), the likelihood ratio (LR) of aminotransferase/platelet ratio index (APRI) > or = 1.5 or < 1.5 in combination with different hyaluronic acid (HA) cut-off points were calculated for the presence of moderate to severe fibrosis/cirrhosis (fibrosis stages 2 and 4) and no to mild fibrosis/cirrhosis (fibrosis stages 0 and 1). RESULTS: The APRI correlated with fibrosis stage in CHB patients. The APRI > or = 1.5 in combination with a cut-off HA cut-off point > 300 ng/mL could detect moderate to severe fibrosis (stages 2-4) in CHB patients. The PPV was 93.7%, the specificity was 98.9%. The APRI < 1.5 in combination with different HA cut-off points could not detect no to mild fibrosis in CHB patients. CONCLUSION: The APRI > or = 1.5 in combination with a HA cut-off point > 300 ng/mL can detect moderate to severe fibrosis (stages 2-4) in CHB patients.