Health-related quality of life after isolated limb perfusion compared to extended resection,or amputation for locally advanced extremity sarcoma: Is a limb salvage strategy worth the effort?

IntroductionThe aim of this study was to compare long-term patient reported outcomes (PROs) in patients with locally advanced extremity soft tissue sarcoma (eSTS) after isolated limb perfusion followed by resection (IR), compared to extended resection (ER), primary amputation (A) or secondary amputation after IR (IR-A).MethodsPatients were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted among sarcoma survivors registered in the Netherlands Cancer Registry (NCR), 2–10 years after diagnosis. Used PROs were the EORTC QLQ-C30, the Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS).ResultsWe identified 97 eSTS survivors: IR = 20, ER = 49, A = 20, IR-A = 8. While there were no differences in PROs between IR and ER, results showed better functioning and functionality in both groups versus the amputation groups. The amputation groups scored significantly lower on physical functioning (A = 62.7, IR-A = 65.7 versus IR = 78.0, ER = 82.7, p = 0.001) and role functioning (A = 67.5, IR-A = 52.8 versus IR = 79.2, ER = 80.6, p = 0.039), both EORTC QLQ-C30 scales. Also for the TESS, the scores were significantly lower for the amputation groups compared to the limb sparing groups (upper extremity p = 0.007 with A = 68.9, IR-A = 71.6 versus IR = 93.3, ER = 91.1; lower extremity p < 0.001 with A = 72.2, IR-A50.9 versus IR = 84.5 and ER = 85.5). There were no significant differences between the groups on cancer worry, anxiety and depression.ConclusionHRQoL in eSTS survivors treated with IR or ER is equal; for maintenance of physical functioning and functionality IR and ER outperform an amputation.     

凉血通瘀方干预高血压大鼠急性脑出血模型对脑组织中差异miRNA表达的影响＊

目的 研究凉血通瘀方对高血压大鼠急性脑出血模型脑组织miRNA表达的影响，对差异表达的miRNA靶基因进行分析，探索凉血通瘀方可能的药效机制。方法 将自发性高血压大鼠随机分成对照组（B）和实验组（C）。适应性饲养一周后，C组灌胃凉血通瘀方，B组灌胃等体积生理盐水，连续5天，每天1次。构建脑出血模型后收集脑组织，借助全转录组测序技术获得miRNA表达量，与miRBase数据库比对获取已知miRNA，使用miRDeep2预测新miRNA。差异分析软件为DESeq2，筛选阈值为|log₂FC| ≥1 并且P <0.05。对显著差异表达的miRNA进行靶基因预测，对靶基因进行GO功能、KEGG通路富集和PPI网络分析。结果 实验组和对照组对比，共发现21个显著差异表达的miRNA，上调有9个，下调有12个，共预测得到1243个有统计学意义的靶基因。GO富集分析发现，生物过程中突触囊泡分泌的调节、神经递质分泌的调节和神经递质运输的调节占前三位，神经元投射终点、全膜、质膜区域和细胞投射则是主要的细胞成分。分子功能分别为小GTPase绑定、底物特异性跨膜转运蛋白活性和离子跨膜转运体活性。通路分析结果显示，靶基因在癌证通路、pI3K-Akt信号通路、人类乳头瘤病毒感染、神经活性配体-受体相互作用和MAPK通路等分布广泛。采用STRING网站和Cytoscape软件，根据MCC算法筛选出ADRA2C、CASR、CCL28、CCR1、DRD2、GNAT3、GRM2、DYNC1LI1、GABBR1、GNAI1等核心靶基因。结论 凉血通瘀方对脑出血急性期鼠脑组织内miRNA的表达有重要影响；显著差异表达miRNAs可能通过靶向核心基因调控凉血通瘀方干预急性脑出血的病理过程及预后。     

治伤巴布剂对大鼠急性软组织损伤模型P38MAPK、AKT信号通路的影响＊

目的 观察治伤巴布剂对急性软组织损伤（acute soft tissue injury， ASTI）模型p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、丝/苏氨酸蛋白激酶（AKT）信号通路的影响，探讨治伤巴布剂干预ASTI的可能作用机制。方法 将40只雄性SD大鼠按照随机数字表法分为正常对照组、模型对照组、治伤巴布剂组、p38MAPK信号通路抑制剂组、AKT信号通路抑制剂组，每组8只。除正常对照组外，其余四组均予以左侧后肢小腿ASTI造模。造模成功后，治伤巴布剂组于标记部位立即予治伤巴布剂（修剪成1.5x3cm大小）外敷，并用胶布固定；其余四组均予等剂量赋形剂（修剪成1.5×3 cm大小）外敷处理，胶布固定；持续外敷，共持续24 h。p38MAPK信号通路抑制剂组在造模前30 min予腹腔注射p38MAPK信号通路抑制剂SB203580（400 μg/kg/天）1次；AKT信号通路抑制剂组在造模前30 min予腹腔注射AKT信号通路抑制剂perifosine（20 mg/kg/天）1次。分别于0（造模前）、2h、4h、8h、12h、24h测量受伤小腿肌肉处的周长，并计算肌肉肿胀率（muscle swelling rate，MSR）。24 h药物干预结束后，采用颈椎脱臼法处死大鼠。后将左侧后肢小腿损伤中心部位进行取材，分成三份。一部分用于观察组织病理学形态变化；一部分用于逆转录聚合酶链反应（RT-PCR）检测核因子-κB（nuclear factor kappa-B，NF-κB）p65 mRNA、肿瘤坏死因子-α（TNF-α）mRNA、白细胞介素-1β（IL-1β）mRNA表达水平；剩下部分用酶联免疫吸附试验（ELISA）法检测骨骼肌组织TNF-α、IL-1β含量水平及蛋白质免疫印迹（Western-blot）法测定p38MAPK、AKT、NF-κB p65、核因子抑制蛋白α（inhibitor kappa B alpha， IκBα）表达水平。结果 与正常对照组相比，模型对照组MSR显著增加（P<0.01）；病理形态学上，骨骼肌组织可见大面积肌细胞排列紊乱，肌细胞变性坏死，间质内可见红细胞聚集及大量炎症细胞浸润；骨骼肌组织TNF-α、IL-1β含量水平显著升高（P<0.01）；磷酸化p38MAPK（p-p38）/总p38MAPK（t-p38），磷酸化-AKT（p-AKT）/总-AKT（t-AKT）明显升高（P<0.01），NF-κB p65及NF-κB p65mRNA表达水平明显升高（P<0.01）。与模型对照组相比，治伤巴布剂组MSR在治疗第8 h、12 h、24 h显著下降（P<0.01），且在治疗第24 h，其MSR较p38MAPK、AKT信号通路抑制剂组下降更明显（P<0.05）；病理学评分显著下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组下降更显著（P<0.05）；骨骼肌组织TNF-α、IL-1β含量水平明显下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组更显著（P<0.05）；p-p38/t-p38及p-AKT/t-AKT明显下降（P<0.01），NF-κB p65及NF-κB p65 mRNA表达水平显著下降（P<0.01），且较p38MAPK、AKT信号通路抑制剂组在降低NF-κB p65及NF-κB p65 mRNA相对表达值方面更显著（P<0.01）。结论 治伤巴布剂可能同时对p38MAPK、AKT信号通路产生了一定的抑制作用，引起NF-κB活性下调，NF-κB p65蛋白的表达下调，进而引起骨骼肌组织TNF-α、IL-1β炎性细胞因子含量水平下调，减轻ASTI炎症反应，从而改善ASTI。     

Application of computer-generated images to train pattern recognition used in semiquantitative immunohistochemistry scoring

This study aimed to clarify whether the pattern recognition involved in scoring proliferation fractions can be trained by abstract computerized images of virtual tissues. Twenty computer-generated images with randomly distributed blue or red dots were scored by 12 probands (all co-workers or collaborators of the Institute of Pathology, University of Bonn). Afterward, the probands underwent a training phase during which they received an immediate feedback on the actual rate of positivity after each image. Finally, the initial testing series was rescored. In a second round with 15 different probands, 20 Ki-67 immunohistochemistry images of tonsil tissue were scored, followed by the same training phase with computer-generated images, before the immunohistochemistry slides were scored again. Paired t-tests were used to compare the differences in mean rates pre- and post-training. Concerning computerized images, untrained probands scored the percentages of positive dots with a mean deviation from the true rates of 8.2%. Following training, the same testing series was scored significantly better with a mean deviation of 4.9% (mean improvement 3.3%, p < 0.001). Scoring real immunohistochemistry slides, the training with computerized images also improved correct estimations, albeit to a lesser degree (mean improvement 1%, p = 0.03). Abstract computerized images of virtual tissues may be a useful tool to train and improve the accuracy of pattern recognition involved in semiquantitative scoring of immunohistochemistry slides. As a side results, this study highlights the value of computer-generated images to verify the performance of image-analysis software.     

Research of connective tissue dysplasia influence on teething

PurposeThis work aimed to study the rate and quality of maturation of the mineral component of retained teeth 3.8, 4.8 and lower jaw fragment of a human in connective tissue dysplasia in different periods of postpartum ontogenesis.MethodsThe study involved 102 men (76 with connective tissue dysplasia and 26 without connective tissue dysplasia) divided into groups by age: 31–40, 41–50, 51–60 years. One tooth 3.8, 4.8 and a fragment of the alveolar part of the lower jaw in the projection of teeth 3.8, 4.8 0.5*0.5 cm in size were extracted from each examinee for medical indications.ResultsLow optical density values are observed at the age of 41–50 years, at the age of 51–60 years, indicating decreased mineral density and the presence of total areas of hypomineralization from the age 31–40 years in connective tissue dysplasia. At the age of 41–50, 51–60 years, at the boundary of connective tissue structures and periosteum, a pronounced sclerosis and deformation of delineation elements were observed; at the age of 31–40 years, the indicated changes were less pronounced. At the age of 31–40 years, the level of bone plate dissection has a local character, after 40 years, it has a generalized character.ConclusionProgressive osteoporosis of the mandible and incomplete amelogenesis are an obstacle to the correct and harmonious teething of the lower wisdom teeth after the age of 30.     

Intraabdominal and retroperitoneal soft-tissue sarcomas – Surgical treatment and outcomes

BackgroundIntraabdominal and retroperitoneal sarcomas (IaRS) are malignant connective tissue tumors. Surgical resection is often the only curative treatment. The primary objective was to report the mid-term outcomes following contemporary treatment protocols and identify prognostic factors.MethodsA retrospective review of consecutive patients (n = 107) with IaRS treated at single center from 2013 until 2018 was conducted. Histological diagnosis, tumor grade, perioperative complications, mortality, and long-time survival were registered and retrieved from patient records. Primary and recurrent tumors were analyzed separately.ResultsA total of 107 patients were identified. Median follow-up time was 3.5 years. Thirty-day mortality was 3.4% and 90-day mortality was 5.6% for all tumors. The major complication rate was 18%. The 5-year estimated survival for primary and recurrent tumors was 55.4% and 48.4%, respectively. Multifocal disease was evident in 32% of the patient cohort, and 58% of patients in the recurrent group. Multivariate analysis for survival revealed a hazard ratio (HR) of 3.1 (95% CI 1.68–8.41) for multifocality, HR 2.9 (95% CI 1.28–6.98) for Clavien-Dindo grade, HR 2.3 (95% CI 1.21–4.31) for tumor grades 2 or 3, and HR 1.002 (95% CI 1.001–1.004) for surgical margins.ConclusionsOur study found overall acceptable morbidity and mortality, and identified prognostic markers for overall survival. Recurrent tumors were not associated with worse survival. Multifocality is associated with a worse overall survival. The prognostic factors identified were; tumor grade, multifocality, intralesional margins and postoperative complications.     

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group

Background

Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined.

Methods

This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered.

Results

The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2–111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6–25.7) and 34.9% (95% CI, 22.7–47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered.

Conclusions

The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge.

Plain Language Summary

• Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors.
• Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases.
• This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.