中国抗癌协会胰腺癌整合诊治指南(精简版)

胰腺癌在中国男性恶性肿瘤发病率居第10位,女性居第12位,恶性肿瘤死亡率居第6位。胰腺癌恶性程度高,预后极差。在“整合医学”理念的推动下,中国抗癌协会胰腺癌专业委员会组织相关专家制订指南,旨在以“防-筛-诊-治-康”为基础,全面、全程地指导胰腺癌的整合治疗和康复管理。期望本指南可以为临床医师提供参考意见,从而提高国内胰腺癌患者的治疗效果。

Recent research hotspots in sequencing and the pancreatic neuroendocrine tumor microenvironment

Multiple endocrine neoplasia 1(MEN1)syndrome,a disease arising from a genetic predisposition to tumor development caused by MEN1 loss-of-function mutations,is characterized by the combined occurrence of neuroendocrine tumors in multiple human organs.With advances in diagnostic technologies and improvements in living standards.

Breaking the geometry-performance tradeoff in compressor deviation modeling:Nested principal component analysis

Uncertainties in the aerodynamic performance of compressors,introduced by manufacturing variations,have received more and more attentions in recent years.The deviation model plays a crucial role in evaluating this uncertainty and facilitating robust design.However,current deviation models with a few variables cannot simultaneously achieve a precise geometric approximation of deviation and provide an accurate assessment of performance uncertainty.This paper introduces a novel deviation modeling method named Nested Principal Component Analysis(NPCA)to break this tradeoff.In this method,both geometry-based and performance-based modes are utilized to describe manufacturing variations.By considering aerodynamic sensitivity,surface deformations that significantly impact aerodynamic performance can be extracted for deviation modeling.To demonstrate the superiority of this newly proposed method,ninety-eight newly manufactured compressor rotor blades were measured using a coordinate measurement machine,and both NPCA and Principal Component Analysis(PCA)were employed to model the real manufacturing variations.The results indicate that,in comparison to the PCA method,the NPCA method achieves an equivalent level of accuracy in geometric reconstruction and evaluation of mean performance.Furthermore,the same level of accuracy can be obtained with eight NPCA modes and fifty PCA modes when assessing the scatter in aerodynamic performance.Finally,the working mechanism of the NPCA method for accurate uncertainty quantification was further investigated.

Development of a deviation package method for low-cost robust optimization in compressor blade design

Manufacture variations can greatly increase the performance variability of compressor blades. Current robust design optimization methods have a critical role in reducing the adverse impact of the variations, but can be affected by errors if the assumptions of the deviation models and distribution parameters are inaccurate. A new approach for robust design optimization without the employment of the deviation models is proposed. The deviation package method and the interval estimation method are exploited in this new approach. Simultaneously, a stratified strategy is used to reduce the computational cost and assure the optimization accuracy. The test case employed for this study is a typical transonic compressor blade profile, which resembles most of the manufacture features of modern compressor blades. A set of 96 newly manufactured blades was measured using a coordinate measurement machine to obtain the manufacture variations and produce a deviation package. The optimization results show that the scatter of the aerodynamic performance for the optimal robust design is 20% less than the baseline value. By comparing the optimization results obtained from the deviation package method with those obtained from widely-used methods employing the deviation model, the efficiency and accuracy of the deviation package method are demonstrated. Finally, the physical mechanisms that control the robustness of different designs were further investigated, and some statistical laws of robust design were extracted.

Multifunctional RGD coated a single-atom iron nanozyme:A highly selective approach to inducing ferroptosis and enhancing immunotherapy for pancreatic cancer

Nanozyme is a new promising approach to cancer therapy for its ability to induce ferroptosis by activating H_(2)O_(2)via a traditional radical pathway and enhance cancer immunotherapy.However,short half-life period of hydroxyl radical(·OH)results in unsatisfied effectiveness.Herein,we synthesized a single-atom iron nanozyme(Fe-SAzyme),which can activate H_(2)O_(2)via a non-radical pathway to generate Fe-based reactive oxygen species(ROS)(O=FeO_(3)=O)for promoting the ferroptosis of pancreatic cancer cells.This Fe-SAzyme could be specifically phagocytosed by pancreatic cancer cells,increasing ROS levels and inhibiting glutathione(GSH)synthesis,which activates ferroptosis.Tumor magnetic resonance imaging(MRI)showed decreased T2 signal after intravenous injection of RGD@Fe-AC(AC=activated carbon).Moreover,RGD@Fe-AC promoted dendritic cell(DC)maturation,overcame Treg-mediated immunosuppression,activated T cells to trigger adaptive immune responses,and enhanced the efficacy ofα-PD-L1 immunotherapy.Our research demonstrated that RGD@Fe-AC provided a straightforward,easily implemented,and selective approach for pancreatic cancer treatment and immunotherapy.

New insights into component matching mechanism in the compression system of double bypass engine

Variable cycle engine(VCE)is one of the most promising technologies for the next-generation aircraft,the matching of different components in the compression system is a key difficulty VCE faced.To investigate the component matching mechanisms in the VCE compression system,an advanced throughflow program is employed to calculate the characteristic lines of each component,and a zero-dimensional method is developed to cap-ture the component performance deviation during the coupling working process.By setting the compressor stall and choke conditions as the boundary,the operation range of the compression system isfirst clarified,and the aerodynamic performance in the operation zone is discussed,thus providing a theoretical basis for optimization of the engine operating con-trol scheme.Results show that the efficiency of the coreflow is optimum at the left-bottom corner of the operation region,while the total pressure ratio peaks at the right-top area,hence a balance is needed when deciding the matching point.Regulations of component control pa-rameters will change the position of the operation zone,as well as the corresponding aerody-namic performance.Decreasing the core driven fan stage rotating speed can improve the total bypass ratio,yet the total pressure ratio of the coreflow will be decreased.Closing the core driven fan stage inlet guide vane can increase the total bypass ratio without changing the core flow aerodynamic performance significantly.The bypass ratio of the compression system can also be increased by increasing the fan stall margin or decreasing its rotating speed,both ways will decrease the total pressure ratio of the core flow.Results of the study will benefit the variable cycle engine design process in operation point evaluation and thermodynamic cycle optimization.

Consensus on the clinical diagnosis and treatment of grade 3 pancreatic neuroendocrine tumors

The World Health Organization(WHO)2017 classifications for neuroendocrine neoplasms(NENs)subdivided grade 3 pancreatic neuroendocrine neoplasms(pNENs)into G3 well-differentiated pancreatic neuroendocrine tumors(G3 pNETs)and poorly differentiated pancreatic neuroendocrine carcinomas(pNECs),according to the mitotic count,Ki-67 index,and cell differentiation.As a new category,G3 pNETs remain a challenging group of tumors to manage by lacking large randomized trials and consensus to support its clinical practice.Therefore,the Chinese Pancreatic Surgery Association,Chinese Society of Surgery,Chinese Medical Association gathered experts in this field to formulate this consensus for the diagnosis and treatment of G3 pNETs.

International expert consensus on laparoscopic pancreaticoduodenectomy

Importance:While laparoscopic pancreaticoduodenectomy(LPD)is being adopted with increasing enthusiasm worldwide,it is still challenging for both technical and anatomical reasons.Currently,there is no consensus on the technical standards for LPD.Objective:The aim of this consensus statement is to guide the continued safe progression and adoption of LPD.Evidence Review:An international panel of experts was selected based on their clinical and scientific expertise in laparoscopic and open pancreaticoduodenectomy.Statements were produced upon reviewing the literature and assessed by the members of the expert panel.The literature search and its critical appraisal were limited to articles published in English during the period from 1994 to 2019.The Web of Science,Medline,and Cochrane Library and Clinical Trials databases were searched,The search strategy included,but was not limited to,the terms'laparoscopic','pancreaticoduodenectomy,'pancreatoduodenectomy','Whipple's operation',and'minimally invasive surgery'.Reference lists from the included articles were manually checked for any additional studies,which were included when appropriate.Delphi method was used to establish expert consensus and the AGREE II-GRS Instrument was applied to assess the methodological quality and externally validate the final statements.The statements were further discussed during a one-day face-to-face meeting at the 1st Summit on Minimally Invasive Pancreatico-Biliary Surgery in Wuhan,China.Findings:Twenty-eight international experts from 8 countries constructed the expert panel.Sixteen statements were produced by the members of the expert panel.At least 80%of responders agreed with the majority(80%)of statements.Other than three randomized controlled trials published to date,most evidences were based on level 3 or 4 studies according to the AGREE II-GRS Instrument.Conclusions and Relevance:The Wuhan international expert consensus meeting on LPD has produced a set of clinical practice statements for the safe development and progression of LPD.LPD is currently in its development and exploration stages,as defined by the international IDEAL framework for surgical innovation.More robust randomized controlled trial and registry study are essential to proceed with the assessment of LPD.

Nonlinear uncertainty quantification of the impact of geometric variability on compressor performance using an adjoint method

Manufactured blades are inevitably different from their design intent,which leads to a deviation of the performance from the intended value.To quantify the associated performance uncertainty,many approaches have been developed.The traditional Monte Carlo method based on a Computational Fluid Dynamics solver(MC-CFD)for a three-dimensional compressor is prohibitively expensive.Existing alternatives to the MC-CFD,such as surrogate models and secondorder derivatives based on the adjoint method,can greatly reduce the computational cost.Nevertheless,they will encounter’the curse of dimensionality’except for the linear model based on the adjoint gradient(called MC-adj-linear).However,the MC-adj-linear model neglects the nonlinearity of the performance function.In this work,an improved method is proposed to circumvent the lowaccuracy problem of the MC-adj-linear without incurring the high cost of other alternative models.The method is applied to the study of the aerodynamic performance of an annular transonic compressor cascade,subject to prescribed geometric variability with industrial relevance.It is found that the proposed method achieves a significant accuracy improvement over the MC-adj-linear with low computational cost,showing the great potential for fast uncertainty quantification.

Signaling pathways in cancer-associated fibroblasts:recent advances and future perspectives

As a critical component of the tumor microenvironment(TME),cancerassociated fibroblasts(CAFs)play important roles in cancer initiation and progression.Well-known signaling pathways,including the transforming growth factor-β(TGF-β),Hedgehog(Hh),Notch,Wnt,Hippo,nuclear factor kappa-B(NF-κB),Janus kinase(JAK)/signal transducer and activator of transcription(STAT),mitogen-activated protein kinase(MAPK),and phosphoinositide 3-kinase(PI3K)/AKT pathways,as well as transcription factors,including hypoxia-inducible factor(HIF),heat shock transcription factor 1(HSF1),P53,Snail,and Twist,constitute complex regulatory networks in theTMEtomodulate the formation,activation,heterogeneity,metabolic characteristics and malignant phenotype of CAFs.Activated CAFs remodel the TME and influence the malignant biological processes of cancer cells by altering the transcriptional and secretory characteristics,and this modulation partially depends on the regulation of signaling cascades.The results of preclinical and clinical trials indicated that therapies targeting signaling pathways in CAFs demonstrated promising efficacy but were also accompanied by some failures(e.g.,NCT01130142 and NCT01064622).Hence,a comprehensive understanding of the signaling cascades in CAFs might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the development of more efficient and safer stroma-targeted cancer therapies.Here,we review recent advances in studies of signaling pathways in CAFs and briefly discuss some future perspectives on CAF research.

Using tandem blades to break loading limit of highly loaded axial compressors

It is confirmed that tandem-blade configurations have potential to enlarge the flow turning in two-dimension(2D) studies. However, the potential of tandem blades to enlarge the design space for highly loaded axial compressors was rarely investigated in open literatures. The present work aims to show the capability of tandem blades to break the loading limit of conventional blades for highly loaded compressors. The 2D models of the maximum static pressure rise derived in previous work were validated by a large amount experimental data, which showed a good agreement. An E parameter was defined to evaluate the stall margin of compressor based on the theoretical models, which indicated that the tandem blade was able to increase the loading limit of axial compressors. A single-blade stage with a loading coefficient of 0.46(based on the blade tip rotating speed) was designed as the baseline case under the guidance of the E parameter. A tandem-blade stage was then designed by ensuring that the velocity triangles were similar to the single-blade stage. The performances of both stages were investigated experimentally. The results showed that the maximum efficiency of the tandem-blade stage was 92.8%, 1% higher than the single;the stall margin increased from 16.9% to 22.3%. Besides, the maximum pressure rise of tandem rotors was beyond the loading limit of 2D single-blade cascades, which confirmed the potential of tandem blades to break the loading limit of axial compressors.

Standard pancreatoduodenectomy versus extended pancreatoduodenectomy with modified retroperitoneal nerve resection in patients with pancreatic head cancer:a multicenter randomized controlled trial

Background:The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial,and more high-level clinical evidence is needed.This study aimed to evaluate the outcome of extended pancreatoduodenectomy(EPD)with retroperitoneal nerve resection in pancreatic head cancer.Methods:This multicenter randomized trial was performed at 6 Chinese highvolume hospitals that enrolled patients between October 3,2012,and September 21,2017.Four hundred patients with stage I or II pancreatic head cancer and without specific pancreatic cancer treatments(preoperative chemotherapy or chemoradiation)within three months were randomly assigned to undergo standard pancreatoduodenectomy(SPD)or EPD,with the latter followed by dissection of additional lymph nodes(LNs),nerves and soft tissues 270◦on the right side surrounding the superior mesenteric artery and celiac axis.The primary endpoint was overall survival(OS)by intention-to-treat(ITT).The secondary endpoints were disease-free survival(DFS),mortality,morbidity,and postoperative pain intensity.Results:TheR1 ratewas slightly lower with EPD(8.46%)thanwith SPD(12.56%).The morbidity and mortality rates were similar between the two groups.The median OS was similar in the EPD and SPD groups by ITT in the whole study cohort(23.0 vs.20.2 months,P=0.100),while the median DFS was superior in the EPD group(16.1 vs.13.2 months,P=0.031).Patients with preoperative CA19–9<200.0 U/mL had significantly improved OS and DFS with EPD(EPD vs.SPD,30.8 vs.20.9 months,P=0.009;23.4 vs.13.5 months,P<0.001).The EPD group exhibited significantly lower locoregional(16.48%vs.35.20%,P<0.001)andmesenteric LNrecurrence rates(3.98%vs.10.06%,P=0.022).The EPD group exhibited less back pain 6 months postoperation than the SPD group.Conclusions:EPD for pancreatic head cancer did not significantly improve OS,but patients with EPD treatment had significantly improved DFS.In the subgroup analysis,improvements in bothOS and DFS in the EPD armwere observed in patients with preoperative CA19–9<200.0 U/mL.EPD could be used as an effective surgical procedure for patients with pancreatic head cancer,especially those with preoperative CA19–9<200.0 U/mL.

Epigenetic regulation in the tumor microenvironment:molecular mechanisms and therapeutic targets

Over decades,researchers have focused on the epigenetic control of DNA-templated processes.Histone modification,DNA methylation,chromatin remodeling,RNA modification,and noncoding RNAs modulate many biological processes that are crucial to the development of cancers.Dysregulation of the epigenome drives aberrant transcriptional programs.A growing body of evidence suggests that the mechanisms of epigenetic modification are dysregulated in human cancers and might be excellent targets for tumor treatment.Epigenetics has also been shown to influence tumor immunogenicity and immune cells involved in antitumor responses.Thus,the development and application of epigenetic therapy and cancer immunotherapy and their combinations may have important implications for cancer treatment.Here,we present an up-to-date and thorough description of how epigenetic modifications in tumor cells influence immune cell responses in the tumor microenvironment(TME)and how epigenetics influence immune cells internally to modify the TME.Additionally,we highlight the therapeutic potential of targeting epigenetic regulators for cancer immunotherapy.Harnessing the complex interplay between epigenetics and cancer immunology to develop therapeutics that combine thereof is challenging but could yield significant benefits.The purpose of this review is to assist researchers in understanding how epigenetics impact immune responses in the TME,so that better cancer immunotherapies can be developed.

Liquid-liquid phase separation in tumor biology

Liquid–liquid phase separation(LLPS)is a novel principle for explaining the precise spatial and temporal regulation in living cells.LLPS compartmentalizes proteins and nucleic acids into micron-scale,liquid-like,membraneless bodies with specific functions,which were recently termed biomolecular condensates.Biomolecular condensates are executors underlying the intracellular spatiotemporal coordination of various biological activities,including chromatin organization,genomic stability,DNA damage response and repair,transcription,and signal transduction.Dysregulation of these cellular processes is a key event in the initiation and/or evolution of cancer,and emerging evidence has linked the formation and regulation of LLPS to malignant transformations in tumor biology.In this review,we comprehensively summarize the detailed mechanisms of biomolecular condensate formation and biophysical function and review the recent major advances toward elucidating the multiple mechanisms involved in cancer cell pathology driven by aberrant LLPS.In addition,we discuss the therapeutic perspectives of LLPS in cancer research and the most recently developed drug candidates targeting LLPS modulation that can be used to combat tumorigenesis.

^99Tc^m-HYNIC-TOC SPECT/CT显像在胰腺神经内分泌肿瘤患者诊断和随访中的临床应用

目的确定^99Tc^m-联肼尼克酰胺(HYNIC)-酪氨酸3-奥曲肽(TOC)SPECT/CT显像在疑似神经内分泌肿瘤的胰腺肿块评价及胰腺神经内分泌肿瘤患者随访中的价值。方法回顾性分析了184例行^99Tc^m-HYNIC-TOCSPECT/CT显像的患者。所有患者分为2组,组1评价该显像对胰腺可疑肿块的诊断效能(n=140),组2术后随访是否有复发及转移(n=44)。比较注射显像剂后2h的显像结果与最终病理诊断结果及临床随访结果,随后分析肿瘤与本底的比值(TBR)和肿瘤分级的关系。结果组1中,67.9%(95/140)的患者诊断为神经内分泌肿瘤,包括85例神经内分泌瘤和10例神经内分泌癌。^99Tc^m-HYNIC-TOCSPECT/CT显像诊断神经内分泌肿瘤的灵敏度、特异性和准确性分别为81.1%、84.4%和82.1%。

Guidelines for the diagnosis and treatment of acute pancreatitis in China (2021)

Acute pancreatitis(AP)is a common acute abdominal condition of the digestive system.In recent years,treatment concepts,methods,and strategies for the diagnosis of AP have advanced,and this has played an important role in promoting the standardization of AP diagnosis and treatment and improving the treatment quality of AP patients.On the basis of previous guidelines and expert consensus,this guideline adopts an evidence-based,problem-based expression;synthesizes important clinical research data at home and abroad in the most recent 5 years;and forms 29 recommendations through multidisciplinary expert discussion,including diagnosis,treatment,and follow-up.It is expected to provide evidence support for the treatment of AP in the clinical setting in China.

Numerical and experimental study of bleed impact in multistage axial compressors

In this study,the influence of inter-stage bleeding on the compressor performance and inter-stage flow field of a multistage axial compressor is investigated by both experimental and numerical methods.The experiment is conducted on a four-stage low-speed axial compressor,and a specific computational model is built to simulate the experiment environment accurately.To illuminate the fluid mechanisms of bleeding effect in detail,both the experiment and the simulation are carried out twice,i.e.,in the first time,the mass flow rate upstream the bleed location is constant under different bleed rate conditions;while in the second time,the mass flow rate downstream the bleed location is constant under different bleed rate conditions.The results demonstrate that inter-stage bleeding has little influence on upstream compressor characteristics,and affects the upstream flow field only in the rear half of the stator.The bleed effect on the downstream flow field is embodied in the variation of an incoming flow profile,an increase as the compressor inlet flow coefficient decreases.Therefore,such an effect is only significant on compressor characteristics at small flow coefficient conditions.In multistage compressors,the variation of compressor characteristics and flow field caused by inter-stage bleeding is the comprehensive result of the bleeding and the variation of the upstream working condition.In addition,the comparison between numerical and experimental results shows that the flow moves towards top half of span through the downstream rotor passage in the numerical simulation,whereas the trend of flow field variation with different bleed rates at the outlet of the downstream rotor and stator is the same with that at the inlet of the downstream rotor in the experiment,which means that the numerical method has overestimated the radial mixing intensity of the flow.

Guidelines for the diagnosis and treatment of pancreatic cancer in China (2021)

The incidence of pancreatic cancer has been rising worldwide,and its clinical diagnosis and treatment remain a great challenge.To present the update and improvements in the clinical diagnosis and treatment of pancreatic cancer in recent years,Chinese Pancreatic Association,the Chinese Society of Surgery,Chinese Medical Association revised the Guidelines for the Diagnosis and Treatment of Pancreatic Cancer in China(2014)after reviewing evidence-based and problem-oriented literature published during 2015-2021,mainly focusing on highlight issues regarding diagnosis and surgical treatment of pancreatic cancer,conversion strategies for locally advanced pancreatic cancer,treatment of pancreatic cancer with oligo metastasis,adjuvant and neoadjuvant therapy,standardized processing of surgical specimens and evaluation of surgical margin status,systemic treatment for unresectable pancreatic cancer,genetic testing,as well as postoperative follow up of patients with pancreatic cancer.Forty recommendation items were finally proposed based on the above issues,and the quality of evidence and strength of recommendations were graded using the Grades of Recommendation,Assessment,Development,and Evaluation system.This guideline aims to standardize the clinical diagnosis and therapy,especially surgical treatment of pancreatic cancer in China,and further improve the prognosis of patients with pancreatic cancer.

The current surgical treatment of pancreatic neuroendocrine neoplasms in China: a national wide cross-sectional study

Objective:The aim of this study is to investigate the current status of the diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms(pNENs)undergoing surgery in China.Methods:This is a multicenter cross-sectional study performed in China.Data from patients with pNENs undergoing surgery at 33 high-volume medical centers,where the number of pancreatectomies exceeds 20 cases per year,were collected and analyzed between March 1,2016 and February 28,2017.Results:In total,392 patients with pNENs were enrolled.The male to female ratio was 1.4.The majority of patients were aged between 40 and 70 years.65.6%of the patients had non-functional tumors.Among those with functional tumors,the percentages of insulinomas,gastrinomas,glucagonomas,and vasoactive intestinal peptide-secreting tumors were 94.8%,1.5%,2.2%,and 1.5%,respectively.Multidisciplinary team(MDT)discussion was conducted for 39.0%of the patients.Minimally invasive surgery was performed on 31.1%of the 392 patients.The incidence of grade B/C pancreatic fistula formation was 4.4%.A total of 89.0%of the surgeries achieved R0 resection,and 41.6%of the tumors were well differentiated.Lymph node metastasis was present in 8.9%of the patients.The percentages of patients with grades G1,G2,and G3 disease were 49.2%,45.7%,and 5.1%,respectively.Conclusion:This multicenter cross-sectional study systematically presents the current status of the diagnosis and treatment of patients with pNENs undergoing surgery in China.MDT consultation for pNENs has not been widely implemented in China.Although the incidence of surgical complications is relatively low,minimally invasive procedures should be further promoted.This study shows us how to improve the outcomes of these patients.

The current surgical treatment of pancreatic cancer in China: a national wide cross-sectional study

Objective: The aim of this study is to investigate the current status of pancreatic cancer patients undoing surgical treatment in China and to find ways to improve the survival of these patients in the future. Methods: This study is a national, multicenter, cross-sectional study in China. Information regarding pancreatic cancer patients undergoing surgical treatment from 34 high-volume tertiary IIIA level hospitals was collected and analyzed from the March 1, 2016 to the February 28, 2017. Results: In total, 2200 pancreatic cancer patients were enrolled from 34 tertiary IIIA level hospitals in 16 provinces across China. The male-to-female ratio was 1.5. More than 80% of the patients were between 50 and 70 years old. The top 4 symptoms were epigastric discomfort, abdominal pain, jaundice, and weight loss. Carbohydrate antigen 19-9 and carcinoembryonic antigen were elevated in 70.9% and 27.1% of patients, respectively. A multidisciplinary team (MDT) discussion was carried out for 35.0% of patients before surgery. The proportion of minimally invasive pancreatic surgeries was approximately 20%. A total of 83.4% of the operations achieved R0 resection, and the incidence of grade 3/4 postoperative complications was 7.7%. Only 13.4% of the patients received postoperative adjuvant chemotherapy. The percentage of pathological stage I tumors was only 24.5%. Conclusion: The majority of pancreatic cancer patients undergoing surgical resection in China are in an advanced stage. The MDT consultations for pancreatic cancer have not been widely carried out. R0 resection has been achieved in most cases, with relatively low incidence of serious complications, but minimally invasive pancreatic surgery should be further promoted. The application of postoperative chemotherapy remains low. This national, multicentre, cross-sectional study comprehensively presents the current status of pancreatic cancer patients undergoing surgical treatment and shows the road to improve survival of these patients in the future.