Safety of oral nemonoxacin: A systematic review of clinical trials and postmarketing surveillance.

Background: Postmarketing safety analysis is an effective supplement for new drugs in clinical practice. Therefore, we aimed to systematically assess the safety of oral nemonoxacin malate, the first approved C-8-methoxy non-fluorinated quinolone, in clinical studies and via postmarketing safety surveillance. Methods: We electronically and manually searched and screened safety data (including premarketing and postmarketing data) of oral nemonoxacin from clinical registries. We standardized and summarized the reported adverse events according to the Medical Dictionary for Regulatory Activities System Organ Class and Preferred Terms. We summarized and reported the number and frequency (%) of the AEs and serious AEs in patients with community-acquired pneumonia and in specific patients. Results: Three Phase II/III comparator studies (n = 670, nemonoxacin), one Phase IV study (n = 461), two special population pharmacokinetic studies (n = 40), four observational studies (n = 1,852), and one 5-year postmarketing surveillance project (n = 257,420) were included in this study. The Phase II/III studies showed that the commonly reported drug-related AEs were similar for oral 500 mg nemonoxacin and levofloxacin treatments, which mainly included increased alanine aminotransferase levels (4.4% vs. 2.5%), neutropenia (2.5% vs. 4.4%), nausea (2.5% vs. 1.6%), and leukopenia (2.3% vs. 3.2%). No drug-related deaths were reported. Postmarketing safety surveillance revealed that known adverse drug reaction characteristics were generally unchanged. Pharmacokinetic data suggested that dose adjustment was not necessary in elderly patients, which was confirmed by a Phase IV study in an elderly population, in patients with renal impairment with CLcr ≥50 ml/min, and in those with mild-to-moderate hepatic impairment. Conclusion: Clinical trial data of approximately 1,450 patients and postmarketing data of >257,420 patients suggest that nemonoxacin is generally well tolerated and can be a suitable alternative to fluoroquinolones for patients with CAP.

An Ovarian Large-Cell Neuroendocrine Carcinoma Accompanied by Clear Cell Carcinoma with Specific High Level of AFP: Case Report and Review of the Literature.

Large cell neuroendocrine carcinoma (LCNEC) is a rare histological subtype of ovarian cancer. A few cases have been reported in the literature with extreme invasiveness and a poor prognosis. However, there still have not been accepted criteria for diagnosis and treatment of LCNEC. Here we report an unmarried 37 year-old woman who was diagnosed with LCNEC associated with clear cell carcinoma and the tumor index was manifested with a specific increase of AFP. The case received six courses of etoposide and carboplatin chemotherapy as an adjuvant therapy after primary curative surgery. However, she relapsed within 6 months after surgery and metastasized rapidly to distant organs despite combined chemotherapy of paclitaxel, cisplatin, and bevacizumab, and died 18 months after primary surgery. This is the first reported case of LCNEC manifested with a specific increase of AFP and characteristically metastasized to the spine as recurrence. Reviewing our case as well as previously reported cases, LCNEC present with aggressive malignancy and vulnerable to distant metastasis through a hematogenous approach, we conjectured that adding Bevacizumab in primary chemotherapy may be beneficial to extend disease-free survival. But so far there is no recommendation of this regimen for treatment of LCNEC in current guidelines. Further research is needed to confirm this view so as to find the best treatment of LCNEC and improve the prognosis of these patients.

Survival of Patients With Cervical Cancer Treated With Definitive Radiotherapy or Concurrent Chemoradiotherapy According to Histological Subtype: A Systematic Review and Meta-Analysis.

Background: Cervical cancer is a leading cause of morbidity and mortality for women worldwide. Different histopathological cervical cancer subtypes (i.e., adenocarcinoma/adenosquamous carcinoma, and squamous cell carcinoma) are all treated similarly with definitive radiotherapy or concurrent chemoradiotherapy, but studies have reported differing survival prognoses. In this review and meta-analysis, we compared the disease-free and overall survivals of patients with cervical cancer treated with definitive radiotherapy or concurrent chemoradiotherapy according to the histopathological subtypes. Objective: To compare the disease-free and overall survivals of patients with adenocarcinoma/adenosquamous carcinoma and squamous cell carcinoma cervical cancer treated with definitive radiotherapy or concurrent chemoradiotherapy. Methods: We systematically searched the Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE academic databases following PRISMA guidelines. We identified publications to conduct a random-effects meta-analysis to evaluate the disease-free and overall survivals of patients with cervical adenocarcinoma/adenosquamous carcinoma and squamous cell carcinoma treated with definitive radiotherapy or concurrent chemoradiotherapy. Results: From 963 studies, we found eight eligible ones with 13,859 patients with cervical cancer (mean age, 52.2 ± 7.9 years). Our meta-analysis revealed a poorer outcome of disease-free (hazard ratio, 1.51; 95% CI, 1.28-1.79) and overall (hazard ratio 1.41; 95% CI, 1.26-1.57) survivals for patients with adenocarcinoma/adenosquamous carcinoma undergoing definitive radiotherapy or concurrent chemoradiotherapy than for those with squamous cell carcinoma undergoing similar treatments. We also observed that larger tumor size and advanced tumor stage are also significant prognostic factors that adversely impact survival outcomes in cervical cancer patients undergoing definitive radiotherapy or concurrent chemoradiotherapy. Conclusion: Our results show poor disease-free and overall survivals for patients with cervical cancer and adenocarcinoma/adenosquamous carcinoma than for those with squamous cell carcinoma after treatment with definitive radiotherapy or concurrent chemoradiotherapy. Our findings clarify the risks associated with the conventional management of cervical cancer according to the histological type.

Pharmacokinetics, safety and bioequivalence of two formulations of progesterone soft capsule in healthy Chinese postmenopausal females: Impacts of a high-fat meal.

Progesterone is an important natural hormone regulating ovulation and menstruation. The present study aimed to investigate the pharmacokinetics and safety of two formulations of progesterone in Chinese postmenopausal females under fasting and fed conditions. The study adopted a single-dose, open-label, randomized, three-period bioequivalence design. A total of 96 subjects were enrolled and randomly assigned to the fasting cohort or fed cohort. A high-fat meal (890 kcal) was used in the fed study. The reference-scaled average bioequivalence method was used for bioequivalence evaluation. A high-fat meal led to a 22-fold higher peak concentration (Cmax ) and a 7-fold higher area under the curve (AUC) while time to reach Cmax and half-life was not significantly affected. The concentration-time curve displayed double peaks suggesting the existence of enterohepatic circulation. The test/reference geometric mean ratios for Cmax and AUC under fasting and fed conditions are all within the range of 80% to 125%. All adverse events (AEs) that occurred during the trial were mild and did not cause drop-out, though these AEs occurred more frequently under fed state. In conclusion, the two formulations of progesterone are bioequivalent in Chinese subjects under fasting and fed conditions. Drug label modification regarding food effects needs further discussion.

A mature cystic teratoma adherent to the vaginal wall: a case report.

We present the case of a woman diagnosed with a teratoma adherent to the vaginal wall. The patient had been misdiagnosed with an ovarian teratoma 8 years previously at her local hospital, but no mass was found in the pelvic cavity during cesarean section. She therefore attended our institution for further examination. Transvaginal ultrasonography, magnetic resonance imaging (MRI), and computed tomography (CT) revealed a large mass on the left side at the bottom of the pelvis, near the side of the vagina, mainly composed of greasy and cystic elements. Gynecological examination showed the mass protruding into the left side of the vaginal wall. The patient therefore underwent vaginal wall incision. During surgery, we found a mass adherent to the vaginal wall, located on the left front of the rectum. Surgery was completed successful with no complications. This case highlights the need for careful preoperative evaluation of teratomas with unusual locations. MRI and CT may be useful for identifying the origin of the tumor and determining its relationship with the surrounding tissues. Surgery should be based on the characteristics and anatomical location of the tumor to minimize damage to other tissues and organs.

Nuclear localization of annexin A1 correlates with advanced disease and peritoneal dissemination in patients with gastric carcinoma.

Annexin A1 (ANXA1) is a multifunctional molecule, which mediates various important physiologic processes depending on its subcelluar localization. The purpose of this study was to investigate the expression of ANXA1 level and its subcellular localization in paired clinical samples of gastric adenocarcinoma and adjacent normal counterpart. The study also assesses the clinical significance of ANXA1 subcelluar localization in gastric adenocarcinoma. A total of 104 paired resected gastric adenocarcinoma and corresponding normal specimens were collected in this study. Expression of ANXA1 was examined by immunohistochemical staining. Both cytoplasmic and nuclear ANXA1 expression levels and their correlation with clinicopathological parameters were assessed. ANXA1 protein expression was positive in 72 of 104 (69.2%) normal tissues and 47 of 104 (45.2%) gastric adenocarcinoma tissues. ANXA1 staining was predominantly localized in the cytoplasm in all 72 ANXA1-positive normal specimens, whereas 12 ANXA1-positive gastric adenocarcinoma specimens showed positive nuclear staining. The positive nuclear staining correlated well with serosal invasion, peritoneal dissemination and TNM stage. Cases with positive nuclear staining presented more peritoneal dissemination (41.7%, 5/12) than those with negative nuclear staining (8.7%, 8/92; P = 0.007). A logistic regression model revealed that positive ANXA1 nuclear staining had an independent association with peritoneal dissemination (P = 0.039; hazards ratio, 9.499; 95% confidence interval, 1.159-77.815). These results indicated that ANXA1 is expressed in both gastric adenocarcinoma and normal tissues. In gastric adenocarcinoma tissues ANXA1 is expressed both in cytoplasm and nucleus and its nuclear localization correlates with advanced disease stage and peritoneal dissemination.

Involvement of annexin A1 in multidrug resistance of K562/ADR cells identified by the proteomic study.

Multidrug resistance (MDR) to chemotherapy is a significant barrier to the effective treatment of chromic myeloid leukemia (CML). In an attempt to identify more factors associated with MDR for an understanding of the mechanism, we first established an adriamycin (ADR)-resistant human erythroleukemia cell line K562/ADR by stepwise selection in vitro using ADR. Besides the elevated resistance to ADR, the K562/ADR cells also showed significantly increased crossed-resistance to vincristin and Gleevec, compared to the parental K562 cells. Then we compared the global protein profiles between K562 and K562/ADR cells. Following two-dimensional gel electrophoresis and image analysis, some of the proteins with different levels between the two cell lines were identified by MALDI TOF/TOF mass spectrometry and Western blot analysis. The differentially expressed proteins were classified into groups based on their functions: calcium-binding proteins, chaperones, metabolic enzymes, proteins related to protein synthesis or DNA synthesis, and proteins related to signal transduction. In particular, ANXA1, a protein that was downregulated in K562/ADR, was analyzed further for its involvement in MDR by transfection and subsequent assays. The functional validation showed that the downregulated ANXA1 expression contributes considerably to the observed drug resistance in K562/ADR cells. These data will be valuable for further study of the mechanisms of MDR and may reveal a potential new diagnostic marker to chemotherapy.

[Expression of (His)(6)-eIF3s4 fusion protein in human breast cancer cell Bcap37].

AIM: To construct eukaryotic expression vector of eukaryotic translation initiation factor 3 subunit 4(eIF3s4) for further functional study. METHODS: The cDNA of eIF3s4 containing full length coding region was amplified by RT-PCR and cloned into pGEM-T Easy. The sequence of the cDNA was verified by DNA sequencing and blast against sequence data in GenBank database. The cDNA was then subcloned into the pcDNA4/HisMaxB to make a (His)(6)-eIF3s4 fusion protein expression vector. The vector was transfected into human breast cancer cell Bcap37 by Lipofectamine 2000, and the expression of (His)(6)-eIF3s4 fusion protein was detected by Western blot. RESULTS: DNA sequencing and sequence blast showed that the cDNA amplified by RT-PCR was consistent with the eIF3s4 sequence in GenBank database, and Western blot results showed the expression of the (His)(6)-eIF3s4 fusion protein in human breast cancer cell Bcap37 as expected. CONCLUSION: The (His)(6)-eIF3s4 fusion protein expression vector is constructed successfully with expression of the fusion protein in Bcap37 breast cancer cells. This work provides the basis for establishing a stable eIF3s4 expressing cell line for further study on the role of eIF3s4 in cancer multidrug resistance.