Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.     

Comparison of microtransplantation,chemotherapy and allogeneic transplantation in post-remission therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) have poor prognosis, and the efficacy of chemotherapy plus tyrosine kinase inhibitors (TKIs) followed by mismatched donor stem cell infusion (microtransplantation, MST) has not been determined. We retrospectively summarized 45 patients including 11 undergoing MST with TKIs, 17 receiving allogeneic transplant and 17 undergoing chemotherapy with TKIs. Improved 4-year overall survival rate was observed in the MST group (91%) compared with either transplant group (31%, P = .005) or chemotherapy group (36%, P = .013). The MST group also had higher 2-year and 4-year leukemia-free survival rates (91% and 72%, respectively) compared with either transplant group (33%, P = .005 and 33%, P = .021, respectively) or chemotherapy group (41%, P = .017 and 31%, P = .023, respectively). 2-year and 4-year cumulative incidences of hematologic relapse were lower in the MST group (9% and 28%, respectively) compared with those in the chemotherapy group (56%, P = .025 and 67%, P = .034, respectively). In patients undergoing MST, donor microchimerism was detected (1.07 × 10^-5 to 6.6 × 10^-4 copies from 9 to 1499 days) in 7 patients, and donor/patient-derived HLA*0201/2402⁺WT1⁺CD8⁺ T cells were found from 0.05% to 0.67% in 6 patients. MST may provide a favorable treatment for patients with Ph⁺ ALL.     

益气养精法对老年肺癌患者肿瘤标志物、生存期影响研究

目的探究益气养精法对老年肺癌患者肿瘤标志物、生存期影响。方法研究纳入60例老年肺癌患者,均由本院2016年1月-2017年1月收治,采取随机数字表法将患者分为两组,对照组患者(30例)常规化疗治疗,观察组患者(30例)在化疗基础上联合益气养精法治疗,比较两组患者治疗效果、治疗前后癌胚抗原(carcino-embryonic antigen,CEA)及血清癌抗原125(serum oncoantigen 125,CA 125)肿瘤标志物水平、不良反应情况及患者2年生存率。结果观察组患治疗有效率高于对照组,P<0.05;治疗前,两组患者CEA及CA 125水平相当,P>0.05,治疗后均改善,观察组优于对照组,P<0.05;观察组患者不良反应与对照组相当,均较低,P>0.05;观察组患者2年生存率高于对照组,P<0.05。结论益气养精法治疗老年肺癌患者效果患者,患者症状改善,不良反应少,安全可靠,且患者2年生存率较高。     

单孔加一孔联合ERAS在高位直肠及乙状结肠癌中的应用

目的 探讨单孔加一孔腹腔镜手术联合 ERAS 治疗高位直肠及乙状结肠癌的近期疗效。方法 回顾性分析 2017 年 11 月至2018 年 10 月在福建省肿瘤医院胃肠肿瘤外科进行加速康复外科干预的 92 例高位直肠及乙状结肠癌患者资料，根 据手术方式的不同，分为单孔加一孔手术联合快速康复外科组39 例及常规腹腔镜手术联合ERAS 组 53 例，对比两组围术 期情况。结果 两组患者基线资料无明显统计学差异（P ＞ 0.05），且在手术时间、出血量、上下切缘、清扫淋巴结数量及 并发症方面无明显统计学差异（P ＞ 0.05）。但单孔加一孔手术联合ERAS 组较常规手术联合ERAS 组，总切口长度更短 [（6.7±1.1）cm 比（8.5±1.3）cm，P=0.000]，术后首次下床时间更早 [（22.2±5.2）h 比（27.1±7.9）h，P=0.001]，首次排便 时间更早[（70.2±19.8）h比（83.1±20.4）h，P=0.005]，术后第一天C反应蛋白值更低[（43.5±28.6）mg/L比（57.2±33.2） mg/L，P=0.038]，术后住院时间更短 [（7.0±1.7）d 比（8.1±2.1）d，P=0.010]，且术后 2~4 天疼痛评分更低（P ＜ 0.05）。 结论 经验丰富的腔镜医师采用单孔加一孔手术治疗高位直肠及乙状结肠癌并联合 ERAS 干预是安全可行的，且单孔加一孔 手术可减低操作难度，具有疼痛轻、术后恢复快等优势，值得临床推广。     

Outcomes after neoadjuvant or adjuvant chemotherapy for cT2-4N0-1 non–small cell lung cancer: A propensity-matched analysis

Objective

Comparative survival between neoadjuvant chemotherapy and adjuvant chemotherapy for patients with cT2-4N0-1M0 non–small cell lung cancer has not been extensively studied.

Deep learning with biopsy whole slide images for pretreatment prediction of pathological complete response to neoadjuvant chemotherapy in breast cancer：A multicenter study

IntroductionPredicting pathological complete response (pCR) for patients receiving neoadjuvant chemotherapy (NAC) is crucial in establishing individualized treatment. Whole-slide images (WSIs) of tumor tissues reflect the histopathologic information of the tumor, which is important for therapeutic response effectiveness. In this study, we aimed to investigate whether predictive information for pCR could be detected from WSIs.Materials and methodsWe retrospectively collected data from four cohorts of 874 patients diagnosed with biopsy-proven breast cancer. A deep learning pathological model (DLPM) was constructed to predict pCR using biopsy WSIs in the primary cohort, and it was then validated in three external cohorts. The DLPM could generate a deep learning pathological score (DLPs) for each patient; stromal tumor-infiltrating lymphocytes (TILs) were selected for comparison with DLPs.ResultsThe WSI feature-based DLPM showed good predictive performance with the highest area under the curve (AUC) of 0.72 among the cohorts. Alternatively, the combination of the DLPM and clinical characteristics offered a better prediction performance (AUC >0.70) in all cohorts. We also evaluated the performance of DLPM in three different breast subtypes with the best prediction for the triple-negative breast cancer (TNBC) subtype (AUC: 0.73). Moreover, DLPM combined with clinical characteristics and stromal TILs achieved the highest AUC in the primary cohort (AUC: 0.82) and validation cohort 1 (AUC: 0.80).ConclusionOur study suggested that WSIs integrated with deep learning could potentially predict pCR to NAC in breast cancer. The predictive performance will be improved by combining clinical characteristics. DLPs from DLPM can provide more information compared to stromal TILs for pCR prediction.     

Pre- or postoperative radiotherapy for soft tissue sarcomas

Sarcomas are rare tumours arising from mesenchymal tissue. A multimodal management in an expert centre combining surgery and radiotherapy is the current standard of care for localized soft-tissue sarcomas of the extremities, to enable limb-sparing strategies. The delivery of pre- radiotherapy or postoperative radiotherapy offers similar local control and survival rates but the toxicity profile is quite different: preoperative radiotherapy increases the risk of wound complications and postoperative radiotherapy affects long-term functional outcomes. While postoperative radiotherapy has long been the rule, especially in Europe, technical improvements with image-guided- and intensity-modulated radiotherapy associated with a better management of postoperative wounds has tended to change practices with more frequent preoperative radiotherapy. More recently the possibilities of a hypofractionated regimen or potentiation by nanoparticles to increase the therapeutic index plead in favour of a preoperative delivery of radiotherapy. The aim of this paper is to report pros and cons of pre- and post-operative radiotherapy for soft-tissue sarcomas.