2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Expert Consensus on Clinical Management of T2DM Combined with Obesity Reversal Treatment in China(2023 Edition)

With lifestyle changes,the incidence of type 2 diabetes(T2DM)and obesity has significantly increased,becoming major chronic diseases that seriously threaten the health of China’s residents.Both domestic and international guidelines and consensus exist regarding the diagnosis and management of this disease.In recent years,T2DM treatment has focused more on new tactics that lean towards a patient-centered comprehensive management approach,replacing the traditional glucose-centered approach.Additionally,an increasing amount of evidence in medicine suggests that the reversal of diabetes is possible.However,there is currently no expert consensus on the clinical management of T2DM combined with obesity reversal treatment.Therefore,experts and scholars in China with extensive experience in T2DM combined with obesity reversal treatment have been invited to develop this consensus.The content includes early identification and diagnosis of T2DM combined with obesity,definition and mechanisms of diabetes reversal,disease assessment and grading,staging of diabetes and goals of reversal,the 2+N reversal strategy,inpatient system treatment combined with comprehensive outpatient management(including weight control,precise nutrition,scientific exercise,glucose-lowering medication,psychological intervention,rehabilitation therapy,and remote follow-up through online platforms),and evaluation of post-reversal efficacy.The aim is to further improve the level of T2DM combined with obesity reversal diagnosis,treatment,and management in China,and to implement the Healthy China strategy.

Impaired motor control after sport-related concussion could increase risk for musculoskeletal injury:Implications for clinical management and rehabilitation

This review presents a conceptual framework and supporting evidence that links impaired motor control after sport-related concussion(SRC)to increased risk for musculoskeletal injury.Multiple studies have found that athletes who are post-SRC have higher risk for musculoskeletal injury compared to their counterparts.A small body of research suggests that impairments in motor control are associated with musculoskeletal injury risk.Motor control involves the perception and processing of sensory information and subsequent coordination of motor output within the central nervous system to perform a motor task.Motor control is inclusive of motor planning and motor learning.If sensory information is not accurately perceived or there is interference with sensory information processing and cognition,motor function will be altered,and an athlete may become vulnerable to injury during sport participation.Athletes with SRC show neuroanatomic and neurophysiological changes relevant to motor control even after meeting return to sport criteria,including a normal neurological examination,resolution of symptoms,and return to baseline function on traditional concussion testing.In conjunction,altered motor function is demonstrated after SRC in muscle activation and force production,movement patterns,balance/postural stability,and motor task performance,especially performance of a motor task paired with a cognitive task(i.e.,dual-task condition).The clinical implications of this conceptual framework include a need to intentionally address motor control impairments after SRC to mitigate musculoskeletal injury risk and to monitor motor control as the athlete progresses through the return to sport continuum.

Atrial fibrillation:mechanism and clinical management

Atrial fibrillation(AF),the most common sustained arrhythmia,is associated with a range of symptoms,including palpitations,cognitive impairment,systemic embolism,and increased mortality.It places a significant burden on healthcare systems worldwide.Despite decades of research,the precise mechanisms underlying AF remain elusive.Current understanding suggests that factors like stretch-induced fibrosis,epicardial adipose tissue(EAT),chronic inflammation,autonomic nervous system(ANS)imbalances,and genetic mutations all play significant roles in its development.In recent years,the advent of wearable devices has revolutionized AF diagnosis,enabling timely detection and monitoring.However,balancing early diagnosis with efficient resource utilization presents new challenges for healthcare providers.AF management primarily focuses on stroke prevention and symptom alleviation.Patients at high risk of thromboembolism require anticoagulation therapy,and emerging pipeline drugs,particularly factor XI inhibitors,hold promise for achieving effective anticoagulation with reduced bleeding risks.The scope of indications for catheter ablation in AF has expanded significantly.Pulsed field ablation,as a novel energy source,shows potential for improving success rates while ensuring safety.This review integrates existing knowledge and ongoing research on AF pathophysiology and clinical management,with emphasis on diagnostic devices,next-generation anticoagulants,drugs targeting underlying mechanisms,and interventional therapies.It offers a comprehensive mosaic of AF,providing insights into its complexities.

Risk factors for postoperative recurrence of cardiac myxoma and the clinical managements： a report of 5 cases in one center and review of literature

Background Recurrence or metastasis of myxomas is not rare risk factors for postoperative cardiac myxoma recurrence and to classification. and can lead to malignancy. We aimed to analyze the summarize its clinical characteristics, treatments and Methods The clinical data of 5 patients with recurrent cardiac myxoma were retrospectively analyzed and our clinical experience was summarized. Moreover, the relevant literatures were reviewed. Results All the five cases of primary myxomas were derived from atypical positions. One patient had early distant metastasis, one had family history, and two suffered malignant recurrence. The recurrence interval was （2.30＋2.16） years and the recurrent tumors were all found in different chambers from those of the corresponding primary tumors. Re-operation was performed after recurrence. One patient died of heart failure after malignant recurrence, and the other 4 cases had satisfactory therapeutic outcomes after re-operations. Our experience advocated a clinical classification of ＂typical＂ and ＂atypical＂ cardiac myxoma, the typical myxomas referred to the tumors locating at the left atria, with single pedicle, rooted at or around the fossa ovalis, involving no genetic causes, and the atypical myxomas included the familial tumors, tumors stemming from multiple chambers, rooted in abnormal positions of the left atrium, with evident genetic mutation, or with malignant tendency.

The influence of ^(18)F-fluorodeoxyglucose positron emission tomography/computed tomography on the N-and M-staging and subsequent clinical management of intrahepatic cholangiocarcinoma

Background:Intrahepatic cholangiocarcinoma(ICC)is a highly metastatic cancer.^(18)F-fluorodeoxyglucose positron emission tomography/computed tomography(^(18)F-FDG PET/CT)enables sensitive tumor and metastasis detection.Our aim is to evaluate the influence of pre-treatment PET/CT on the N-and M-staging and subsequent clinical management in ICC patients.Methods:Between August 2010 and August 2018,660 consecutive ICC patients,without prior anti-tumor treatments nor other malignancies,were enrolled.The diagnostic performance of PET/CT on the N-and M-staging was compared with conventional imaging,and the preoperative staging accuracy and treatment re-allocation by PET/CT were retrospectively calculated.Survival difference was compared between patients receiving PET/CT or not after propensity score matching.Results:Patients were divided into group A(n=291)and group B(n=369)according to whether PET/CT was performed.Among 291 patients with both PET/CT and conventional imaging for staging in group A,PET/CT showed significantly higher sensitivity(83.0%vs.70.5%,P=0.001),specificity(88.3%vs.74.9%,P<0.001)and accuracy(86.3%vs.73.2%,P<0.001)than conventional imaging in diagnosing regional lymph node metastasis,as well as higher sensitivity(87.8%vs.67.6%,P<0.001)and accuracy(93.5%vs.89.3%,P=0.023)in diagnosing distant metastasis.Overall,PET/CT improved the accuracy of preoperative staging from 60.1%to 71.8%(P<0.001),and modified clinical treatment strategy in 5.8%(17/291)of ICC patients,with unique roles in different tumor-node-metastasis(TNM)stages.High tumor-to-non-tumor ratio(TNR)predicted poor overall survival[hazard ratio(HR)=2.17;95%confidence interval(CI):1.49-3.15;P<0.001].Furthermore,patients performing PET/CT had longer overall survival compared with those without PET/CT(HR=0.74;95%CI:0.58-0.93;P=0.011)after propensity score matching.Conclusions:PET/CT was valuable for diagnosing regional lymph node metastasis and distant metastasis in ICC patients,and facilitated accurate tumor staging and optimal treatment allocation.

Diagnosis and Management of Obesity: A Joint Statement by Practicing Endocrinologists

Obesity is not always recognized as a primary disease, leading to shortage of insurance coverage, clear dispositions about therapeutic strategies, prevention programs and legislation. Worldwide, physicians face the challenge to design affordable and effective treatments against obesity, to improve patient health and wellbeing and reduce the burden on healthcare systems. While international guidelines for obesity management are available, straightforward recommendations applicable in developing countries are needed. In order to develop local consensus recommendations, a panel of endocrinologists with experience in overweight and obesity convened and provided opinions about obesity aetiology, diagnosis, and management, in a structured discussion. Opinions were then developed into recommendations. There was unanimous agreement on recognizing obesity as a disease, which could be diagnosed by any trained physician and best managed by endocrinologists or obesity-trained physicians. The panel reiterated that lifestyle and behaviour changes remain the cornerstone of treatment;underscoring, however, the need for pharmacotherapy or bariatric surgery in some cases. They also identified stakeholders in the fight against obesity (ministries, third-party payers, healthcare providers and others). The establishment of an obesity registry was encouraged, which will pave the way for enhanced obesity research and prevention programs. These recommendations, endorsed by the World Obesity Federation, would be of interest to clinicians worldwide. .

Advances in Zika virus vaccines and therapeutics:A systematic review

Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.

Diabetic foot ulcers:Classification,risk factors and management

Diabetic foot ulceration is a devastating complication of diabetes that is associated with infection,amputation,and death,and is affecting increasing numbers of patients with diabetes mellitus.The pathogenesis of foot ulcers is complex,and different factors play major roles in different stages.The refractory nature of foot ulcer is reflected in that even after healing there is still a high recurrence rate and amputation rate,which means that management and nursing plans need to be considered carefully.The importance of establishment of measures for prevention and management of DFU has been emphasized.Therefore,a validated and appropriate DFU classification matching the progression is necessary for clinical diagnosis and management.In the first part of this review,we list several commonly used classification systems and describe their application conditions,scope,strengths,and limitations;in the second part,we briefly introduce the common risk factors for DFU,such as neuropathy,peripheral artery disease,foot deformities,diabetes complications,and obesity.Focusing on the relationship between the risk factors and DFU progression may facilitate prevention and timely management;in the last part,we emphasize the importance of preventive education,characterize several of the most frequently used management approaches,including glycemic control,exercise,offloading,and infection control,and call for taking into account and weighing the quality of life during the formulation of treatment plans.Multidisciplinary intervention and management of diabetic foot ulcers(DFUs)based on the effective and systematic combination of these three components will contribute to the prevention and treatment of DFUs,and improve their prognosis.

Multiorgan dysfunction syndrome due to high-dose cantharidin poisoning:A case report

BACKGROUND This report delves into the diagnostic and therapeutic journey undertaken by a patient with high-dose cantharidin poisoning and multiorgan dysfunction syndrome(MODS).Particular emphasis is placed on the comprehensive elucidation of the clinical manifestations of high-dose cantharidin poisoning,the intricate path to diagnosis,and the exploration of potential underlying mechanisms.CASE SUMMARY A patient taking 10 g of cantharidin powder orally subsequently developed MODS.The patient was treated with supportive care,fluid hydration and antibiotics,and hemoperfusion and hemofiltration therapy for 24 h and successfully recovered 8 d after hospital admission.Cantharidin poisoning can cause lifethreatening MODS and is rare clinically.This case underscores the challenge in diagnosis and highlights the need for early clinical differentiation to facilitate accurate assessment and prompt intervention.CONCLUSION This article has reported and analyzed the clinical data,diagnosis,treatment,and prognosis of a case of high-dose cantharidin poisoning resulting in MODS and reviewed the relevant literature to improve the clinical understanding of this rare condition.

Ferric carboxymaltose for anemia in Crohn’s disease patients at a tertiary center:A retrospective observational cohort study

BACKGROUND Although the gastrointestinal tract is the most affected by Crohn’s disease(CD),the condition triggers other consequent manifestations,and iron deficiency anemia(IDA)is one of the most common.Intravenous(IV)iron replacement is currently available through several drugs,such as ferric hydroxide sucrose and ferric carboxymaltose(FCM).However,the clinical management of these conditions can be challenging.AIM To elucidate the drug’s effectiveness,the present study analyzed,through medical records,the clinical and epidemiological data of a cohort of patients with active CD who received IV FCM for the IDA treatment.METHODS This retrospective observational study included 25 patients with active CD,severe anemia,and refractory to previous conventional treatments.Patients were evaluated two times:During the last treatment with ferric hydroxide sucrose and treatment with FCM.RESULTS After treatment with FCM,parameters of IDA assessment significantly improved,serum hemoglobin(Hb)levels increased in 93%of patients(P<0.0001),and in 44%,there was an increase of≥2 g/dL in a single application.In addition,86%of the patients showed an increase in serum iron(P<0.0001)and ferritin(P=0.0008)and 50%in transferrin saturation(P=0.01).The serum iron levels at baseline showed a negative association with the ileal and colonic CD and use of biologics and a positive association with patients who developed CD later in life after the age of 40(A3)and with a stenosing(B2)and fistulizing(B3)phenotype.The values of Hb and hematocrit after ferric hydroxide sucrose treatment remained similar to those found before treatment.CONCLUSION This study demonstrated that FCM is an important therapeutic strategy for treating IDA in CD patients,achieving satisfactory results in refractory cases.

Late presentation of dural tears:Two case reports and review of literature

BACKGROUND The late presentation of dural tears(LPDT)has a low incidence rate and hidden symptoms and is easily ignored in clinical practice.If the disease is not treated in time,a series of complications may occur,including low intracranial pressure headache,infection,pseudodural cyst formation,and sinus formation.Here,we describe two cases of LPDT.CASE SUMMARY Two patients had sudden fever 1 wk after lumbar surgery.Physical examination showed obvious tenderness in the operation area.The patients were confirmed as having LPDT by lumbar magnetic resonance imaging and surgical exploration.One case was caused by continuous negative pressure suction and malnutrition,and the other was caused by decreased dural ductility and low postoperative nutritional status.The first symptom of both patients was fever,with occasional headache.Both patients underwent secondary surgery to treat the LPDT.Dural defects were observed and dural sealants were used to seal the dural defects,then drainage tubes were retained for drainage.After the operation,the patients were treated with antibiotics and the patients’surgical incisions healed well,without fever or incision tenderness.Both recovered and were discharged 1 wk after the operation.CONCLUSION LPDT is a rare complication of spinal surgery or neurosurgery that has hidden symptoms and can easily be overlooked.Since it may cause a series of complic-ations,LPDT needs to be actively addressed in clinical practice.

Gestational TSH Levels and Their Association with Obstetric and Neonatal Outcomes in Lebanon: A National Observational Retrospective Study

Objectives: Gestational hypothyroidism is associated with obstetric complications and disturbances in the offspring development;however, it remains easy to treat. The objective of the study was to describe thyroid-stimulating hormone (TSH) levels in pregnant women and analyze their association with pregnancy course and outcome. Design: This national, observational, retrospective study analyzed data on Lebanese pregnant women visiting their obstetrician as part of their routine follow up. Participants, Setting and Methods: Enrolled subjects were all pregnant women who visited the obstetrics clinic from 01 September 2017 until 31 August 2018, as part of their routine follow up and have a TSH level record. In 2020, during their routine follow-up visit, the participants signed an informed consent to allow the investigator to access the data retrospectively and enter them into his database. Relevant participant characteristics and outcome data were collected from clinic files of the private clinic of Dr Abi Tayeh, at the Department of Obstetrics and Gynecology, H?tel-Dieu de France University Hospital, Beirut, Lebanon. Results: A total of 419 women were enrolled, 11.5% of them reported at least one comorbidity prior to pregnancy, most often the antiphospholipid syndrome, followed by thrombophilia and hypothyroidism. At least one complication was reported for 18.4% of participants. Around 87.6% of participants delivered a full-term baby with normal birth weight for most. The average TSH value for all participants was within the normal range at all time-points. Highest TSH values were recorded during the first trimester. As treatment was immediately initiated in women with abnormal TSH levels, no correlation was observed between TSH levels and pregnancy outcomes or pregnancy complications at any time-point. Conclusions: This study highlights satisfactory routine practice in the management of thyroid disorders in pregnancy and underscores the need for routine TSH screening for all pregnant women.

Pancreatic neuroendocrine tumors G3 and pancreatic neuroendocrine carcinomas: Differences in basic biology and treatment

In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms(p NENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3(p NETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas(p NECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the p NENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated p NECs and compare them to those of well-differentiated p NETs G3. For p NETs G3 and p NECs(due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between p NETs G3 and p NECs in order to deepen understanding of these diseases and discuss future research directions.

Liquid biopsy approach to pancreatic cancer

Pancreatic cancer(PC)continues to pose a major clinical challenge.There has been little improvement in patient survival over the past few decades,and it is projected to become the second leading cause of cancer mortality by 2030.The dismal 5-year survival rate of less than 10%after the diagnosis is attributable to the lack of early symptoms,the absence of specific biomarkers for an early diagnosis,and the inadequacy of available chemotherapies.Most patients are diagnosed when the disease has already metastasized and cannot be treated.Cancer interception is vital,actively intervening in the malignization process before the development of a full-blown advanced tumor.An early diagnosis of PC has a dramatic impact on the survival of patients,and improved techniques are urgently needed to detect and evaluate this disease at an early stage.It is difficult to obtain tissue biopsies from the pancreas due to its anatomical position;however,liquid biopsies are readily available and can provide useful information for the diagnosis,prognosis,stratification,and follow-up of patients with PC and for the design of individually tailored treatments.The aim of this review was to provide an update of the latest advances in knowledge on the application of carbohydrates,proteins,cell-free nucleic acids,circulating tumor cells,metabo-lome compounds,exosomes,and platelets in blood as potential biomarkers for PC,focusing on their clinical relevance and potential for improving patient outcomes.

Misidentification of hepatic tuberculosis as cholangiocarcinoma:A case report

BACKGROUND Hepatic tuberculosis(TB)is uncommon clinically.Because of a lack of specific signs,characteristic symptoms and clinical manifestations and because pathological samples are difficult to obtain,hepatic TB is easily missed or misdiagnosed.CASE SUMMARY A 62-year-old Chinese man presented with jaundice for 1 wk and no abnormal laboratory tests other than elevated bilirubin,aminotransferases and C-reactive protein.Computed tomography(CT)of the abdomen showed a mass in the left lobe of the liver and hepatic hilum with striped calcified foci.Mild enhancement was visible at the edges,along with extensive intrahepatic biliary ductal dilatation in the right lobe of the liver.In the arterial phase of both CT and magnetic resonance imaging,the main trunk and right branch of the portal artery were partially visualized.Magnetic resonance cholangiopancreatography(MRCP)indicated that the left lobe of the liver and most of the bile ducts in the hilum were not visible.Pathological examination revealed coagulative necrosis,and granulomatous nodules were seen around areas of necrosis;therefore,TB was considered.CONCLUSION Hepatic tuberculosis is easily misdiagnosed or missed on imaging.Percutaneous puncture biopsy is the most useful tool for definitive diagnosis.

Providing higher value care for hepatocellular carcinoma rather than diagnosis:What can current radiologists do?

Medical imaging is of great value for the comprehensive evaluation of hepatocellular carcinoma from diagnosis to prognosis,which contributes to optimal clinical management making.

Clinical Application of Chromosome Microarray Analysis in Han Chinese Children with Neurodevelopmental Disorders

Chromosome microarray analysis(CMA) is a cost-effective molecular cytogenetic technique that has been used as a first-line diagnostic test in neurodevelopmental disorders in the USA since 2011. The impact of CMA results on clinical practice in China is not yet well studied, so we aimed to better evaluate this phenomenon.We analyzed the CMA results from 434 patients in our clinic, and characterized their molecular diagnoses, clinical features, and follow-up clinical actions based on these results. The overall diagnostic yield for our patients was 13.6%(59 out of 434). This gave a detection rate of 14.7%for developmental delay/intellectual disability(DD/ID,38/259) and 12% for autism spectrum disorders(ASDs,21/175). Thirty-three recurrent(n≥2) variants were found, distributed at six chromosomal loci involving known chromosome syndromes(such as DiGeorge, Williams Beuren, and Angelman/Prader-Willi syndromes).The spectrum of positive copy number variants in our study was comparable to that reported in Caucasian populations, but with specific characteristics. Parental origin tests indicated an effect involving a significant maternal transmission bias to sons. The majority of patients with positive results(94.9%) had benefits, allowing earlier diagnosis(36/59), prioritized full clinical management(28/59), medication changes(7/59), a changed prognosis(30/59), and prenatal genetic counseling(15/59). Our results provide information on de novo mutations in Chinese children with DD/ID and/or ASDs. Our data showed that microarray testing provides immediate clinical utility for patients. It is expected that the personalized medical care of children with developmental disabilities will lead to improved outcomes in long-term developmental potential.We advocate using the diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility.

Malignant field expression signatures in biopsy samples at diagnosis predict the likelihood of lethal disease in patients with localized prostate cancer

Aim:Overtreatment of early-stage low-risk prostate cancer patients represents a significant problem in disease management and has significant socio-economic implications.Changes in prostate cancer screening and treatment practices in the United States have been associated with the recent decline in overall incidence and concomitant significant increase of the annual incidence of metastatic prostate cancer has been documented.Therefore,development of genetic and molecular markers of clinically significant disease in patients diagnosed with low grade localized prostate cancer would have a major impact in disease management.Methods:Identification of gene expression signatures(GES)associated with lethal prostate cancer has been performed using microarray analyses of biopsy specimens obtained at the time of diagnosis from 281 patients with Gleason 6(G6)and G7 tumors in a Swedish watchful waiting cohort with up to 30 years follow-up.The performance of GES has been validated in independent cohort of 568 prostate cancer patients of the Cancer Genome Anatomy Project Prostate Cancer database.Results:GES c omprising 98 genes identified 89%and 100%of all death events 4 years after diagnosis in G7 and G6 patients,respectively.At 6 years follow-up,83%and 100%of all deaths events were captured in G7 and G6 patients,respectively.Remarkably,the 98-gene signature appears to perform successfully in patients stratification with as little as 2%of cancer cells in a specimen,strongly indicating that it captures a malignant field effect in human prostates harboring cancer cells of different degrees of aggressiveness.In G6 and G7 tumors from prostate cancer patients of age 65 or younger,GES identified 86%of all death events during the entire follow-up period.In G6 and G7 tumors from prostate cancer patients of age 70 or younger,GES identified 90%of all death events 6 years after diagnosis.Conclusion:Classification performance of the reported in this study 98-genes GES of lethal prostate cancer appeared suitable to meet design and feasibility requirements of a prospective 4 to 6 years clinical trial,which is essential for regulatory approval of diagnostic and prognostic tests in clinical setting.Prospectively validated GES of lethal PC in biopsy specimens of G6 and G7 tumors will help physicians to identify,at the time of diagnosis,patients who should be considered for exclusion from active surveillance programs and who would most likely benefit from immediate curative interventions.