Biological Pathways Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy: A Preliminary Study

Radical hemithoracic radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of biological pathways, retrieved through whole exome sequencing (WES), possibly associated to the development of lung adverse effects in MPM patients treated with RHR. The study included individuals with MPM, treated with lung-sparing surgery and chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the strong impact of grade 3 pulmonary toxicities on the quality of life, compared with less serious adverse events, for genetic analyses, patients were divided into a none or tolerable pulmonary toxicity (NoSTox) group (grade ≤2) and a severe pulmonary toxicity (STox) group (grade = 3). Variant enrichment analysis allowed us to identify different pathway signatures characterizing NoSTox and Stox patients, allowing to formulate hypotheses on the protection from side effects derived from radiotherapy as well as factors predisposing to a worst response to the treatment. Our findings, being aware of the small number of patients analyzed, could be considered a starting point for the definition of a panel of pathways, possibly helpful in the management of MPM patients.

Extracranial carotid ultrasound evaluation for ischemic moyamoya disease in adults with different collateral circulation patterns

OBJECTIVE: To explore the possibility and application value of extracranial carotid ultrasound in assessing the progress of MMD. METHODS: We retrospectively analyzed the extracranial carotid ultrasound and DSA data of 89 cases of 53 patients with MMD (moyamoya group) and 90 cases of 45 control patients (control group). According to the DSA data of the moyamoya group, collateral circulation patterns’ grade and Suzuki stage were performed. We analyzed the correlation between collateral circulation patterns and Suzuki stage, and compared the difference of hemodynamic parameters between different grades of collateral circulation patterns. RESULTS: (1) As the Suzuki stage increased, the grade of the collateral circulation pattern subsequently increased. (2) Compared with the control group, the PSV of ICA in the moyamoya group was lower (P<0.01)，but the RI value of CCA and PSV of VA was increased (P<0.05). And the differences in hemodynamic parameters of ECA (including PSV and RI) were not statistically different. (3) Comparing hemodynamic parameters between the different grades of collateral circulation patterns of the control group, Grade 2 showed higher PSV of VA compared with Grade 1 (P <0.05); Grade 3 showed lower RI of ECA compared with Grade 1 and Grade 2 (P < 0.05). CONCLUSION: There is a correlation between collateral circulation patterns and Suzuki stage in adult ischemic MMD. There are differences in the hemodynamic parameters of extracranial carotid ultrasound in different grades of collateral circulation patterns. Extracranial carotid ultrasound can assess the progress of MMD in a timely, effective and convenient manner.

Development of a Clinical Nomogram for Prediction of Response to Neoadjuvant Chemotherapy in Patients with Advanced Gastric Cancer

Objective:The efficacy of neoadjuvant chemotherapy (NAC) among advanced gastric cancer (GC) is still a controversial issue. Our aim is to find the factors associated with chemosensitivity of NAC, and provide optimal therapeutic strategy for GC patients who received NAC.Methods: Clinical information was collected from 230 gastric cancer patients who received NAC in West China Hospital from January 2016 to December 2020. LASSO logistic regression analysis was performed to find the possible predictors which a nomogram model for prediction of response to NAC was based on.Results: A total of 230 patients were finally included in this study, including 154 males (67.0%) and 76 females (33.0%). And mean age was (59.37±10.60) years, ranging from 24 to 80 years. Based on the TRG standard, there were 95 cases in the obvious response group (grade 0 or grade 1) and 135 cases in the non-obvious response group (grade 2 or grade 3), and the obvious response rate was 41.3%. LASSO analysis showed that four risk factors that were significantly related to the efficacy of NAC, which included tumor location (P<0.001) , histological differentiation (P=0.001), clinical T stage (P=0.008) , CA724 (P=0.008) . The C-index for prediction nomogram was 0.806, and the calibration curve revealed the predicted value exhibited good agreement with the actual value, decision curve analysis showed that the nomogram had a good value in clinical application.Conclusions: The nomogram which combined tumor location, histological differentiation，clinical T stage and CA724 showed satisfactory predictive power to response of NAC, and could be used by gastrointestinal surgeons to identify optimal treatment strategy for advanced gastric cancer patients.

Molecular Signatures Associated With the Development of Pulmonary Toxicities in Mesothelioma Patients Treated With Radical Hemithoracic Radiation Therapy

Background. Radical Hemithoracic Radiotherapy (RHR), after lung-sparing surgery, has recently become a concrete therapeutic option for malignant pleural mesothelioma (MPM), an asbestos-related, highly aggressive tumor with increasing incidence and poor prognosis. Although the toxicity associated to this treatment has been reduced, it is still not negligible and must be considered when treating patients. Genetic factors appear to play a role determining radiotherapy toxicity. The aim of this study is the identification of genetic markers able to predict the relative susceptibility for newly diagnosed MPM patients to develop lung adverse effects if they were to be treated with RHR. Methods. The study included individuals with MPM, treated with lung-sparing surgery and neoadjuvant chemotherapy, followed by RHR with curative intent, and followed up prospectively for development of pulmonary toxicity. Due to the impact of grade 3 pulmonary toxicities on the quality of life, for further genetic analyses patients were divided into a none or tolerable pulmonary toxicity group (Grade ≤2) and a severe pulmonary toxicity group (Grade=3). Whole exome sequencing (WES) was performed to identify genetic variants in biological pathways associated to pulmonary toxicity after radiotherapy.Results. We identified crucial pathways driving the lung response to ionizing radiations in patients affected by mesothelioma: by affecting both the fibrinolytic activity and RNA editing pathways, irradiation could be responsible of the severe toxicity events reported by some patients, who present specific mutations in genes involved in these pathways. Conclusions. Our preliminary results could pave the way for the definition of a panel of predictive genomic variants, capable of supporting the management of MPM patients. By allowing for early identification of patients at high risk for treatment-dependent pulmonary toxicity, this predictive tool could play a major role in the design of new therapeutic combinations.

The Acute and Late Toxicities of MRI-Guided External Beam Partial Breast Irradiation Delivered Using a Once-Per-Day Regimen

Background and PurposeThe use of external beam accelerated partial breast irradiation (APBI) using a twice-per-day regimen has raised concerns about increase rates of late toxicities. We compared toxicity outcomes of external beam APBI using a once-per-day regimen and accelerated hypofractionated whole breast irradiation (AWBI) in patients with early-stage breast cancer.Materials and MethodsThis was a single-institution, retrospective cohort study. Patients aged ≥50 years with pTisN0 or pT1N0 breast cancer who underwent breast-conserving surgery and adjuvant radiotherapy were included. APBI was delivered at 38.5 Gy in 10 fractions once daily using magnetic resonance imaging (MRI)-guided radiotherapy only to patients who were strictly “suitable”, according to the ASTRO-APBI guidelines. AWBI was delivered at 40.5–43.2 Gy in 15 or 16 fractions with or without a boost.ResultsBetween October 2015 and December 2018, 173 and 300 patients underwent APBI and AWBI, respectively. At a median follow-up of 34.9 months (range 7.1 to 55.4 months), the 3-year recurrence-free survival rates of the APBI and AWBI groups were both 99.2% (p=0.63). Acute toxicities were less frequent in the APBI than AWBI group (grade 1: 95 [54.9%] vs. 233 [77.7%] patients; grade 2: 7 [4.0%] vs. 44 [14.7%] patients; no grade ≥3 toxicities were observed in either group, p&lt;0.001). Late toxicities were less common in the APBI than AWBI group (grade 1: 112 [64.7%] vs. 197 [65.7%] patients; grade 2: 9 [5.2%] vs. 64 [21.3%] patients; grade 3: 0 vs. 5 [1.7%] patients, p&lt;0.001). Multivariate analysis showed that APBI was significantly associated with fewer late toxicities of grade ≥2 compared with AWBI (odds ratio 4.17, p=0.006).ConclusionOnce-per-day APBI afforded excellent locoregional control and fewer toxicities compared with AWBI. This scheme could be an attractive alternative to AWBI in patients who meet the ASTRO-APBI guidelines.

Effectiveness of Pharmacological Pain Relief Methods on Birth Experience: A Systematic Review and Meta-Analysis

Background:: The use of pharmacological pain relief methods during labour is increasing, however there is no clear evidence that pharmacological interventions can also improve women’s satisfaction with birth experience. Objective:: To assess the effectiveness of pharmacological interventions on women's satisfaction with birth experience (primary outcome) and satisfaction with the received method (secondary outcome). Methods:: We searched databases in English (MEDLINE, Cochrane Library, Embase, ProQuest, Scopus and Web of Science) and Persian languages (SID and Magiran) from inception until April 30, 2018 for clinical trials that pharmacological pain relief methods were compared with standard or routine cares, or non-pharmacological methods. The evaluation of studies in term of risk of bias was conducted using the Cochrane Handbook. Meta-analysis results were reported as OR and 95% confidence interval. In meta-analysis, subgroup analysis was performed based on the type of intervention. Due to the heterogeneity of over 30%, random effect was reported instead of the fixed effect. The heterogeneity was evaluated using I2, T2 and Chi2. The evaluation of the quality of the studies was also examined using the Grading of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach. Results:: The results of 7 studies with low-quality in meta-analysis, showed that pharmacological methods significantly improved satisfaction with birth experience (OR = 2.99; 95% CI: 1.37 to 6.52; P = 0.006). However, meta-analysis of subgroups showed that only inhalation of Entonox gas (OR = 6.51; 95% CI: 3.47 to 12.22; P < 0.001), in contrast to epidural analgesia (OR = 1.19; 95% CI: 0.62 to 2.27; P = 0.60) and Hyoscine injection (OR = 2.58; 95% CI: 0.93 to 7.20; P = 0.07) significantly improved satisfaction with birth experience. Conclusion:: Pharmacological interventions such as epidural, although introduced as one of the effective methods for pain relief, may not provide women with satisfaction with birth. However, more studies with precise methodology, high sample size, and standard tools should be performed to more accurately investigate the effect of pharmacological interventions on birth experience.

Safety assessment of preoperative oil chemoembolization with nanoparticle albumin-bound paclitaxel in patients with pancreatic head adenocarcinoma

Results of combined treatment of 36 patients suffering from pancreatic head ductal adenocarcinoma are evaluated, including preoperative chemotherapy using nanodispersed albumin-stabilized paclitaxel (nab-paclitaxel) in intraarterial oil chemoembolization or intravenous administration and radical surgical treatment. Intraarterial oily chemoembolization of the pancreatic head consisted of the introduction of 17 patients (main group) into the gastroduodenal artery of an emulsion of super-liquid lipiodol (Lipiodol Ultra Fluid) in an aqueous solution of nab-pacliaxel 50 mg/m2 and gemcitabine 400 mg/m2. 19 patients (control group) were administered nab-paclitaxel 100 mg/m2 and gemcitabine 1000 mg/m2 intravenously according to standard guidelines. Safety and tolerability assessment of combined treatment with preoperative application of nab-paclitaxel was carried out in advance. Pil-preserving pancreatoduodenal resection is considered safe on day 710, after completion of preoperative chemotherapy with nab-paclitaxel. The use of nab-paclitaxel in preoperative intraarterial oily chemoembolization of the pancreatic head requires extension of the pancreatic crossing boundary to body level. Postoperative lethality and 4th degree complications according to the Clavien-Dindo classification were not observed. In the main group, grade 3a complication was observed in 2 (12%) patients and was represented by bleeding from acute gastric erosions resolved endoscopically. In the control group, complications of degree 3 were also noted in 2 (11%) patients and were represented by: one bleeding from acute stomach erosions that required endoscopic hemostasis and an intraabdominal abscess allowed by percutaneous drainage. In the main group, complications of the 2nd degree were recorded in 8 (47%) patients: in 3 (17%) patients the formation of pancreatic fistula was noted, in 4 (23%) postoperative pancreatitis was detected, and in 1 (6%) gastrostasis phenomena that required conservative therapy. In the control group, complications of the 2nd degree were observed in 11 (58%) patients and were presented: pancreatic fistulae in 2 (10%) patients, postoperative pancreatitis in 6 (31%) and gastrostasis in 3 (16%) patients. The most common complication observed in both groups was the suppression of a postoperative wound, corresponding to the 1st degree of severity: in the main group in 5 (29%) patients, in the control group in 7 (37%) patients. Thus, the use of intraarterial oil chemoembolization with nab-paclitaxel as a preoperative antitumor treatment can be considered safe.

THE INFLUENCE OF THE STUDENT FACILITATOR AND EXPLAINING ON STUDENT LEARNING OUTCOMES IN ELEMENTARY SCHOOLS

The research objective was to describe the effect of using the Student Facilitator and Explaining model of learning on thematic learning at SDN Balongbesuk, Diwek, Jombang. The experimental method used in this study, and the research design used the Noneequivalent Control Group. Grade IV students were used as subjects in this study. Data were collected by observation, interviews, and tests. The t-test formula is used to analyze the data results. It is shown by the results of the research on learning mechanisms to be more effective by using the Student Facilitator And Explaining learning model, because it participates and engages students directly in the learning mechanism. Make students competent to express ideas or ideas to their friends. The use of the Student Facilitator And Explaining model can increase students' insight while learning, direct student involvement in the learning mechanism, because it can increase student learning outcomes.

Anti-Androgen Drugs in the Treatment of Obsessive-Compulsive Disorder: A Systematic Review

Objective: This study aimed to systematically investigate whether anti-androgens could significantly reduce Obsessive-Compulsive Disorder (OCD) symptoms compared to placebo or usual care in OCD patients. Methods: PubMed, EMBASE, CENTRAL and International Clinical Trials Registry Platform (ICTRP) databases were searched up to October 2018 using relevant keywords. All randomized and if not available non-randomized studies conducted on a population including OCD patients who were administered with anti-androgen, which reported changes in their symptoms, were included. The studies on compulsive hypersexuality were excluded. Required data were extracted from full-text of the included articles by two independent authors. One randomized and four non-randomized trials were found. Results: The only randomized trial showed that flutamide, an anti-androgen agent, was effective in reducing compulsion scores in male OCD patients with comorbid Tourette syndrome, compared to placebo. Three out of four non-randomized trials showed that different anti-androgens including finasteride, cyproterone acetate and triptorelin were effective in reducing OCD symptoms. The only study, which failed to show the efficacy of an anti-androgen agent, administered OCD patients with flutamide. Despite the positive results, available studies provide the evidence with low quality based on the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) approach. Conclusions : Available studies are not sufficient for a precise answer to our study question. There is still a need for further large randomized blinded clinical trials to evaluate the effectiveness of antiandrogens in OCD patients. It is recommended that gender, comorbidities and subscales of Yale- Brown Obsessive-Compulsive Score (Y-BOCS) should be considered in designing the studies and interpreting their results.

Predictive Model for Oral Mucositis of Nasopharyngeal Carcinoma Patients Receiving Chemo-radiotherapy

Purpose To analyze risk factors for severe acute oral mucositis of nasopharyngeal carcinoma patients (NPCs) receiving chemo-radiotherapy and build predictive models.Methods 270 NPCs receiving radical chemo-radiotherapy were included. Oral mucosa structure was contoured by oral cavity contour (OCC) and mucosa surface contour (MSC) methods. Oral mucositis during treatment was divided into severe mucositis group (grade 3) and non-severe mucositis group (grade = 1, 2) according to RTOG criteria. Statistical analyses were completed by IBM SPSS Statistics 25.0 and IBM SPSS Modeler 18.0.ResultsIntermediate to high Vx (%) were strongly associated with severe oral mucositis (V40-V70(%)). Multivariate analysis showed that V55 (%) was the most important predictor for severe oral mucositis followed by overweight and retropharyngeal lymph node region irradiation (RLN). Two predictive models were built based on these two methods. AUC of OCC and MSC based model in training set were 0.786 both. Higher AUC of MSC-base model was observed in validation set when compared to OCC (0.721 vs. 0.622). Conclusion Dosimetric parameter is the most important predictive factors for severe oral mucositis in nasopharyngeal carcinoma patients during chemo-radiation. Of the two models generated in this study, performance of MSC-based model in validation data is mildly better than OCC.