Abstract Background Aberrant transforming growth factor (TGF)-β signaling is involved in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate the predictive value of the ...upstream ligand of TGF-β signaling (TGF-β1) on long-term mortality and the clinical characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) and heritable PAH (HPAH). Methods and Results Plasma TGF-β1 levels were measured in 151 IPAH and 65 HPAH patients retrospectively enrolled between January 2008 and March 2013, and compared to 61 healthy subjects. Data for mortality over time were obtained from hospital databases and from telephone follow-ups. The main outcome was all-cause death. Plasma TGF-β1 was significantly higher in IPAH/HPAH patients compared to control subjects (4.74 vs. 2.61 ng/mL, respectively; P < 0.001). Mean follow-up time was 3.4 ± 1.8 years, during which 86 patients died. ROC curves were utilized to determine TGF-β1 cutoff values. Compared to patients with TGF-β1 of < 3.74 ng/mL, heart function was significantly impaired (percentage of patients with WHO functional class III/IV, 51.4% vs. 65.5%, P = 0.043) and mortality risk was elevated ( P = 0.009) for patients with TGF-β1 > 3.74 ng/mL. However, the difference in mortality rate between patients with higher and lower TGF-β1 levels was only statistically significant for female patients ( P = 0.004), despite a similar trend for male patients. Multivariate analyses revealed TGF-β1 (HR after log transformation base of 10: 2.623; 95%CI: 1.228–5.603; P = 0.013) emerged as the independent predictor for all-cause mortality. Conclusion High circulating levels of TGF-β1 were an independent predictor of a poor outcome for IPAH/HPAH patients.
Abstract Carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1) is a cell-cell adhesion receptor and is implicated in several cellular functions. It is rarely reported in ovarian tumors. ...The aim of this study is to determine the expression of CEACAM1 in ovarian tumors, trying to see whether CEACAM1 has different expression patterns as a function of histotype. Antigen expression was examined by immunohistochemistry with mouse anti-human antibody for CEACAM1. Immunohistochemistry was performed using avidin-biotin-diaminobenzide staining. The results were expressed as average score ± SD (0, negative; 8, highest) for each histotype. In ovarian tumors, the benign serous and mucinous cystadenoma negatively or weakly expressed CEACAM1, the malignant epithelial tumors strongly expressed CEACAM1, and there was significant difference between benign epithelial tumor and adenocarcinoma ( P < .05). The well-differentiated serous adenocarcinoma expressed CEACAM1 mainly with membrane pattern, and the intermediately and poorly differentiated serous adenocarcinomas expressed CEACAM1 mainly with cytoplasmic pattern ( P < .05). In addition, CEACAM1 expression is elevated in solid tumors of ovary but variable as a function of histotype. Compared with membranous expression, the cytoplasmic expression was observed almost in metastatic carcinoma that might decrease the adhesive interactions of the carcinoma cells with the surrounding cells, especially with tumor cells, and this could facilitate the tumor cells to metastasize to distant regions. So, we thought that cytoplasmic CEACAM1 might play an important role in tumor progression, especially in tumor metastasis.
Purpose Piezosurgery has been used widely in oral and maxillofacial surgery, but there has been no report systematically describing an osteotomy method with piezosurgery for complicated mandibular ...third molar removal. The aim of this study was to introduce 4 osteotomy methods using piezosurgery and evaluate their effects. Materials and Methods A retrospective study was conducted of patients with a complicated impacted mandibular third molar requiring extraction. The predictor variable was the extraction technique. Four osteotomy methods using piezosurgery were tested according to different impaction types: method 1 involved complete bone removal; method 2 involved segmental bone removal; method 3 involved bone removal combined with tooth splitting; and method 4 involved block bone removal. Outcome variables were success rate, operative time, major complications (including nerve injury, mandible fracture, severe hematoma, or severe edema), and serious pyogenic infection. Data were analyzed using descriptive statistics. Results The study was composed of 55 patients with 74 complicated impacted mandibular third molars. All impacted mandibular third molars were removed successfully. The average surgical time was 15 minutes (range, 8 to 26 minutes). Thirty-eight molars (51.4%) were extracted by method 1, 18 molars (24.3%) by method 2, 12 molars (16.2%) by method 3, and 6 molars (8.1%) by method 4. Two cases (2.7%) developed postoperative infections and recovered within 1 week using drainage and antibiotic administration. Conclusion The 4 osteotomy methods with piezosurgery provide effective ways of removing complicated impacted mandibular third molars.
Abstract Background Relapsed or refractory Hodgkin's lymphoma is a challenge for medical oncologists because of poor overall survival. We aimed to assess the feasibility, safety, and efficacy of ...CD30-targeting CAR T cells in patients with progressive relapsed or refractory Hodgkin's lymphoma, in which CD30 expression is mostly positive. Methods This open-label, phase 1 study took place at the Chinese PLA General Hospital. Eligible patients (aged 16–80 years) had relapsed or refractory Hodgkin's lymphoma. All patients received a conditioning chemotherapy regimen at the discretion of physician, followed by the infusion of CD30-directed CAR T cells. Using escalating doses to avoid severe toxicity associated with infusion, patients received a starting dose of 3·2 × 105 CAR T cells per kg and then infused by 5-fold increments continuously for 3–5 days. After the dose-escalation infusion, no patients experienced greater than grade 3 toxicity events. We periodically monitored the expression level of CAR transgenes in peripheral blood and biopsied tumour tissues according to assigned protocol by quantitative PCR. Two-way analysis of variance (ANOVA) was used to determine the significance of the differences between means in all experiments. This trial was approved by the Institutional Review Board at the Chinese PLA General Hospital and is registered with ClinicalTrials.gov , number NCT02259556 . All patients gave written informed consent before enrolment. Findings Between Dec 1, 2014, and Mar 1, 2015, 11 patients were enrolled. All of whom had a heavy pretreatment history (15 previous treatments, range 6–24) or multiple tumour lesions (3·3 lymph node regions involved, range 0-7; involvement of one or more extralymphatic organs), or both. The patients received a mean of 1·5×107 CAR-positive T cell per kg (SD 0·25, range 1·2–2·1) in total during infusion. Nine (82%) patients responded to the treatment: one (9%) patient maintained continuous complete remission, five (46%) patients achieved partial response, and three (27%) patients achieved stable disease. All patients experienced tolerable infusion-related febrile syndrome. One (9%) patient had 5 days of self-limiting arthralgia, myalgia, and dual knee swelling 2 weeks after cell infusion. The copy number of CAR transgene in peripheral blood peaked 3–17 days after infusion, which was accompanied by a two-times higher increase in the number of lymphocytes. Analysis of biopsied tissues revealed a highly efficient trafficking of CAR T cells into the targeted sites. Interpretation CD30-directed CAR T-cell therapy was safe, feasible, and efficient in patients with relapsed or refractory Hodgkin's lymphoma and guaranteed a large-scale patients recruitment. Funding Science and Technology Planning Project of Beijing City (No. Z151100003915076) and National Natural Science Foundation of China (Nos. 31270820, 81230061, 81121004, and 81402566).
Summary Background Utidelone, a genetically engineered epothilone analogue, has shown promise as a potential treatment for breast cancer in phase 1 and 2 trials. The aim of this phase 3 trial was to ...compare the efficacy and safety of utidelone plus capecitabine versus capecitabine alone in patients with metastatic breast cancer. Methods We did a multicentre, open-label, superiority, phase 3, randomised controlled trial in 26 hospitals in China. Eligible participants were female patients with metastatic breast cancer refractory to anthracycline and taxane chemotherapy regimens. We randomly assigned participants (2:1) using computer based randomisation and block sizes of 6 to a 21-day cycle of either utidelone (30 mg/m2 intravenously once per day on days 1–5) plus capecitabine (1000 mg/m2 orally twice per day on days 1–14), or capecitabine alone (1250 mg/m2 orally twice per day on days 1–14), until disease progression or unacceptable toxicity occurred. Patients, physicians, and assessors were not masked to treatment allocation; however, an independent radiology review committee used to additionally assess response was masked to allocation. The primary endpoint was centrally assessed (by an independent radiology review committee) progression-free survival, and analysed using the Kaplan-Meier product-limit method in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Follow-up is ongoing. This study is registered at ClinicalTrials.gov , number NCT02253459. Findings Between Aug 8, 2014, and Dec 14, 2015, we enrolled and randomly assigned 270 patients to treatment with utidelone plus capecitabine, and 135 to capecitabine alone. Median follow-up for progression-free survival was 6·77 months (IQR 3·81–10·32) for the utidelone plus capecitabine group and 4·55 months (2·55–9·39) for the capecitabine alone group. Median progression-free survival by central review in the utidelone plus capecitabine group was 8·44 months (95% CI 7·95–9·92) compared with 4·27 months (3·22–5·68) in the capecitabine alone group; hazard ratio 0·46, 95% CI 0·36–0·59; p<0·0001. Peripheral neuropathy was the most common grade 3 adverse event in the utidelone plus capecitabine group (58 22% of 267 patients vs 1 <1% of 130 patients in the capecitabine alone group). Palmar-plantar erythrodysaesthesia was the most prominent grade 3 adverse event in the capacitabine alone group (in 10 8% of 130 patients) and was the next most frequent grade 3 event in the utidelone plus capecitabine group (in 18 7% of 267 patients). 16 serious adverse events were reported in the combination therapy group (diarrhoea was the most common, in three 1% patients) and 14 serious adverse events were reported in the monotherapy group (the most common were diarrhoea, increased blood bilirubin, and anaemia, in two 2% patients for each event). 155 patients died (99 in the combination therapy arm, 56 in the monotherapy arm). All deaths were related to disease progression except for one in each group (attributed to pericardial effusion in the combination therapy group and dyspnoea in the monotherapy group) that were considered possibly or probably treatment-related. Interpretation Despite disease progression with previous chemotherapies, utidelone plus capecitabine was more efficacious compared with capecitabine alone for the outcome of progression-free survival, with mild toxicity except for peripheral sensory neuropathy, which was manageable. The findings from this study support the use of utidelone plus capecitabine as an effective option for patients with metastatic breast cancer. Funding Beijing Biostar Technologies, Beijing, China.
Abstract Objectives To investigate the effects of bed width on the quality of chest compressions during simulated in-hospital resuscitation. Methods Each candidate performed two 2-minute cycles of ...compression-only cardiopulmonary resuscitation on an adult manikin placed on either an emergency stretcher (narrow bed) or a standard hospital bed (wide bed) in random order at 1 day intervals. We conducted subjective assessments of cardiopulmonary resuscitation quality and rescuer fatigue at the end of each session, using surveys. Results There were no significant differences between narrow and wide bed sessions in either mean depth or the percentage of compressions with adequate depth ( P = .56 and .58, respectively). The mean rate of compressions and the percentage of compressions with adequate rate were also similar between sessions ( P = .24 and .27, respectively). However, the percentage of correct hand position and complete chest recoil was significantly higher in the narrow bed session than in the wide bed session ( P = .02 and .02, respectively). In addition, survey results showed that rescuers felt more comfortable and less exhausted in the narrow bed session compared with the wide bed session ( P < .001 and < .001). Conclusions When rescuers performed chest compressions on an emergency stretcher, chest compression quality increased, and the fatigue of rescuers decreased compared with a standard hospital bed. Therefore, we propose a narrow bed for critically ill inpatients with high risk of cardiac arrest.
Abstract Purpose Increasing evidence has demonstrated that Bcl2-inhibitor of transcription (Bit1) involves a variety of biological processes in the process of tumor development and progression. We ...hypothesize that Bit 1 is overexpressed in oral squamous cell carcinoma (OSCC); therefore, we examined Bit 1 gene expression and protein production, as well as explored the effect of elevated Bit 1 on OSCC cells. Methods We investigated the use of quantitative real-time RT-PCR and immunohistochemistry for Bit1 mRNA and protein levels.75 OSCC specimens, 25 tumor-adjacent dysplasia specimens, and 25 normal oral tissue samples that matched OSCC specimens were used in this study. We also transfected Bit1 cDNA into human oral cancer cells (Tca8113) to further investigate the potential role of Bit1 in OSCC. Results We found that Bit1 levels in OSCC tissues were significantly higher than those in tumor-adjacent dysplasia specimens and normal oral tissue (P < 0.05). We also confirmed that Bit1 overexpression in the cytosol of Tca8113 cells induced apoptosis. Conclusion Our findings suggest Bit1 overexpression may contribute to oral cancer cell survival and dissemination. In the future, Bit 1 may be an important diagnostic and therapeutic target.
This study was to investigate the incidences of DVT in lower extremities after pelvic fracture before and after operation, and explore the risk factors. The records of patients with pelvic fractures ...receiving operation were collected. The patients were examined by preoperative and postoperative ultrasonography, and divided into thrombosis group and non-thrombosis group according to the preoperative and postoperative ultrasonographic results. Totally, 128 patients with pelvic fractures were included in this study. The incidence of DVT was 21.09% preoperatively, and increased to 35.16% postoperatively. Peripheral DVT constituted 92.60% and 86.67% of preoperative and postoperative DVTs, respectively. The results showed that age (odds ratio OR = 1.07; 95% CI: 1.01-1.12; P = 0.013), fracture classification (OR = 3.80; 95% CI: 1.31-11.00; P = 0.014) and D-dimer at admission (OR = 1.04; 95% CI: 1.00-1.08; P = 0.029) were independent risk factors of preoperative DVT, and female (OR = 0.21; 95% CI: 0.06-0.81; P = 0.023) was independent protective factor. In addition, age (OR, 1.06; 95% CI, 1.00-1.11; P = 0.026), operative blood transfusion (OR, 1.34; 95% CI, 1.05-1.72; P = 0.020) were independent risk factors of postoperative DVT. In conclusion, the DVT prevention strategy has not changed the high incidence of DVT in pelvic fractures, and orthopedic surgeons should pay more attention to perioperative DVT. When a male or patient with Tile-C type pelvic fracture is at admission, it is should be reminded that the screening the DVT in lower extremities. In addition, the surgeon should stanch bleeding completely, to reduce the blood transfusion and formation of DVT.
Bosentan has an established role in the management of pulmonary arterial hypertension (PAH). This clinical trial assessed the benefits of bosentan in the Chinese population.
We investigated the ...efficacy and safety of bosentan in 92 Chinese citizens (mean +/- standard deviation age, 29.0 +/- 3.8 years) with PAH for a minimum of 12 weeks. All received bosentan (62.5 mg twice daily) for 4 weeks; then, patients who weighed <40 kg received 62.5 mg bosentan twice daily and patients who weighed >40 kg received 125 mg twice daily. All patients were eligible to continue bosentan beyond 12 weeks. The primary end point was a change in exercise capacity from baseline to 12 and 24 weeks. Secondary end points included a change in World Health Organization (WHO) functional class and changes in cardiopulmonary hemodynamics.
At baseline, 66 patients (72%) were in WHO functional class III; presentation was 37 (40%) with idiopathic PAH (iPAH), 34 (37%) with PAH related to congenital heart disease (CHD), and 21 (23%) with PAH related to connective tissue disease (CTD). Exercise capacity increased to 67.8 m after 12 weeks and 92.6 m after 24 weeks (p < 0.001). After 24 weeks, WHO functional class decreased (-0.8 +/- 0.6; p < 0.001), mean pulmonary artery pressure and pulmonary vascular resistance decreased (p < 0.01), and cardiac output increased (p < 0.001). Twelve patients (13%) experienced at least 1 adverse event.
Bosentan improved exercise capacity, functional class, and cardiopulmonary hemodynamics in this patient cohort and was well tolerated.
Our purpose was to investigate the prognostic role of plasma Epstein-Barr virus (EBV) DNA levels in the middle of intensity modulated radiation therapy (IMRT).
In total, 1881 patients with stage ...III-IVa tumors were included. The overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method, and the differences were compared using the log-rank test. Receiver operating characteristic curve analysis was performed to analyze the diagnostic value of EBV DNA levels for tumor progression or death. Multivariate analyses using the Cox model were used to evaluate potential prognostic factors.
The positive predict value and negative predict value of plasma EBV DNA > 0 copies/mL in the middle of IMRT in predicting nasopharyngeal carcinoma progression was 37.4% and 85.5%, respectively. In patients with plasma EBV DNA level = 0 copies/mL, no significant differences in OS were observed between patients treated with 200 mg/m² cisplatin and those treated with >200 mg/m² cisplatin (5-year OS, 94.9% vs 94.4%; PFS, 81.5% vs 87.6%). However, those treated with >200 mg/m² cisplatin had higher PFS. In patients with plasma EBV DNA level > 0 copies/mL, patients treated with >200 mg/m² cisplatin displayed a favorable 5-year OS (84.6% vs 73.9%) and PFS (72.3% vs 54.8%) compared with those treated with 200 mg/m² cisplatin. Additionally, higher incidences of grade 3 and 4 adverse events were recorded in patients treated with >200 mg/m² cisplatin than in those treated with 200 mg/m² cisplatin.
Plasma EBV DNA > 0 copies/mL in the middle of IMRT suggests that higher doses of chemotherapy should be used. For concurrent chemoradiation therapy, >200 mg/m² cisplatin is recommended for patients with plasma EBV DNA level > 0 copies/mL in the middle of IMRT but not for patients with plasma EBV DNA level = 0 copies/mL considering the similar OS rates.
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