Immune response evaluation criteria in solid tumors for assessment of atypical responses after immunotherapy

In 2017,immune response evaluation criteria in solid tumors(iRECIST)were introduced to validate radiologic and clinical interpretations and to better analyze tumor’s response to immunotherapy,considering the different time of following and response,between this new therapy compared to the standard one.However,even if the iRECIST are worldwide accepted,to date,different aspects should be better underlined and well reported,especially in clinical practice.Clinical experience has demonstrated that in a non-negligible percentage of patients,it is challenging to determine the correct category of response(stable disease,progression disease,partial or complete response),and consequently,to define which is the best management for those patients.Approaching radiological response in patients who underwent immunotherapy,a new uncommon kind of target lesions behavior was found.This phenomenon is mainly due to the different mechanisms of action of immunotherapeutic drug.Therefore,new groups of response have been described in clinical practice,defined as“atypical responses,”and categorized into three new groups:pseudoprogression,hyperprogression,and dissociated response.This review summarizes and reports these patterns,helping clinicians and radiologists get used to atypical responses,in order to identify patients that respond best to treatment.

A Practical Solution to the Small Sample Size Bias and Uncertainty Problems of Model Selection Criteria in Two-Input Process Multiple Response Surface Methodology Datasets

Multiple response surface methodology (MRSM) most often involves the analysis of small sample size datasets which have associated inherent statistical modeling problems. Firstly, classical model selection criteria in use are very inefficient with small sample size datasets. Secondly, classical model selection criteria have an acknowledged selection uncertainty problem. Finally, there is a credibility problem associated with modeling small sample sizes of the order of most MRSM datasets. This work focuses on determination of a solution to these identified problems. The small sample model selection uncertainty problem is analysed using sixteen model selection criteria and a typical two-input MRSM dataset. Selection of candidate models, for the responses in consideration, is done based on response surface conformity to expectation to deliberately avoid selection of models using the problematic classical model selection criteria. A set of permutations of combinations of response models with conforming response surfaces is determined. Each combination is optimised and results are obtained using overlaying of data matrices. The permutation of results is then averaged to obtain credible results. Thus, a transparent multiple model approach is used to obtain the solution which gives some credibility to the small sample size results of the typical MRSM dataset. The conclusion is that, for a two-input process MRSM problem, conformity of response surfaces can be effectively used to select candidate models and thus the use of the problematic model selection criteria is avoidable.

Comparison of RECIST version 1.0 and 1.1 in assessment of tumor response by computed tomography in advanced gastric cancer

Objective： Response Evaluation Criteria in Solid Tumors （RECIST） guideline version 1.0 （RECIST 1.0） was proposed as a new guideline for evaluating tumor response and has been widely accepted as a standardized measure. With a number of issues being raised on RECIST 1.0, however, a revised RECIST guideline version 1.1 （RECIST 1.1） was proposed by the RECIST Working Group in 2009. This study was conducted to compare CT tumor response based on RECIST 1.1 vs. RECIST 1.0 in patients with advanced gastric cancer （AGC）. Methods： We reviewed 61 AGC patients with measurable diseases by RECIST 1.0 who were enrolled in other clinical trials between 2008 and 2010. These patients were retrospectively re-analyzed to determine the concordance between the two response criteria using the κ statistic. Results： The number and sum of tumor diameters of the target lesions by RECIST 1.1 were significantly lower than those by RECIST 1.0 （P〈0.0001）. However, there was excellent agreement in tumor response between RECIST 1.1 and RECIST 1.0 0（κ=0.844）. The overall response rates （ORRs） according to RECIST 1.0 and RECIST 1.1 were 32.7% （20/61） and 34.5% （20/58）, respectively. One patient with partial response （PR） based on RECIST 1.0 was reclassified as stable disease （SD） by RECIST 1.1. Of two patients with SD by RECIST 1.0, one was downgraded to progressive disease and the other was upgraded to PR by RECIST 1.1. Conclusions： RECIST 1.1 provided almost perfect agreement with RECIST 1.0 in the CT assessment of tumor response of AGC.

Tumor response assessment by the single-lesion measurement per organ in small cell lung cancer

Background： The criterion of two target lesions per organ in the Response Evaluation Criteria in Solid Tumors （RECIST） version I. 1 is an arbitrary one, being supported by no objective evidence. The optimal number of target lesions per organ still needs to be investigated. We compared tumor responses using the RECIST 1.1 （measuring two target lesions per organ） and modified RECIST I. 1 （measuring the single largest lesion in each organ） in patients with small cell lung cancer （SCLC）. Methods： We reviewed medical records of patients with SCLC who received first-line treatment between January 2004 and December 2014 and compared tumor responses according to the two criteria using computed tomography. Results： There were a total of 34 patients who had at least two target lesions in any organ according to the RECIST 1.1 during the study period. The differences in the percentage changes of the sum of tumor measurements between RECIST 1.1 and modified RECIST 1.1 were all within 13%. Seven patients showed complete response and fourteen showed partial response according to the RECIST I.I. The overall response rate was 61.8%. When assessing with the modified RECIST 1.1 instead of the RECIST 1.1, tumor responses showed perfect concordance between the two criteria （k= 1.0）. Conclusions： The modified RECIST 1.I showed perfect agreement with the original RECIST 1.I in the assessment of tumor response of SCLC. Our result suggests that it may be enough to measure the single largest target lesion per organ for evaluating tumor response.

A time-domain nonlinear effective-stress non-Masing approach of ground response analysis of Guwahati city, India

The response of subsoil strata subjected to seismic excitations plays an important role in governing the response of the overlying superstructures at any site. Ground response analysis(GRA) helps to assess the influence of soil characteristics on the propagating seismic stress waves from the bedrock level to the ground surface during an earthquake. For the northeastern region of India, located in the highest seismic zone in the country, conducting an extensive GRA study is of prime importance. Conventionally, most of the GRA studies are carried out using the equivalent linear method, which, being a simplistic approach, cannot capture the nonlinear behavior of soil during seismic shaking. This paper presents the outcomes of a one-dimensional effective stress based nonlinear GRA conducted for Guwahati city(located in northeast India) incorporating the non-Masing load/unload/reload characteristics. The various ground response parameters evaluated from this study help in assessing the ground shaking, soil amplification, and site responses expected in this region. 2D contour maps, which are representative of the distribution of some of these parameters throughout Guwahati city, are also developed. The results presented herein can serve as guidelines for the design of foundations and superstructures in this region.

Radiological response and inflammation scores predict tumour recurrence in patients treated with transarterial chemoembolization before liver transplantation

To investigate the prognostic value of the radiological response after transarterial chemoembolization (TACE) and inflammatory markers in patients affected by hepatocellular carcinoma (HCC) awaiting liver transplantation (LT).METHODSWe retrospectively evaluated the preoperative predictors of HCC recurrence in 70 patients treated with conventional (n = 16) or doxorubicin-eluting bead TACE (n = 54) before LT. The patient and tumour characteristics, including the static and dynamic alpha-fetoprotein, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) measurements, were recorded. Treatment response was classified according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and the European Association for the Study of the Liver (EASL) criteria as complete response (CR), partial response (PR), stable disease or progressive disease. After examination of the explanted livers, histological necrosis was classified as complete (100% of the cumulative tumour area), partial (50%-99%) or minimal (< 50%) and was correlated with the preoperative radiological findings.RESULTSAccording to the pre-TACE radiological evaluation, 22/70 (31.4%) and 12/70 (17.1%) patients were beyond Milan and University of San Francisco (UCSF) criteria, respectively. After TACE procedures, the objective response (CR + PR) rates were 71.4% and 70.0% according to mRECIST and EASL criteria, respectively. The agreement between the two guidelines in defining the radiological response was rated as very good both for the overall and target lesion response (weighted k-value: 0.98 and 0.93, respectively). Complete and partial histological necrosis were achieved in 14/70 (20.0%) and 28/70 (40.0%) patients, respectively. Using histopathology as the reference standard, mRECIST criteria correctly classified necrosis in 72.9% (51/70) of patients and EASL criteria in 68.6% (48/70) of cases. The mRECIST non-response to TACE [Exp(b) = 9.2, p = 0.012], exceeding UCSF criteria before TACE [Exp(b) = 4.7, p = 0.033] and a preoperative PLR > 150 [Exp(b) = 5.9, p = 0.046] were independent predictors of tumour recurrence.CONCLUSIONThe radiological response and inflammatory markers are predictive of tumour recurrence and allow the proper selection of TACE-treated candidates for LT.

Imaging response predictors following drug eluting beads chemoembolization in the neoadjuvant liver transplant treatment of hepatocellular carcinoma

BACKGROUND Drug-eluting bead transarterial chemoembolization(DEB-TACE)is an endovascular treatment to release chemotherapeutic agents within a target lesion,minimizing systemic exposure and adverse effects to chemotherapeutics.Therefore,identifying which patient characteristics may predict imaging response to DEB-TACE can improve treatment results while selecting the best candidates.Predictors of the response after DEB-TACE still have not been fully elucidated.This is the first prospective study performed with standardized DEBTACE technique that aim to identify predictors of radiological response,assessing patients clinical and laboratory characteristics,diagnostic imaging and intraprocedure data of the hepatocellular carcinoma treated in the neoadjuvant context for liver transplantation.AIM To identify pre-and intraoperative clinical and imaging predictors of the radiological response of drug-eluting bead transarterial chemoembolization(DEB-TACE)for the neoadjuvant treatment of hepatocellular carcinoma(HCC).METHODS This is prospective,cohort study,performed in a single transplant center,from 2011 to 2014.Consecutive patients with HCC considered for liver transplant who underwent DEB-TACE in the first session for downstaging or bridging purposes were recruited.Pre and post-chemoembolization imaging studies were performed by computed tomography or magnetic resonance.The radiological response of each individual HCC was evaluated by objective response using mRECIST and the percentage of necrosis.RESULTS Two hundred patients with 380 HCCs were examined.Analysis of the objective response(nodule-based analysis)demonstrated that HCC with pseudocapsules had a 2.01 times greater chance of being responders than those without pseudocapsules(P=0.01),and the addition of every 1mg of chemoembolic agent increased the chance of therapeutic response in 4%(P<0.001).Analysis of the percentage of necrosis through multiple linear regression revealed that the addition of each 1mg of the chemoembolic agent caused an average increase of 0.65%(P<0.001)in necrosis in the treated lesion,whereas the hepatocellular carcinoma with pseudocapsules presented 18.27%(P<0.001)increased necrosis compared to those without pseudocapsules.CONCLUSION The presence of a pseudocapsule and the addition of the amount of chemoembolic agent increases the chance of an objective response in hepatocellular carcinoma and increases the percentage of tumor necrosis following drug-eluting bead chemoembolization in the neoadjuvant treatment,prior to liver transplantation.

Optimized management of advanced hepatocellular carcinoma:Four long-lasting responses to sorafenib

The therapeutic options for hepatocellular carcinoma (HCC) have been so far rather inadequate.Sorafenib has shown an overall survival benefit and has become the new standard of care for advanced HCC.Nevertheless,in clinical practice,some patients are discontinuing this drug because of side effects,and misinterpretation of radiographic response may contribute to this.We highlight the importance of prolonged sorafenib ad-ministration,even at reduced dose,and of qualitative and careful radiographic evaluation.We observed two partial and two complete responses,one histologically confirmed,with progression-free survival ranging from 12 to 62 mo.Three of the responses were achieved following substantial dose reductions,and a gradual change in lesion density preceded or paralleled tumor shrinkage,as seen by computed tomography.This report supports the feasibility of dose adjustments to allow prolonged administration of sorafenib,and highlights the need for new imaging criteria for a more appropriate characterization of response in HCC.

New approaches for precise response evaluation in hepatocellular carcinoma

With the increasing clinical use of cytostatic and novel biologic targeted agents,conventional morphologic tumor burden assessments,including World Health Organization criteria and Response Evaluation Criteria in Solid Tumors,are confronting limitations because of their difficulties in distinguishing viable tumor from necrotic or fibrotic tissue.Therefore,the investigation for reliable quantitative biomarkers of therapeutic response such as metabolic imaging or functional imaging has been desired.In this review,we will discuss the conventional and new approaches to assess tumor burden.Since targeted therapy or locoregional therapies can induce biological changes much earlier than morphological changes,these functional tumor burden analyses are very promising.However,some of them have not gone thorough all steps for standardization and validation.Nevertheless,these new techniques and criteria will play an important role in the cancer management,and provide each patient more tailored therapy.

Objective response rate assessment in oncology: Current situation and future expectations

The tumor objective response rate(ORR)is an important parameter to demonstrate the efficacy of a treatment in oncology.The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials.World Health Organization and Response Evaluation Criteria in Solid Tumors(RECIST)are anatomic response criteria developed mainly for cytotoxic chemotherapy.These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography(CT)or magnetic resonance imaging.Anatomic response criteria may not be optimal for biologic agents,some disease sites,and some regional therapies.Consequently,modifications of RECIST,Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors.Despite its limitations,RECIST v1.1 is validated in prospective studies,is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents.Finally,some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors.Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging.Some graphical methods may be useful to show longitudinal change in the tumor burden over time.Tumor tissue is a tridimensional heterogenous mass,and tumor shrinkage is not always symmetrical;thus,metabolic response assessments using positron emission tomography(PET)or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments.The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage,possibly preventing delays in drug approval.Computer-assisted automated volumetric assessments,quantitative multimodality imaging in radiology,new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients

Sorafenib is an effective anti-angiogenic treatment forhepatocellular carcinoma(HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients,avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume(viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume,density or perfusion. Perfusion computed tomography and Dynamic ContrastEnhanced-UltraS ound can measure the vascularization of HCC lesions and help predict tumor response to antiangiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable,reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue,allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.

RAMAN SPECTROSCOPIC STUDY ON PREDICTION OF TREATMENT RESPONSE IN CERVICAL CANCERS

Concurrent chemoradiotherapy(CCRT)is the choice of treatment for locally adv anced cervical cancers;however,tumors exhibit diverse response to treatment.Early prediction of tumor response leads to individualizing treatment regimen.Response evaluation criteria in solid tumors(RECIST),the current modality of tumor response assessment,is often subject ive and carried out at the first visit after treatment,which is about four months.Hence,there is a need for better predictive tool for radioresponse.Optical spectroscopic techniques,sensitive to molecular alteration,are being pursued as potential diagnostic tools.Present pilot study ains to explore the fiber-optic-based Raman spectroscopy approach in prediction of tumor response to CCRT,before taking up extensive in vivo studies.Ex vivo Raman spectra were acquired from biopsies collected from 11 normal(148 spectra),16 tumor(201 spectra)and 13 complete response(151 CR spectra),one partial response(8 PR spectra)and one nonresponder(8 NR spectra)subjects.Data was analyzed using principal component linear discriminant analysis(PC-LDA)followed by leave-one-out cross-validation(LOO-CV).Findings suggest that normal tissues can be efficiently classified from both pre-and post-treated tumor biopsies,while there is an overlap between pre-and post-CCRT tumor tissues.Spectra of CR,PR and NR tissues were subjected to principal component analysis(PCA)and a tendency of classification was observed,corroborating previous studies.Thus,this study further supports the feasibility of Raman spectroscopy in prediction of tumor radioresponse and prospective noninvasive in vivo applications.

Evaluation of the Reliability Performance of Failure Criteria for Composite Structures

Evolution of materials, following the design requirements of special structures, has shifted interest towards development of composite members able to meet strength requirements “tailored” to specific applications. These members can provide appropriate, more cost effective structures, however absence of generic design guidelines raise constraints towards derivation of optimized structures. Reliability-based assessment can overcome this limitation by ensuring that acceptable levels of target reliability are achieved throughout their service life. This paper presents a methodology for reliability assessment of composite members based on appropriate limit state functions derived according to fundamental failure criteria, Tsai-Hill and Tsai-Wu, applicable to composite materials. The methodology that is proposed employs a Stochastic Response Surface Method (SRSM) which combines in discrete steps FEA modelling, numerical simulations and analytical probabilistic assessment techniques, allowing use of commercial and custom developed specialized numerical tools. Application of the proposed methodology on a complex composite structural geometry will illustrate its efficiency and evaluate the reliability performance of the limit states derived and examined.

杭州湾溶解性无机氮、活性磷酸盐营养物基准研究

制定氮磷营养物基准是预防和控制水体富营养化的重要手段。本研究梳理了2010-2022年杭州湾历史监测数据,通过主成分分析、相关性分析等方法筛选了杭州湾营养物基准关键指标,并综合运用频数分布法、压力-响应模型等方法对指标进行统计分析,推导营养物基准值。结果表明:①溶解性无机氮(DIN)和活性磷酸盐(SPR)是制定杭州湾营养物基准的关键营养物指标,其浓度变化直接影响水体的富营养化程度和生态系统的稳定性;Chla和DO则是关键生物学指标,可用于评价水体健康程度。②由于频数分布法和压力-响应模型法的适用性不同,两种方法推导出的杭州湾营养物基准值存在较大差异,由压力响应模型法得出的营养物基准值比频数分布法高。③根据杭州湾目前的水质状况和富营养化水平,本研究提出杭州湾DIN、SPR的基准值分别为0.732和0.033 mg/L。研究显示,采用多种方法联合推导出的营养物基准值更符合水生态保护的实际需求,本研究结果可为杭州湾水体富营养化控制及营养物标准修订提供科学支撑。

维生素E黏胶/石墨烯锦纶/蚕丝复合功能交织物的制备与研究

高附加值、多功能纺织品成为纺织研究界探索的重要领域。本文通过将蚕丝、维生素E黏胶和石墨烯锦纶进行复合,设计织造了15种织物,对其进行抗氧化性、远红外性能、抗紫外性能与抗静电性能的测试研究。采用响应面分析技术(RSM)研究了投纬比例和组织结构对功能性表达的影响关系,结合模糊多准测决策法(F-MCDM)对最佳工艺参数进行了评估。结果表明:两种纬纱的投纬比和织物组织对织物的功能性表达都有不同程度的影响,且影响是交互的复杂作用。当纬纱中维生素E黏胶和石墨烯锦纶的投纬比为1︰1、织物组织为八枚缎纹时,织物试样的四种功能性表达最好。

基于成长体系的电动汽车充电站需求响应方法研究

随着中国新型电力系统建设的逐步开展,需求响应作为优化电网调控的方式之一,在新型电力系统中得到了广泛的应用。为解决电动汽车充电站对不同类型的电动汽车用户需求响应激励不足的问题,提出了一种基于成长体系的电动汽车充电站需求响应方法。该方法采用电动汽车充电需求和电池退化成本计算电动汽车充电站需求响应成本,通过电动汽车用户需求响应成长值等级激励措施,实现了对不同需求的电动汽车用户需求响应价格的浮动,从而保持了前段电动汽车用户的需求响应活跃度,提升了电动汽车充电站需求响应的盈利能力。在某城市的实例运行表明,相较于多时间尺度随机优化需求响应方法,该方法的利润提高了77.97%。该方法能激励电动汽车参与需求响应,提升电动汽车充电站盈利能力。

Managing immune checkpoint inhibitor-associated gastritis: Insights and strategies

Immune checkpoint inhibitors(ICIs)are widely used due to their effectiveness in treating various tumors.Immune-related adverse events(irAEs)are defined as adverse effects resulting from ICI treatment.Gastrointestinal irAEs are a common type of irAEs characterized by intestinal side effects,such as diarrhea and colitis,which may lead to the discontinuation of ICIs.

爆破地震作用下建(构)筑物安全标准探讨

基于爆破地震效应的2个重要的因素:爆破地震本身的特性和爆破震动作用下建(构)筑物的结构响应特性,运用MATLAB小波分析工具箱的平台,利用现代的信号分析处理手段,从能量的角度出发,研究建(构)筑物在爆破震动作用下的能量响应,推导出响应速度的计算,探讨建立响应速度做为爆破震动安全评价指标。并结合工程实例说明了此方法比振速-频率相关的双因素安全判据更加有效。

区域生态安全评价指标与标准研究

全球范围内 ,生态安全形势越来越严峻 ,局部地区的生态安全态势甚至已经损坏了社会经济与农业生产可持续发展的基础 ,但是从学术层面上区域生态安全研究尚不充分。该文研究建立了区域生态安全评价的指标体系和评价标准 ,并对PSR框架模型作了扩展 ,制定了区域生态安全评价指标体系概念框架 。

全身炎症反应综合征诊断标准的探讨—附1025例分析

目的为探讨全身炎症反应综合征（ＳＩＲＳ）诊断标准与临床应用的可行性。方法将ＡＣＣＰ／ＳＣＭＭ标准做了相应的修订，其中心率＞９０次／ｍｉｎ和呼吸＞２０次／ｍｉｎ，分别修订为心率＞１００次／ｍｉｎ和呼吸＞２２次／ｍｉｎ。分析我院１９９５年１０月～１９９６年７月１０个月１０２５例ＳＩＲＳ的临床资料，病人至少符合修订后２项以上ＳＩＲＳ标准，包括发热、体温过低、心动过速、呼吸急促或白细胞计数异常。结果共观察病人１９０９例，其中１０２５例（５３７％）符合修订后２项或２项以上ＳＩＲＳ标准。１０２５例中符合２项ＳＩＲＳ标准者３８１例（３７２％），３项者３９５例（３８５％），４项者２４９例（２４３％）。１０２５例中死亡１４２例（２３８％），其中符合２项标准者死亡２０例（７８％），３项者死亡５５例（２３９％），４项者死亡５７例（２２９％），病死率随ＳＩＲＳ项数增加而升高，２项与３项、２项与４项、３项与４项比较均相差非常显著（Ｐ＜００１）。死亡者增多并发多器官功能障碍综合征（ＭＯＤＳ），随着病情发展ＳＩＲＳ的项数增加及ＳＩＲＳ发展为ＭＦＤ、ＡＲＤＳ、ＡＲＦ和ＤＩＣ的例数也增加，合并症随ＳＩＲＳ项数增加而升高（Ｐ?