[Acupuncture of revised acupoint combination around the skull base for post-stroke mild cognitive impairment: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of acupuncture of revised acupoint combination around the skull base in treating post-stroke mild cognitive impairment (PSMCI), and preliminary explore its action mechanism. METHODS: A total of 76 PSMCI patients were randomly divided into an observation group (38 cases, 4 cases dropped off) and a control group (38 cases, 3 cases dropped off, 1 case was removed). In the observation group, acupuncture of revised acupoint combination around the skull base (bilateral Fengchi [GB 20], Wangu [GB 12], Tianzhu [BL 10] and Yamen [GV 15], Baihui [GV 20]) was used for treatment. In the control group, 8 non-meridian and non-acupoint points at the distal end were selected for shallow puncture treatment. Retaining the needles of 30 min, once every other day,3 times a week for 4 weeks in both groups. The scores of Montreal cognitive assessment (MoCA), mini-mental state examination (MMSE), Barthel index (BI) and serum levels of cystatin C (Cys-C) and homocysteine (Hcy) were compared in the two groups before and after treatment, and the clinical efficacy was evaluated. RESULTS: After treatment, the scores of MoCA were increased compared with those before treatment in the two groups (P<0.05), and the score in the observation group was higher than that in the control group (P<0.05). The scores of MMSE and BI were increased compared with those before treatment in the observation group (P<0.05), and the score of MMSE in the observation group was higher than that in the control group (P<0.05). After treatment, the serum levels of Cys-C and Hcy were decreased compared with those before treatment in the observation group (P<0.05), and lower than those in the control group (P<0.05). After treatment, the serum level of Cys-C was increased compared with that before treatment in the control group (P<0.05). The total effective rate of the observation group was 88.2% (30/34), which was higher than 32.4% (11/34) of the control group (P<0.05). CONCLUSION: Acupuncture of revised acupoint combination around the skull base can improve cognitive function and daily living ability of PSMCI patients, which may be related to the down regulation of serum levels of Cys-C and Hcy.

An integrated strategy by absorbed component characterization, pharmacokinetics, and activity evaluation for identification of potential nephroprotective substances in Zhu-Ling decoction.

An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases.

Simultaneous determination of multiple constituents of Qi-Lin pill by UPLC-MS/MS: Applications to pharmacokinetics and testicular tissue distribution in rats.

Qi-Lin pill (QLP) is an effective traditional Chinese medicine prescription (TCMP) that has been used for the treatment of the oligoasthenozoospermia in China. Recently, some articles described the pharmacological effects of QLP and multiple ingredients in QLP contribute to its effects. However, the pharmacokinetic and target tissue distribution data of QLP are still unknown. In the present study, according to the Bioanalytical Method Validation Guidance of FDA, a sensitive and selective UPLC-MS/MS method was developed and validated for simultaneous determination of multiple constituents in rat plasma and testicular tissue, including morusimic acid A, codonopyrridium B, magnoflorine, emodin, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), ecliptasaponin A, paeoniflorin, albiflorin, gallic acid, danshensu, salvianolic acid A, catechin, isosinensetin, nobiletin, formononetin, calycosin, icariside II, icariin and epimedin C. For 19 analytes, the LLOQs reached 0.01-4 ng/mL. And all calibration curves showed favorable linearity (r ≥ 0.9903) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.92 %, and the accuracies (as relative error) were in the range of - 6.44 % to 6.22 %. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The method was successfully applied for the pharmacokinetics and testis distribution of multiple chemical constituents in QLP after a single oral dose. As a result, high exposure of danshensu, gallic acid, paeoniflorin and albiflorin were observed in rat plasma and testicular tissue. Among the flavonoids, isosinensetin and nobiletin had high exposure in testicular tissue. Moreover, alleviation of progesterone reduction was evaluated in H2O2-induced R2C leydig cells, and danshensu, gallic acid, paeoniflorin, albiflorin and nobiletin showed potent activity. Therefore, these five components were considered to be the effective components of QLP due to their relatively high exposure in vivo and biological activity. This finding also provided relevant information on action mechanism of QLP in the treatment of oligoasthenozoospermia.

Pharmacokinetics, hepatic disposition, and heart tissue distribution of 14 compounds in rat after oral administration of Qi-Li-Qiang-Xin capsule via ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry.

In the present study, a specific and sensitive approach using ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry was developed and validated for the quantitative analysis of 14 constituents in rat plasma, liver, and heart. The method was fully validated and successfully applied to pharmacokinetic, hepatic disposition, and heart tissue distribution studies of 14 compounds after the oral administration of Qi-Li-Qiang-Xin capsule. Ginsenoside Rb1, alisol A, astragaloside IV, and periplocymarin were found to be highly exposed in rat plasma, while toxic components such as hypaconitine, mesaconitine, and periplocin had low circulation levels in vivo. Moreover, sinapine thiocyanate, neoline, formononetin, calycosin, and alisol A exhibited significant liver first-pass effects. Notably, high levels of alisol A, periplocymarin, benzoylmesaconine, and benzoylhypaconine were observed in the heart. Based on high exposure and appropriate pharmacokinetic features in the systemic plasma and heart, astragaloside IV, ginsenoside Rb1, periplocymarin, benzoylmesaconine, benzoylhypaconine, and alisol A can be considered as the main potentially effective components. Ultimately, the results provide relevant information for discovery of effective substances, as well as further anti-heart failure action mechanism investigations of Qi-Li-Qiang-Xin capsule.

Discovery of potential Q-marker of traditional Chinese medicine based on plant metabolomics and network pharmacology: Periplocae Cortex as an example.

BACKGROUND: Quality control exerted great importance on the clinical application of drugs for ensuring effectiveness and safety. Due to chemical complexity, diversity among different producing areas and harvest seasons, as well as unintentionally mixed with non-medicinal parts, the current quality standards of traditional Chinese medicine (TCM) still faced challenges in evaluating the overall chemical consistency. PURPOSE: We aimed to develop a new strategy to discover potential quality marker (Q-marker) of TCM by integrating plant metabolomics and network pharmacology, using Periplocae Cortex (GP, the dried root bark of Periploca sepium Bge.) as an example. METHODS: First, plant metabolomics analysis was performed by UPLC/Q-TOF MS in 89 batches of samples to discover chemical markers to distinguish medicinal parts (GP) and non-medicinal parts (the dried stem bark of Periploca sepium Bge. (JP)), harvest seasons and producing region of Periplocae Cortex. Second, network pharmacology was applied to explore the initial linkages among chemical constituents, targets and diseases. Last, potential Q-marker were selected by integrating analysis of plant metabolomics and network pharmacology, and the quantification method of Q-marker was developed by using UPLC-TQ-MS. RESULTS: The chemical profiling of GP and JP was investigated. Fifteen distinguishing features were designated as core chemical markers to distinguish GP and JP. Besides, the content of 4-methoxybenzaldehyde-2-O-ß-d-xylopyranosyl-(1→6)-ß-d-glucopyranoside could be used to identify Periplocae Cortex harvested in spring-autumn or summer. Meanwhile, a total of 15 components targeted rheumatoid arthritis were screened out based on network pharmacology. Taking absorbed constituents into consideration, 23 constituents were selected as potential Q-marker. A simultaneous quantification method (together with 11 semi-quantitative analysis) was developed and applied to the analysis of 20 batches of commercial Periplocae Cortex on the market. The PLS-DA model was successfully developed to distinguish GP and JP samples. In addition, the artificially mixed GP sample, which contained no less than 10% of the adulterant (JP), could also be correctly identified. CONCLUSION: Our results indicated that 9 ingredients could be considered as Q-marker of Periplocae Cortex. This study has also demonstrated that the plant metabolomics and network pharmacology could be used as an effective approach for discovering Q-marker of TCM to fulfill the evaluation of overall chemical consistency among samples from different producing areas, harvest seasons, and even those commercial crude drugs, which might be mixed with a small amount of non-medicinal parts.

Dissection of the potential anti-influenza materials and mechanism of Lonicerae japonicae flos based on in vivo substances profiling and network pharmacology.

Lonicerae japonicae flos.(LJF) was widely used as a drug to treat upper respiratory tract infection or a tea to clear heat in Asian countries for thousands of years. Despite of its curative effects confirmed by modern pharmacological methods, its functional materials and mechanism against influenza were still unclear and needed further investigation. In this study, an integrated strategy based on in vivo substances profiling and network pharmacology was proposed and applied to screen out the potential anti-influenza substances and mechanism of LJF. An UHPLC/Q-TOF MS method was utilized to profile the chemical components in LJF and their metabolites in rats. The targets of absorbed prototypes were predicted by Swiss Target Prediction, and they were further analyzed by String and Kyoto Encyclopedia of Genes and Genomes (KEGG). As a result, a total of 126 chemical components mainly featuring three chemical structure types were characterized, including 70 iridoid glycosides, 17 caffeoylquinic acids, 24 flavonoids, and 15 other types compounds. Among them, ten N-contained iridoid glycosides were characterized as potential novel compounds. Moreover, 141 xenobiotics (74 prototypes and 67 metabolites) were clearly screened out in rat plasma and urine after ingestion of LJF. Phase II reactions (sulfation, glucuronidation, methylation) and phase I reactions (dehydroxylation, hydrogenation, hydrolysis, N-heterocyclization) were the main metabolic reactions of LJF in rats. Further, a total of 338 targets were predicted and TNF, PTGS2 and EGFR were the three main targets involved in the pathology of influenza. In addition to normal NF-κB pathway, T cell signal pathway and mTOR signal pathway were the other patterns for LJF to achieve its anti-flu effects. Our work provided the meaningful data for further pharmacological validation of LJF against influenza, and a new strategy was also proposed for minimizing the process to reveal the mechanism and functional basis of TCMs.

Discovery of anti-flu substances and mechanism of Shuang-Huang-Lian water extract based on serum pharmaco-chemistry and network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuang-Huang-Lian preparation has captured wide attention since its clinical applications for the successful treatment of upper respiratory tract infection. However, its functional basis under actual therapeutic dose in vivo was still unrevealed. AIM OF THE STUDY: This study aimed to reveal the anti-flu substances and mechanism of Shuang-Huang-Lian water extract (SHL) on H1N1 infected mouse model by a strategy based on serum pharmaco-chemistry under actual therapeutic dose and network pharmacology. MATERIALS AND METHODS: H1N1 infected mouse model was employed for evaluation of the anti-flu effects of SHL. A simultaneous quantification method was developed by UPLC-TQ-XS MS coupled switch-ions mode and applied to characterize the pharmacokinetics of the multiple components of SHL under actual therapeutic dose. The potential active ingredients were screened out based on their pharmacokinetic parameters. And then, a compound mixture of these active candidates was re-evaluated for the anti-flu activity on H1N1 infected mouse model. Furthermore, the anti-flu mechanism of SHL was also predicted by network pharmacology coupled with the experimental result. RESULTS: SHL significantly increased the survival rate and prolonged survival days on H1N1 infected mice at a dosage of 20 g crude drug/kg/day by reversing the increased lung index, down-regulating the inflammatory cytokines (TNF-α, IL-1ß, IL-6) and inhibiting the release of IFN-ß in bronchoalveolar lavage fluids (BALF). Concomitantly, the pharmacokinetic parameters of fourteen quantified and twenty-one semi-quantified constituents of SHL were characterized. And then, five compounds (baicalin, sweroside, chlorogenic acid, forsythoside A and phillyrin), which displayed satisfactory pharmacokinetic features, were considered as potential active ingredients. Thus, a mixture of these five ingredients was administered to H1N1-infected mice at a dose of 4.24 mg/kg/day. As a result, the therapeutical effects of the mixture were similar to SHL in terms of survival rate, lung index and the release of cytokines (TNF-α, IL-1ß and IL-6) in BALF. Moreover, network pharmacology analysis indicated that the TNF-signal pathways might play a role in the anti-flu mechanism of SHL. CONCLUSIONS: A mixture of five compounds (baicalin, sweroside, chlorogenic acid, forsythoside A and phillyrin) were the anti-flu substances of SHL. The strategy based on serum pharmaco-chemistry under actual therapeutic dose provided a new sight on exploring in vivo effective substances of TCM.

Systematically characterization of in vivo substances of Ziziphi Spinosae Semen in rats by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis.

Ziziphi Spinosae Semen (ZSS), the seeds of Ziziphus jujuba var. spinosa, is widely used in China or other Asian countries for the treatment of insomnia and palpitation. In our previous work, chemical constituents in ZSS were profiled by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC/Q-TOF MS). Notably, characterization of substances in vivo was of great importance to reveal the therapy basis or mechanism in further work. Till now, there were few reports about in vivo substances' investigation of ZSS. In the present study, an integrated strategy contained represented compounds and diagnostic ions extraction was applied to characterize metabolism feature of ZSS in rats based on UHPLC/Q-TOF MS method. First, the metabolic information of four compounds (spinosin, isovitexin, jujuboside B, betulinic acid) featuring three representative chemical structures (flavonoids, saponins, terpenes) in ZSS was conducted, and their metabolism features were summarized, especially for flavonoid C-glycosides. Second, the absorbed compounds and representative compounds-related metabolites were quickly screened out; during this time, the diagnostic ions were sorted out. Last, with the help of diagnostic ions and summarized metabolic reactions, other metabolites were characterized. As a result, a total of 151 xenobiotics (58 prototypes and 93 metabolites) were identified or tentatively characterized in rats after ingestion of ZSS. Among them, 16 substances were presented in plasma, 114 in urine, 51 in bile, and 120 in feces, respectively. Hydrogenation, hydrolysis, and glucuronidation were the major metabolic reactions of ZSS in rats. The present study provided meaningful data for further pharmacological mechanism research or pharmacokinetics evaluation of ZSS.

An integrated strategy for revealing the pharmacological changes based on metabolites profiling and network pharmacology: Arctiin as an example.

Traditional Chinese medicine was widely used in China since its definite effects and therapy. The components of TCM were absorbed into the circle system as the format of prototypes or metabolites, which contributed to the therapy or side effects. Declaring the functional changes in this process was of great importance to the clinical applications. In this work, an integrated strategy based on metabolites' profiling and network pharmacology was proposed for exploring the pharmacological changes of compounds in vivo. Arctiin, the main component in Fructus Arctii with various kinds of bioactivities, was used as an example. An ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry and metabolynx™software was applied to characterize the metabolites of arctiin in rats at a dosage of 100 mg/kg; network pharmacology was applied to characterize the functional changes. As a result, fifty-three metabolites (32 in plasma, 40 in urine, 19 in bile, 20 in feces, 1 in brain, 12 in liver and 4 in lungs) were screened out and characterized, and 3 of them were unambitiously identified by comparison with standard substances. Among them, 38 metabolites were reported for the first time. It was found the major metabolic pathways of arctiin in rats were demethylation, lactone-opening and phase II conjugations with sulfate and glucuronide.It also confirmed that M14, M15, M18, M23, M22, M43 and M45 were the major circulating forms of arctiin in rats following oral administration. In addition to the above metabolic reactions, phase I reactions of hydrolysis, demethylation, dehydroxylation were also observed, and dehydrogenation were first revealed metabolic patterns of arctiin in rats. Meanwhile, in addition to the main targets of arctiin (MTOR, EGFR and MAPK14), its metabolites targeted additional 392 targets with additional functions of anti-hepatitis B or viral carcinogenesis (SRC, CAPS3, PIK3CA, CDK4, ESR1, MMP9 and ERBB2). The above results provided very important information for understanding the metabolism and functional changes of arctiinin vivo, and supporting data for further pharmacological evaluation. Our work also provided a newsight for elucidation of functional changes of TCMs in vivo.

Characterization of lignans in Forsythiae Fructus and their metabolites in rats by ultra-performance liquid chromatography coupled time-of-flight mass spectrometry.

OBJECTIVES: This study was designed to profile the chemical information of Forsythiae Fructus (FF) and investigate the in-vivo FF-related xenobiotics, especially for lignans. METHODS: Rats were oral administrated of FF and pinoresinol-4-O-glucoside, respectively. Blood and urine samples were collected after ingestion, and xenobiotics was profiled by an UPLC/Qtof MS method. KEY FINDINGS: A total of 19 lignans were identified or tentatively characterized in FF, and 63 lignan-related xenobiotics were found in rat plasma and urine after ingestion of FF. It was found that lignans could be transformed into metabolites by furan ring opening, hydrogenation, demethylation, dehydration and phase II reactions (sulfation and glucuronidation). The whole metabolic behaviour of bisepoxylignan was revealed by evaluating the metabolism of pinoresinol-4-O-glucoside in vivo. It was found that the configuration of C-8/C-8' was retained after furan ring opening and metabolic reactions always occurred at position of C-3/C-4/C-5 or C-3'/C-4'/C-5'. Additionally, other types components in FF and in vivo were also characterized. CONCLUSIONS: This work revealed the in-vivo metabolism of FF, and reported the characteristic metabolic reactions of lignans for the first time. It was also provided the foundation for the further investigation on pharmacodynamic components of FF or TCMs containing FF.

Characterization of chemical components of Periplocae Cortex and their metabolites in rats using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry.

Periplocae Cortex, named Xiang-Jia-Pi in China, has been widely used to treat autoimmune diseases, especially rheumatoid arthritis. However, the in vivo substances of Periplocae Cortex remain unknown yet. In this study, an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used for profiling the chemical components and related metabolites of Periplocae Cortex. A total of 98 constituents were identified or tentatively characterized in Periplocae Cortex: 42 C21 steroidal glycosides, 10 cardiac glycosides, 23 organic acids, 4 aldehydes, 7 triterpenes, and 12 other types. Among them, 18 components were unambiguously identified by comparison with reference standards. In addition, 176 related xenobiotics (34 prototypes and 142 metabolites) were screened out and characterized in rats' biosamples (plasma, urine, bile, and feces) after the oral administration of Periplocae Cortex. Moreover, the metabolic fate of periplocoside S-4a, a C21 steroidal glycoside, was proposed for the first time. In summary, phase II reactions (methylation, glucuronidation, and sulfation), phase I reactions (hydrolysis reactions, oxygenation, and reduction), and their combinations were the predominant metabolic reactions of Periplocae Cortex in rat. It is the first report to reveal the in vivo substances and metabolism feature of Periplocae Cortex. This study also provided meaningful information for further pharmacodynamics study of Periplocae Cortex, as well as its quality control research.

Clinical features and treatment outcomes of 14 cases of primary ovarian non-Hodgkin's lymphoma: a single-center experience.

To analyze the clinical characteristics, results of treatment, and prognostic factors of patients diagnosed as primary ovarian non-Hodgkin's lymphoma (PONHL). Fourteen cases of PONHL treated in Fudan University Cancer Center during a 10-year period were retrospectively reviewed, and the clinical data of the patients were analyzed for correlation between KPS, clinical stage, tumor size, IPI, ovary involvement, treatment and prognosis. The median age was 45 years, and thirteen patients were diagnosed of diffuse large B-cell lymphoma and one patient lymphoblastic lymphoma. Four patients were stage IE, three stage IIE, and seven stage IVE. The median tumor size was 8 cm (range, 4.0-15.0 cm). The median overall survival (OS) of the 14 patients was 23.0 months (range 11.5-71.2 months). Thirty-six percentage of patients with bilateral ovary involvement had a shorter survival time than those with unilateral ovary involvement (median OS: 19.0 vs. 37.2 months, P=0.014). The OS of Stage IVE was worse than stage IE and stage IIE (median OS: 18.75 vs. 37.5 months, P=0.047). Patients with IPI>2 had worse prognosis than those with IPI≤2 (median OS: 19.0 vs. 42.1 months, P=0.03). PONHL patient with larger tumor mass had worse prognosis (median OS: 19.1 vs. 37.2 months, P=0.019). R-CHOP regimens had a tendency to improve the OS but was not shown to be statistically significant (median OS: 22.4 vs. 37.2 months, P=0.436). The management of PONHL should be based on multi-modality treatment including surgery and chemotherapy. The significant prognostic factors of survival are tumor size, Ann Arbor staging, and IPI.

[Nerve-sparing radical hysterectomy and radical hysterectomy: a retrospective study].

OBJECTIVE: To compare Piver radical hysterectomy (RH) with nerve-sparing radical hysterectomy (NSRH) for cervical cancer patients in terms of postoperative physiology of pelvic autonomic nerve and perioperative complications. METHODS: Ninety-three consecutive patients with invasive cervical cancer underwent RH (69 cases) or NSRH (24 cases) from March 2005 to March 2006 at Fudan University Cancer Hospital. The postoperative function of bladder, bowel and sexual function and perioperative morbidity were assessed. RESULTS: Compared with patients received RH, patients underwent NSRH presented a significantly prompter recovery of bladder function (8.7 vs. 14.8 days, P < 0.01) and bowel function (2.9 vs. 3.2 days, P < 0.01). However, there were not significant difference in terms of operative time (146.7 vs. 143.3 minutes, P > 0.05), estimated blood loss (441.7 vs. 565.9 ml, P > 0.05) and hospital stay (10.21 vs. 10.19 days, P > 0.05). No positive surgical margin was found in both groups. No surgery complication was found in NSRH group, while there were 1 case presented the infection of lymphocyst and 1 case presented intestinal obstruction in RH group. After following up postoperative 6 months, the patients received NSRH had a higher rate of satisfaction at sex activity than those received RH (29% vs. 9%, P = 0.042). CONCLUSION: NSRH is safe and feasible surgical management for cervical cancer patients, which would improved the physiology of pelvic autonomic nerve postoperatively.

EMMPRIN expression as a prognostic factor in radiotherapy of cervical cancer.

PURPOSE: Overexpression of extracellular matrix metalloproteinase inducer (EMMPRIN), a member of the immunoglobulin family and a glycoprotein enriched on the surface of many types of tumor cells, has been reported to be linked to invasion, metastasis, growth, and survival of malignant cells. Cervical cancer, the second most prevalent cancer in women worldwide and the fifth leading cause of cancer deaths, responds to radiotherapy variably, with 30% of cases recurring after therapy. The purpose of this study was to determine whether expression of EMMPRIN affects the response of cervical cancer to radiation therapy, and whether this membrane protein can be used as a prognostic marker for cervical cancer. EXPERIMENTAL DESIGN: The retrospective cohort study included 82 patients with invasive cervical cancer referred to the Department of Gynecologic Oncology at The Cancer Hospital of Fudan University (Shanghai) between 1991 and 2000. These patients were treated with brachytherapy at a dose of 15 Gy at point A before radical hysterectomy. Expression of EMMPRIN in cervical tumor specimens was examined by immunohistochemistry staining before and after brachytherapy and scored for both staining intensity and percentage of tumor cells stained. EMMPRIN immunoreactivity and clinicopathologic data were analyzed with respect to survival end points using univariate and multivariate approaches. RESULTS: The frequency of EMMPRIN overexpression was 52.4% in primary cervical cancer. After brachytherapy, EMMPRIN overexpression was significantly reduced (13.4%) compared with corresponding tumor before brachytherapy (P = 0.032). EMMPRIN expression was associated with pelvic lymph node metastasis (P = 0.026) and reduction in primary tumor volume following brachytherapy (P = 0.008). Although EMMPRIN expression before or after brachytherapy did not correlate with tumor-specific survival, but increased expression of EMMPRIN following brachytherapy tended to predict poor outcomes by univariate survival analysis (P = 0.0008). In addition, lymph vascular space invasion, deep stromal invasion, and lymph node metastasis were significantly associated with poor prognosis. In multivariate analysis, the independent prognostic factors for tumor-specific survival included the decreased expression of EMMPRIN after brachytherapy (P = 0.002; hazard ratio, 0.339; 95% confidence interval, 0.172-0.672) as well as lymph node metastasis (P = 0.044; hazard ratio, 2.053; 95% confidence interval, 1.020-4.133). CONCLUSION: Expression of EMMPRIN was associated with a decrease in the reduction of cervical tumor following brachytherapy, and increased EMMPRIN expression after brachytherapy seemed to be an important predictor of poor survival in this patient cohort. Our study suggests that expression of EMMPRIN confers resistance to radiotherapy. Therefore, EMMPRIN expression in cervical cancer may be regarded both as a prognostic factor and a therapeutic target.

Weekly induction intraperitoneal chemotherapy after primary surgical cytoreduction in patients with advanced epithelial ovarian cancer.

BACKGROUND: Traditional intraperitoneal (IP) therapy administered simultaneously with intravenous (IV) chemotherapy in the primary setting has been well documented. This retrospective study was conducted to investigate the role of weekly IP therapy as an inducing intervention before front-line IV chemotherapy, particularly in patients with bulky residual disease after surgery. METHODS: A total of 426 patients with advanced ovarian cancer treated between 1990 and 1999, were reviewed. Follow-up data were available in 409 patients. Of whom, 230 patients received postoperative weekly IP therapy with a median cycles of 4, other 179 patients who did not receive any IP therapy were used as the control group. RESULTS: The median age of the patients was 51 years (range, 20-77 years). One hundred eighty-nine patients with stage III disease and 41 patients with stage IV disease were treated with postoperative IP therapy, respectively. Complications and toxicity were observed in 68 patients (29.5%), but there were no grade 4 toxicities and no patients died of complications or toxicities. In patients with residual disease > 1 cm, the median survival of those with IP delivery of chemotherapy and those without was 21.6 months and 18.8 months, respectively (hazard ratio [HR]= 0.69, P = 0.02). Whereas, in patients with residual disease

[A multicenter randomized clinical trial of weekly paclitaxel and carboplatin vs three weeks paclitaxel and carboplatin as first line chemotherapy in epithelial ovarian cancer].

OBJECTIVE: To compare the efficacy of combination regiments of taxol given weekly plus carboplatin and taxol given every three weeks plus carboplatin. To observe the toxicity of the two regiments. To observe the two-year survival rate in the two groups. METHODS: Total 125 eligible patients in 13 centers of CGOG were entered into the two arms of this randomized clinical trial, of whom 51 were entered into weekly taxol group and 74 entered into 3 weeks taxol group. RESULTS: 81.6% (102/125) of patients had satisfactory decreasing of CA125 level after optimal cytoreductive surgery and chemotherapy. 86.3% (44/51) of patients is in weekly group and 78.4% (58/74) of patients in three weeks group (P > 0.05). Relapse frequency is 29.7% in every three weeks group and 19.6% in weekly group (P > 0.05). Median interval to relapse is 15.7 months in every three weeks group and 13.6 months in weekly group (P > 0.05). One-year survival rate is 95.2% in every three weeks and 93.9% in weekly group (P > 0.05). Two-year survival rate is 78.7% in every three weeks and 85.3% in weekly group (P > 0.05). Grade III and IV myelosuooression is 45.9% in three weeks group and, 27.5% in weekly group (P < 0.05). CONCLUSION: (1) The two regiments had equal efficacy. (2) Myelosuppression was less frequency in the weekly group than in every three weeks group. (3) Weekly taxol therapy has mild toxicity and is more suitable for the old and feeble patients. Weekly taxol therapy can be conveniently administered in outpatients department.

[Multidisciplinary therapy after radical surgery in stage I b1-II b cervical cancer patients with positive lymph nodes].

OBJECTIVE: To study the modality of multidisciplinary therapy and prognosis of cervical cancer patients with positive lymph nodes after radical surgery. METHODS: From January 1990 to June 2003, 215 patients with clinical stage I b1-II b node-positive cervical carcinoma who underwent radical hysterectomy and pelvic lymphadenectomy and were histologically confirmed to have lymph node involvement were analyzed. These patients were divided into four groups as chemoradiotherapy group (107 cases), radiotherapy group (45 cases), chemotherapy group (22 cases) and no adjuvant therapy group (41 cases). The prognosis and potential prognostic variables of the four groups were studied by survival analysis. RESULTS: The 3-year disease-free survival (DFS) rate of the chemoradiotherapy group, chemotherapy group, radiotherapy group and no adjuvant therapy group were 60.7%, 53.5%, 47.4% and 36.0% respectively. The 3-year DFS rate of the chemoradiotherapy group was significantly higher than that of the no adjuvant therapy group (P = 0.001). However, the 3-year DFS rate of the chemotherapy group, radiotherapy group were not significantly higher than that of the no adjuvant therapy group (P = 0.060 and 0.159). Among the four groups, the pelvic recurrent rate of the chemoradiotherapy group (7.5%) was much lower than those of the other three groups (22.7%, 26.7%, 34.1%, respectively; P < 0.01). However, the distant metastases rate did not decrease significantly (16.8%, 18.2%, 15.6%, 22.0%, respectively; P > 0.05), neither did the distant metastasis with pelvic recurrent rate (P > 0.05). COX proportional hazard model analysis showed that tumor size, histological type, the number of positive lymph node and postoperative adjuvant therapy were independent survival predictors of the patients with positive lymph node (P < 0.05). CONCLUSION: Chemoradiotherapy after radical surgery significantly improves the 3-year DFS, and decreases the pelvic recurrence in the cervical cancer patients with positive lymph node.

[Transposed ovarian function conservation in cervical cancer patients with radiotherapy].

OBJECTIVE: To evaluate the transposed ovarian function and complications in cervical cancer patients with postoperative pelvic radiotherapy. METHODS: Sixty-two women with stage I-IIa cervical cancer were treated with radical hysterectomy and pelvic lymphadenectomy and transposition of both ovaries to paracolic gutters from 1997 to 2003 at the Cancer Hospital of Fudan University. Menopausal symptoms, levels of follicle-stimulating hormone (FSH) and E2 were evaluated to assess ovarian function. RESULTS: Of 31 patients with stage IIa or poorly differentiated tumor or tumor > or = 2 cm in diameter, preoperative vaginal radiation was employed to deliver a dose of 15 Gy at point A. Postoperative pelvic radiation was performed in 15 patients. Totally 20% (6/30) of patients undergoing ovaries transposition without any radiation experienced ovarian failure within a mean of 15.7 months. In 35% (6/17) of patients with preoperative vaginal radiation, ovarian failure occurred within a mean of 12.0 months. When patients receiving postoperative pelvic radiation and ovaries transposition were considered together, 64% (9/14) experienced ovarian failure within a mean of 9.2 months (P < 0.05). Only 2 (3%) patients had cysts in transposed ovaries not requiring further surgery. There was no metastasis of the ovaries. CONCLUSIONS: Lateral ovarian transposition is safe to patients with early stage cervical cancer. Both pre- and post-operative radiation significantly damages the ovarian function. Even ovaries transposition procedure also reduces the effectiveness.

[Multidisciplinary treatment of recurrent epithelial ovarian carcinoma and prognostic analysis].

OBJECTIVE: To investigate individualized and multi-phase management of recurrent epithelial ovarian carcinoma in order to improve survival of the patients. METHODS: From 1998 to 2002, 70 patients with recurrent epithelial ovarian carcinoma were enrolled in the present study. The treatments were divided into: (1) Induction of tumor remission: platinum sensitive patients were treated with paclitaxol + cisplatin (TP) or carboplatin + cyclophosphamide (CP) regimen; platinum resistant patients used Taxol + mitomycin (TM) or etoposide + mitomycin (VM) regimen. Resection of tumors was done in an attempt to reduce the residual tumor with a diameter less than 1 cm. Local radiotherapy was performed for those with residual tumor and who achieved clinical response after chemotherapy or surgery. (2) Consolidation therapy: chemotherapy with lower doses was administrated after disease remission. Interferon was used as immunotherapy during chemotherapy and radiotherapy. Survival analysis was done. RESULTS: (1) The 1, 2, 3, 4, 5-year survival rates were 67%, 51%, 45%, 38%, 32%. Median survival was 38.57 months. (3) The 1, 2, 3-year progression-free survival rates of the research arm were 41%, 37%, 24%. Median progression-free survival was 12.00 months. (4) Multivariate analysis revealed that platinum-free interval (P < 0.05), Karnofsky performance scale (P < 0.01), residual disease (P < 0.01) and courses of second-line chemotherapy (P < 0.05) were independent prognostic factors. Residual disease (P < 0.05) and courses of second-line chemotherapy (P < 0.01) contributed to progression-free survival. CONCLUSIONS: Individualized and multi-phase treatment of recurrent epithelial ovarian carcinoma is efficacious. Optimal second cytoreduction and second-line chemotherapy are beneficial to improve the survival.

[Benefit of palliative surgery for bowel obstruction in recurrent ovarian carcinoma].

OBJECTIVE: Intestinal obstruction is a frequent sequela of recurrent ovarian cancer and difficult to deal with. We analyzed a series of such patients to determine if their outcomes have changed after undergoing palliative surgery. METHOD: We retrospectively reviewed 67 patients undergoing surgery for intestinal obstruction due to recurrent ovarian carcinoma and 75 patients receiving non-surgical treatment from 1997 to 2002. RESULTS: During the study period, 67 operations were performed on 67 patients. Among them, surgical procedure was completed in 58 cases. Successful palliation was achieved in 64.2% of cases in which surgical correction was possible. The median survival of the entire cohort was 7.8 months, and 12.6 months for the surgically successfully relieved patients and 3.7 months for those non-surgical patients. The rate of major surgical morbidities was 22.4%. The perioperative mortality rate was 6.0%. Successful palliation was associated with the absence of two prognostic factors: multiple obstructive sites and palpable abdominal and pelvic masses. CONCLUSION: Palliative surgery for bowel obstruction in recurrent ovarian cancer can be worthwhile, and properly selected patients are the key to its success.