Quality of Regional Nodal Irradiation Plans in Breast Cancer Patients Across a Large Network—Can We Translate Results From Randomized Trials Into the Clinic?

PurposeRegional nodal irradiation (RNI) improved disease-free survival by 3% to 5% in 2 large randomized trials, but this small absolute advantage relies on accurate contouring and dose delivery. We audited our network to determine compliance on regional nodal coverage, contouring, and dosimetric parameters with respect to accepted guidelines.Methods and MaterialsIn our network, we have established a clinical pathway for patients with node-positive breast cancer that guides indications for RNI and dosimetric goals. We reviewed records of 183 patients with nodal macrometastases after upfront surgery or involved nodes of any size after neoadjuvant chemotherapy. Radiation treatment plans were examined to determine lymph node volumes treated, whether nodes were contoured, quality of nodal contours, and whether target coverage and normal organ dosimetric constraints were met when RNI was delivered.ResultsDespite the presence of macrometastases on sentinel lymph node biopsy, no lymph nodes were treated in 2.2% (4 of 183). Of 179 patients who received nodal irradiation, 18 received radiation to axillary levels 1 and 2 only, and 161 patients received RNI. Overall, regional nodes were not treated despite strong indications in 7.6% (14 of 183). Treated nodes were not contoured for 2.2% (4 of 179), and lymph node contours were unacceptable in 15.4% (27 of 175). Of patients receiving RNI, 14.9% (24 of 161) did not have adequate nodal target volume coverage, mean heart dose was >4 Gy for 3.1% (5 of 161), and lung V20 Gy was >35% for 8.7% (14 of 161).ConclusionsAdherence to indications for regional nodal treatment was high, but nodes were either not contoured or had unacceptable contour quality in 18% of plans, and coverage was inadequate in 15%. Because the small disease-free survival advantage seen in trials may be decreased with these deviations, routine clinical practice requires detailed peer review to fully translate results of clinical trials.     

Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Esophageal Calibration with Soft Orogasrtric Tube During Laparoscopic Nissen Fundoplication may Reduce Postoperative Transient Dysphagia

Gastroesophageal reflux is the most common benign disorder of the esophagus and laparoscopic Nissen fundoplication has become the standard surgical treatment for its treatment. In our area, where the use of bougie calibration is debatable, postoperative dysphagia is encountered often after this surgery although it is usually not permanent. The aim of this study was to investigate the effect of using a soft silicone tube 39 F in diameter for esophageal calibration during laparoscopic Nissen fundoplication on the incidence of postoperative dysphagia. We divided cases scheduled to undergo laparoscopic Nissen fundoplication between January 2009 and November 2010 into two groups, each consisting 25 patients. Esophageal calibration with a 39 F silicone orogastric tube was used for the first group while there was no operative calibration in the second group. The surgical duration was recorded; the presence and severity of the postoperative dysphagia was calculated by using a dysphagia severity scoring system during the 1-year postoperative follow-up. The dysphagia severity scores were significantly lower in group 1 than group 2 on the postoperative second day and at the end of the first week and first month. We did not find a significant difference at the end of the 6-month and first year. There was also no significant difference regarding surgery duration. The use of a soft orogastric tube 39 F in diameter for esophagus calibration during laparoscopic Nissen fundoplication has significantly decreased the incidence of postoperative transient dysphagia without affecting the duration of surgery. Although dysphagia gradually resolves in the majority of patients, a safe and easy calibration method for its prevention is worth developing, and we believe that the use of our method in larger series could be beneficial.     

针刺辅助治疗难治性肠易激综合征临床试验方案关键点设计的思考＊

肠易激综合征（Irritable bowel syndrome，IBS）是临床常见病、多发病，其治疗方法丰富，但部分患者疗效欠佳，发展成难治性IBS。目前国内外关于针灸治疗难治性IBS的临床随机对照试验尚不多见。本文立足试验方案设计的“PICOS”原则，从研究对象及诊断标准、干预措施、对照措施、结局指标四个方面入手，重点探讨针刺辅助治疗难治性肠易激综合征临床试验设计的关键要点。从选择特色优势病种、明确诊断标准、制定符合临床实际的干预方案、运用符合目标的安慰针刺、结合研究设计和目的选定结局指标几个角度，阐述试验相关环节设计的原因和思考。     

去势比格犬腹部脂肪与相关血清学指标及骨密度的变化关系

目的通过建立去势比格犬模型,观察绝经早期腹部脂肪变化规律,并通过对脂肪与骨代谢相关血清学指标的测量与分析,探讨脂肪及骨代谢的关键影响因素。方法选取6只成年雌性比格犬进行去势术,分别在术前、术后4个月、6个月、10个月进行腰椎定量CT(quantatitive computed tomography,QCT)腹部脂肪面积、骨密度(bone mineral density,BMD)、MRI腰椎骨髓脂肪含量及血清学指标的检测,比较不同时间各指标的变化趋势及关系。结果比格犬腹内脂肪面积(visceral fat area,VFA)、皮下脂肪面积(subcutaneous fat area,SFA)、腹部总脂肪面积(total fat area,TFA)在术后6个月、10个月均增加(P0.05),术后10个月VFA增加百分比均值为84.39%,且为三者中最大;术后比格犬BMD并未明显降低。体重、BMD、瘦素(leptin,LP)、VFA、高密度脂蛋白(high-density lipoprotein,HDL)与SFA相关。SFA、体重、低密度脂蛋白(low-density lipoprotein,LDL)、内脏脂肪素(visfatin,VFN)与BMD相关。结论去势比格犬模型可用于研究绝经后雌激素缺乏所引起的脂肪代谢变化,但短期内BMD并未明显丢失,骨、脂肪代谢之间存在交互作用。     

纯化痘病毒筛选的常用方法

痘病毒是自然界普遍存在的DNA病毒，能够高效表达外源基因，诱导较强的细胞免疫和体液免疫，受到基因治疗学者的广泛关注。痘病毒发生同源重组的概率较低，所以有效地筛选和纯化痘病毒十分重要。目前常用的筛选重组痘病毒方法有基于CRISPR进行筛选；根据报告基因GFP、LacZ、GPT等进行筛选；利用TK^-和Brdu结合荧光进行筛选；利用药物抗性基因与荧光或显色基因融合，即可在药物筛选的同时观察荧光或显色基因表达情况。本文旨在对目前常用的痘病毒的筛选纯化方法进行综述。     

远程胎儿监护的临床应用

远程胎儿监护是应用互连网及计算机技术，孕妇在家中或远程监护终端将胎心监护图形传输到中央监护站，医生即可通过电脑或手机APP远程判读。对高危孕妇实行远程监护，便于及时发现胎儿宫内缺氧情况和及时处理，改善围产儿结局。     

Biopharmaceutics classification and intestinal absorption of chikusetsusaponin IVa

The objective of this study was to investigate the absorption behavior of chikusetsusaponin IVa (CHS‐IVa) in the rat intestine using single‐pass intestinal perfusion (SPIP) and to classify CHS‐IVa into the biopharmaceutics classification system (BCS). The equilibrium solubility of CHS‐IVa was determined by the shaker method. The absorption mechanism of CHS‐IVa in the intestine was studied by comparing the P_eff of different concentrations of CHS‐IVa. The intestinal site dependence of CHS‐IVa absorption was studied by comparing the P_eff of the same concentration of CHS‐IVa in different intestinal segments. The relationship between CHS‐IVa and intestinal efflux protein was studied by perfusion with an efflux protein inhibitor. The permeability of CHS‐IVa was investigated by comparing the P_eff of CHS‐IVa and the reported value. The solubility of CHS‐IVa over the pH range 1.0–7.5 was 14.4 ± 0.29 to 16.9 ± 0.34 mg/ml. The P_eff of CHS‐IVa in the duodenum was 1.76 × 10^?3 to 2.00 × 10^?3 cm/min. The P_eff of CHS‐IVa in the jejunum was 1.26 × 10^?3 to 1.39 × 10^?3 cm/min. The P_eff of CHS‐IVa in the ileum was 1.25 × 10^?3 to 1.31 × 10^?3 cm/min. The P_eff of CHS‐IVa in the colon was 1.02 × 10^?3 to 1.08 × 10^?3 cm/min. There was no statistical difference of the P_eff in the four segments at different CHS‐IVa concentrations. The P_eff of CHS‐IVa (0.07, 0.7 and 7.0 mg/ml) were all notably smaller than the reported P_eff (3.00 × 10^?3 cm/min) in the jejunum. The P_eff of CHS‐IVa was not influenced by verapamil (P‐gp inhibitor), indomethacin (MRP inhibitor) and pantoprazole (BCRP inhibitor). CHS‐IVa was classified as high solubility, low permeability and BCS III. The main absorptive tracts were the upper intestinal tracts and the rank order of intestinal permeability was duodenum > jejunum ≈ ileum > colon. The transport mechanism of CHS‐IVa in all intestinal segments might be primarily passive transport. CHS‐IVa was not a substrate of P‐gp, MRP and BCRP.