The new insight of prostate-specific antigen reduction during finasteride therapy in aging men

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上海市第一人民医院国家临床重点专科申报书——泌尿外科

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彩色超声波诊断仪彩色超声波诊断仪单光子发射扫描仪直线加速器治疗计划系统（TBS）模拟机核磁共振仪 64 排 CT 扫描机高压液相色谱仪图像传输与存储系统数字化 X 光机 CR 计算机成像系统移动式 C 臂 X 光机 C 臂 X 光机肺功能测定仪肌电图仪麻醉机流式细胞仪（BD）分选监护除颤仪心输出量测定仪血气分析仪电动呼吸机带显示器手术无影灯
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二膦酸盐类药物对转移性骨肿瘤作用研究进展

济宁医学院学报ＪＯＵＲＮＡＬＯＦＪＩＮＩＮＧＭＥＤＩＣＡＬＵＮＩＶＥＲＳＩＴＹＶ０１．３２Ｎｏ．６２００９４４５二膦酸盐类药物对转移性骨肿瘤作用研究进展徐兴华王建礼（济宁医学院基础学院．山东日照２７６８２６）关键词二膦酸盐；转移性骨肿瘤中图分类号：Ｒ７３０．５３文献标志码：Ａ文章编号：１０００—９７６０（２００９）１２—０４４５－０３二膦酸盐是１８６５年首次在德国合成的一类焦膦酸类似物，与焦膦酸不同的是以Ｐ－Ｃ－Ｐ键代替焦膦酸盐中Ｐ—ｏＰ键，这种变化改变了二膦酸盐的体内代谢过程，使其可以抵抗水解酶的作用而不被降解，在体内保持一定的稳定性。

１９６８年开始利用其具有显著的抑制烃基磷酸钙结晶溶解的生物特性，用于骨代谢疾病的治疗。

目前二膦酸盐类药物广泛用于治疗恶性骨疾病（如骨质疏松，骨肿瘤性疾病，ＰＡＧＡＥＴｓ病，高钙血症等）的治疗。

尤其是骨质疏松和转移性骨肿瘤的治疗。

现就二膦酸盐类药物对转移性骨肿瘤作用方面的研究进展做一综述。

１二膦酸盐类药物的分类二膦酸盐类药物常依它们的化学结构和作用机制而分成两类，其中一类被称作含氮二膦酸盐类药物，它包括阿仑膦酸钠（ａｌｅｎｄｒｏｎａｔｅ）、伊班膦酸钠（ｉｂａｎｄｒｏｎａｔｅ）、帕米膦酸二钠（ｐａｍｉｄｒｏｎａｔｅ）、利塞膦酸钠（ｒｉｓｅｄｒｏｎａｔｅ）和唑来膦酸（ｚｏｌｅｄｒｏｎｉｃａｃｉｄ）；另一类称之为非含氮二膦酸盐类药物，它包括氯屈膦酸钠（ｃｌｏｄｒｏｎａｔｅ）和依替膦酸钠（ｅｔｉｄｒｏｎａｔｅ）等。

在这两类二膦酸盐类药物中，含氮二膦酸盐类药物因能抑制法尼基二膦酸合成酶，故其作用较不含氮二膦酸盐类药物更强。

法尼基二膦酸合成酶是朋固醇生物合成途径中的一种酶。

通过抑制破骨细胞中的法尼基二膦酸合成酶．含氮二膦酸盐类药物可以干扰脂质粘着到调控蛋白上，进而引致破骨细胞的灭活。

２二膦酸盐对转移性骨肿瘤的作用目前所了解和掌握的恶性肿瘤发生骨转移的机制主要涉及三个方面：肿瘤细胞自身所固有的内在特性，即它具有离开原发病灶迁移到远处骨骼组织中的能力；骨骼系统的特定部位所具有的解剖学特性允许其接受并容纳播散的肿瘤细胞；受累骨骼对转移的肿瘤细胞所产生的各种生物学反应．使得瘤细胞能够在宿主骨骼中繁殖、生长并破坏正常骨组织的形态和结构。

新gre练习题

新gre练习题GRE填空题1. Though the volume of radioactive waste produced by nuclear power plants is________, the problem of how to dispose of that waste is not: rather, it is of major importance. [单选题] *A.unmanageableB.troublingC.significantD.small(正确答案)E.deceptive2. Investors are grateful that the attorney general has stepped in to pursue inquiries into the misfeasance in the financial markets, given that the regulators officially charged with policing the industry have been________. [单选题] *A.tenaciousB.diffident(正确答案)C.meticulousD.implacableE.straightforward3. The author suggests that cinema archives should become more like museums, justifying their existence by selecting, grouping and commenting on important films. By thus (i)________films,archives would not only serve as repositories, but would provide (ii)________as well.*A. improvingB. restoringC. interpreting(正确答案)D. conservationE. education(正确答案)F. income4. “Argument” may be an overly (i)________word to apply to the gossamer contrivance that is A summer of Humming birds. In what seems a self-conscious (ii)________ of its mascot, the book flits from one subjects or moment in history to another, following the various whims of its authors.*A. archaicB. impreciseC. strong(正确答案)D. repudiationE. emulation(正确答案)F. misrepresentation5. The skin of the poison dart frog contains deadly poison called batrachotoxins. But the(i)of the toxins has remained an enigma, as the frog does not (ii)________them. Now an analysis suggests that the melyrid beetle is the source. Collected beetle specimens all contained batrachotoxins, suggesting that these beetles are(iii)________ by the frogs.*A. effectB. origin(正确答案)C. purposeD.pressureE. produce(正确答案)F.suffer fromG. eaten(正确答案)H. neutralizedI. poisoned6. When a new scientific model emerges, research studies (i)________that paradigm tend to dominate in the scientific literature: the process of selecting articles for publication is tilted towardpositive results. But once the paradigm (ii)________, the academic incentives shift in the opposite direction: research results are more likely to be consideredworthy of publication when they(iii)________what has become the established view.*A. tweakingB. affirming(正确答案)C. controvertingD. is initially articulatedE. has become entrenched(正确答案)F. is about to be attackedG. bolsterH. circumventI. undermine(正确答案)7. The beauty of the scientific approach is that even when individual researchersdo________bias or partiality, others can correct them using a framework of evidence on which everyone broadly agrees. *A.overreact toB.deviate fromC.succumb to(正确答案)D.recoil fromE.yield to(正确答案)F.shrink from8.The initial, widely shared pessimism turned out to be________, because it ignored the many things that would be done with resources left behind. *A.unimportantB.unintelligibleC.unfathomableD.unfounded(正确答案)E.unimaginativeF.unjustified(正确答案)9. Despite a tendency to be overtly________, the poetry does not consist solely of pious sentiments: It sparks the imagination and provides lively entertainment. *A.preachy(正确答案)B.querulousC.insincereD.sanctimonious(正确答案)E.plaintiveF.disingenuous10. Though it may seem as if more than a century of________has made the electrical grid an all-encompassing web connecting the whole of the continent, many vast and beautiful areas remain without power. *A.refinementB.expansion(正确答案)C.ubiquityD.augmentation(正确答案)E.omnipresenceF.isolation11. With the numerous opponents of the controversial new taxation measure in such a fury, anyone who publicly advocated the measure did not fail to meetwith________usage. [单选题] *A.politicB.severe(正确答案)C.soberD.respectfulE.dejected12. The paleontologist examined the problem afresh, believing that the accepted classification________the essential continuity of the specimens by making specious distinctions among them. [单选题] *A.disprovedB.belied(正确答案)C.conflatedD.divulgedE.relaxed13.Invention was (i)________the work of the ancient Greek historians, whose writings were filled with long and often purely fictitious speeches by great historical figures. The animating force in historical writing was rhetoric rather than (ii)________. Even well into the eighteenth century, not a few historians continued to understand themselves as artists, given a license to invent.*A. discouraged inB. a hallmark of(正确答案)C. exceptional inD. eloquenceE. evidence(正确答案)F. imagination14. Scholars have marveled over the (i)________that Shakespeare displays in his works, noting that such broad learning is all the more remarkable given that books were relatively (ii)________ in Shakespeare's time.*A. meticulousnessB. humorC. erudition(正确答案)D. edifyingE. scarce(正确答案)F. inexpensive15.She was never (i)________: she was nothing if not discreet, so she (ii)________ for the present to declare her passion.*A. precipitate(正确答案)B. tactfulC. thoughtfulD. pretendedE. decidedF. forbore(正确答案)16.The slow pace of job creation was without precedent for the period of recovery from a recession,but the conditions that conspired to cause the recession were also (i)________. The stock market declined sharply, and rampant business investment slumped. Then an ensuing spate of scandals (ii)________ public trust in the way companies were run. And yet,despite these powerful (iii)________ to growth, the recession proved surprisingly mild.*A. hearteningB. atypical(正确答案)C. ambiguousD. weakened(正确答案)E. illuminatedF. consolidatedG. counterforce(正确答案)H. stimulantsI. concomitants17.A cure for the common cold has been so elusive that it has become a modern symbol of______. *A.dangerB.futility(正确答案)C.uneaseD.pointless(正确答案)E.slothF.apathy18.The dictators gleaming military uniform and imperial paraphernalia sharply contrast with the________fashion favored by most other contemporary political leaders. *A.unostentatious(正确答案)B.modest(正确答案)C.augustD.majesticE.formalF.casual19. Despite her rather________choices, Moreland was neither a rebellious spirit nor someone who saw herself as anything out of the ordinary. *A.unconventional(正确答案)B.impracticalC.quirky(正确答案)D.flamboyantE.successfulF.lucrative20. His premiership, seemingly cast-iron a year ago, is now so vulnerable that even a good day at the office does no more than buy him a few weeks of________from rebels within his own party. *A.controversyB.reproachC.respite(正确答案)D.relief(正确答案)E.blameF.deference21.In the last two hundreds years, the practice of archaeology has changed greatly, from digging up ancient artifacts for use by wealthy individuals as art objects to analyzing the detritus of everyday life in the laboratory, and thus from________to data collection. [单选题] *A.suppositionB.theorizingC.fact-findingD.treasure hunting(正确答案)E.scientific discovery22.The identity of hominid remains found in a cave in the Altai Mountainswas________until Paabo and his colleagues ended the speculation by showing that DNA sequences indicated the bones belonged to Neanderthals. [单选题] *A.extraneousB.conjectural(正确答案)C.improbableD.demonstrableE.consistent23. The documentation of Earth’s biodiversity is complicated by the(i)________taxonomists. Those experts in classifying species tent to be (ii)________ North America and Europe, whereas most of the undocumented biodiversity is likely in the tropics.*A. uneven distribution of(正确答案)B. theoretical commitments ofC. professional rivalries amongD. clustered in(正确答案)E. oblivious toF. exported from24. For decades, economic ideas have been (i)________ political purpose. Economists, for example, have peddled their theories as a way of gaining public prominence or political appointment, while politicians have (ii)________economic doctrines as possible solutions to the nation’s social problems.*A. undermined byB. inspired byC. exploited for(正确答案)D. rejectedE. ignoredF. promoted(正确答案)25. Computers make it spectacularly easy to search for particular pieces of information in downloaded texts. And doing research in this strategic, targeted manner can feel(i)________. Instead of (ii)________ the organizing logic of the book you are reading, you can approach the book with your own questions and (iii)________. You, not the author, are the master.*A. disorientingB. humblingC. empowering(正确答案)D. disregardingE. surrendering to(正确答案)F. imitatingG. begin to discern the author’s intentH. glean precisely what you want from it(正确答案)I. evaluate the book on its own terms26.There are two opposing theories about mountain formation and climate over the past 40 million years: either the surge of mountain building (i)________the global cooling, or vice versa. The first of these two theories asserts that widespread mountain buildingcooled the earth as a result of the(ii)________mountains and climate. For example, mountain glaciers tent to be (iii)________: once established, they increase the reflectivity of the surface, thus lowering temperatures and allowing more ice to form.*A. supersededB. haltedC. caused(正确答案)D. disparity betweenE. feedback between(正确答案)F. complexity ofG. unpredictableH. staticI. self-perpetuating(正确答案)27. If giant x-ray flares churn circumstellar disks enough to keep newborn planets, such as Earth once was, from spiraling into their suns, it would be an ironic twist on our conception of x-ray flares as ______ . *A.dangerous(正确答案)B.predictableC.ancientD.ephemeralE.perilous(正确答案)F.foreseeable28. Despite their cultural and social significance, rapid growth, and widespread appeal in China, video game—unlike traditional media—have received________attention from international communication researches. *A.undueB.scant(正确答案)C.excessiveD.focusedE.limited(正确答案)F.dwindling29. Although Wynne claims to recognize that________evidence is available to make definitive statements, she offers them nonetheless, arriving at some sweeping generalizations. *A.concreteB.finiteC.insufficient(正确答案)D.indirectE.conclusiveF.meager(正确答案)30.Although the biography never explicitly assesses what role the dynamic between Mr. Merrills parents might have played in the development of his personality, the author offers plenty of _____ *A.mystificationB.elucidationC.speculation(正确答案)D.reflectionE.obfuscationF.conjecture(正确答案)GRE阅读题GRE阅读题【1】At a certain period in Earth’s history, its atmosphere contained almost no oxygen, although plants were producing vast quantities of oxygen. As a way of reconciling these two facts, scientists have hypothesized that nearly all of the oxygen being produced was taken up by iron on Earth’s surface. Clearly, however, this explanation is inadequate. New studies show that the amount of iron on Earth’s surface was not sufficient to absorb anywhere near as much oxygen as was being produced. Therefore, something in addition to the iron on Earth’s surface must have absorbed much of the oxygen produced by plant life.1. In the argument given, the two portions in boldface play which of the following roles? [单选题] *A. The first is a claim made by the argument in support of a certain position; the second is that position.B. The first is a judgment made by the argument about a certain explanation; the second is that explanation.C. The first expresses the argument’s dismissal of an objection to the position it seeks to establish; the second is that position.D. The first sums up the argument’s position with regard to a certain hypothesis; the second provides grounds for that position.(正确答案)E. The first is a concession by the argument that its initial formulation of the position it seeks to establish requires modification; the second presents that position in a modified form.Rain-soaked soil contains less oxygen than does drier soil. The roots of melon plants perform less efficiently under the low-oxygen conditions present in rain soaked soil. When the efficiency of melon roots is impaired, the roots do not supply sufficient amounts of the proper nutrients for the plants to perform photosynthesis at their usual levels. It follows that melon plants have a lower-than-usual rate of photosynthesiswhen their roots are in rain-soaked soil. When the photosynthesis of the plants slows, sugar stored in the fruits is drawn off to supply the plants with energy. Therefore, ripe melons harvested after a prolonged period of heavy rain should be less sweet than other ripe melons.2. In the argument given, the two portions in boldface play which of the following roles? [单选题] *A. The first states the conclusion of the argument as a whole; the second provides support for that conclusion.B. The first provides support for the conclusion of the argument as a whole; the second provides evidence that supports an objection to that conclusion.C. The first provides support for an intermediate conclusion that supports a further conclusion stated in the argument; the second states that intermediate conclusion.(正确答案)D. The first serves as an intermediate conclusion that supports a further conclusion stated in the argument; the second states the position that the argument as a whole opposes.E. The first states the position that the argument as a whole opposes; the second supports the conclusion of the argument.Columnist: Until very recently, Presorbin and Veltrex, two medications used to block excess stomach acid, were both available only with a prescription written by a doctor. In an advertisement for Presorbin, its makers argue that Presorbin is superior on the grounds that doctors have written 200 million prescriptions for Presorbin, as compared to 100 million for Veltrex. It can be argued that the number of prescriptions written is never a worthwhile criterion for comparing the merits of medicines, but that the advertisement’s argument is absurd is quite adequately revealed by observing that Presorbin was available as a prescription medicine years before Veltrex was.3. In the columnist’s argument, the two highlighted portions play which of the following roles? [单选题] *A. The first is a claim that the columnist’s argument seeks to clarify; the second states a conclusion drawn about one possible interpretation of that claim.B. The first identifies the conclusion of an argument that the columnist’s argument is directed against; the second states the main conclusion of the columnist’s argument.(正确答案)C. The first states the main conclusion of the columnist’s argument; the second states a conclusion that the columnist draws in defending that conclusion against an objection.D. The first identifies an assumption made in an argument that the columnist's argument is directed against; the second states the main conclusion of the columnist’s argument.E. The first is a claim that has been offered as evidence to support a position that the columnist opposes; the second states the main conclusion of the columnist’s argument. Politician: The number of traffic deaths in our region has increased over the past several years. Because the poor condition of our roads and highways has caused a number of fatal accidents, the road commission recommended that, to reduce traffic deaths, the budget for road maintenance should be increased. Many major traffic deaths, however, are attributed to traffic congestion than to poor road condition, and better road will encourage people to drive more, worsen traffic congestion. So a better strategy for the road commission to recommend would be to reduce traffic congestion, though the best means for doing so remains to be determined. Improving mass transit is only one possibility.4. In the politician’s argument, the two highlighted portions play which of the following roles? [单选题] *A. The first introduce the position that the politician seeks to establish, the second provides evidence to support that position.B. The first introduces the position that the politician seeks to establish, the second is evidence that was cited in support of the position that the politician opposes.C. The first introduces the position that the politician seeks to establish, the second is an intermediate conclusion that is made in order to support that position.D. The first introduces a problem, the response to which is presented in the argument, the second provides evidence that is aimed at arguing that a proposed response to this problem will turn out to be counterproductive.(正确答案)E. The first introduces a problem, the response to which is presented in the argument, the second is evidence that was cited in support of a response that the politician opposes. Stylistic evidence and laboratory evidence strongly support the claim that the magnificent painting Garden of Eden is a work of the Flemish master van Eyck. Nevertheless, the painting must have been the work of someone else, as anyone with a little historical and zoological knowledge can tell merely by looking at the painting. The animals in the painting are all vivid representations of actual animals, including armadillos. Yet armadillos are native only to Americas, and van Eyck died decades before Europeans reached the Americas.5. In the argument given, the two highlighted portions play which of the following roles? [单选题] *A. The first is a position that the argument seeks to reject, the second is evidence that the argument uses against that position.B. The first and the second are each pieces of evidence that have been used to support the position that the argument opposes.C. The first presents the main conclusion of the argument; the second provides evidence in support of that conclusion.(正确答案)D. The first is a judgment that serves as the basis for the main conclusion of the argument; the second states that main conclusion.E. The first is an intermediate conclusion drawn in order to support a further conclusion stated in the argument; the second provides evidence in support of that intermediate conclusion.GRE阅读题【2】A ten-year comparison between the United States and the Soviet Union in terms of crop yields per acre revealed that when only planted acreage is compared, Soviet yields were equal to 68 percent of United States yields. When total agricultural acreage (planted acreage plus fallow acreage) is compared, however, Soviet yield was 114 percent of United States yield.1. From the information above, which of the following can be most reliably inferred about United States and Soviet agriculture during the ten-year period? [单选题] *A. A higher percentage of total agricultural acreage was fallow in the United States than in the Soviet Union.(正确答案)B. The United States had more fallow acreage than planted acreage.C. Fewer total acres of available agricultural land were fallow in the Soviet Union than in the United States.D. The Soviet Union had more planted acreage than fallow acreage.E. The Soviet Union produced a greater volume of crops than the United States produced.New methods developed in genetic research have led taxonomists to revise their views on the evolutionary relationships between many species. Traditionally the relatedness of species has been ascertained by a close comparison of their anatomy. The new methodsinfer the closeness of any two species’ relationship to each other directly from similarities between the species’ genetic codes.2. Which of the following conclusions is best supported by the information? [单选题] *A. The apparent degree of relatedness of some species, as determined by anatomical criteria, is not borne out by their degree of genetic similarity.(正确答案)B. When they know the differences between two species’ genetic codes, taxonomists can infer what the observable anatomical differences between those species must be.C. The degree to which individuals of the same species are anatomically similar is determined more by their genetic codes than by such environmental factors as food supply.D. The traditional anatomical methods by which taxonomists investigated the relatedness of species are incapable of any further refinement.E. Without the use of genetic methods, taxonomists would never be able to obtain any accurate information about species’ degrees of relatedness to one another.Years ago, consumers in Frieland began paying an energy tax in the form of two Frieland pennies for each unit of energy consumed that came from nonrenewable sources. Following the introduction of this energy tax, there was a steady reduction in the total yearly consumption of energy from nonrenewable sources.3. If the statements in the passage are true, then which of the following must on the basis of them be true? [单选题] *A. There was a steady decline in the yearly revenues generated by the energy tax in Frieland.(正确答案)B. There was a steady decline in the total amount of energy consumed each year in Frieland.C. There was a steady increase in the use of renewable energy source in Frieland.D. The revenues generated by the energy tax were used to promote the use of energy from renewable sources.E. The use of renewable energy sources in Frieland greatly increased relative to the use of nonrenewable energy sources.GRE阅读题【3】During the day in Lake Constance, the zooplankton D. hyalina departs for the depths where food is scarce and the water cold. D. galeata remains near the warm surface wherefood is abundant. Even though D. galeata grows and reproduces much faster, its population is often outnumbered by D. hyalina.1. Which of the following, if true, would help resolve the apparent paradox presented above? [单选题] *A. The number of species of zooplankton living at the bottom of the lake is twice that of species living at the surface.B. Predators of zooplankton, such as whitefish and perch, live and feed near the surface of the lake during the day.(正确答案)C. In order to make the most of scarce food resources,D. hyaline matures more slowly than D. galeata.D. D. galeata clusters under vegetation during the hottest part of the day to avoid the Sun’s rays.E. D. galeata produces twice as many offspring per individual in any given period of time as does D. hyalina.In the past ten years, there have been several improvements in mountain-climbing equipment. These improvements have made the sport both safer and more enjoyable for experienced climbers. Despite these improvements, however, the rate of mountain climbing injuries has doubled in the past ten years.2. Which of the following, if true, best reconciles the apparent discrepancy presented in the passage? [单选题] *A. Many climbers, lulled into a false sense of security, use the new equipment to attempt climbing feats of which they are not capable.(正确答案)B. Some mountain-climbing injuries are caused by unforeseeable weather conditions.C. Mountain climbing, although a dangerous sport, does not normally result in injury to the experienced climber.D. In the past ten years there have been improvements in mountain-climbing techniques as well as in mountain-climbing equipment.E. Although the rate of mountain-climbing injuries has increased, the rate of mountain-climbing deaths has not changed.Despite the fact that the health-inspection procedure for catering establishments are more stringent than those for ordinary restaurant, more of the cases of food poisoning reported to the city health department were brought on by banquets served by catering services than were brought on by restaurant meals.3. Which of the following, if true, helps explain the apparent paradox in the statement above? [单选题] *A. A significantly larger number of people eat in restaurants than attend catered banquets in any given time period.B. Catering establishments know how many people they expect to serve, and therefore are less likely than restaurants to have, and serve, leftover foods, a major source of food poisoning.C. Many restaurant provide catering services for banquets in addition to serving individual meals.D. The number of reported food-poisoning cases at catered banquets is unrelated to whether the meal is served on the caterer’s or the client’s premises.E. People are unlikely to make a connection between a meal they have eaten and a subsequent illness unless the illness strikes a group who are in communication with one another.(正确答案)Despite a dramatic increase in the number of people riding bicycles for recreation in Parkville, a recent report by the Parkville Department of Transportation shows that the number of accidents involving bicycles has decreased for the third consecutive year.4. Which of the following, if true during the last three years, best reconciles the apparent discrepancy in the facts? [单选题] *A. The Parkville Department of Recreation confiscated abandoned bicycles and sold them at auction to any interested Parkville residents.B. Increased automobile and bus traffic in Parkville had been the leading cause of the most recent increase in automobile accidents.C. Because of the local increase in the number of people bicycling for recreation, many out-of-town bicyclists ride in the Parkville area.D. The Parkville Police Department enforced traffic rules for bicycle riders much more vigorously and began requiring recreational riders to pass a bicycle safety course.(正确答案)E. The Parkville Department of Transportation canceled a program that required all bicycles to be inspected and registered each year.Although initially symptomless, glaucoma can eventually cause blindness when not properly treated. Tests under laboratory conditions of the traditional treatment, daily administration of eyedrops, show it to be as effective in relieving the internal ocular pressure that causes glaucoma as is a new laser-surgical procedure. Yet glaucoma-related blindness occurs in a significantly smaller percentage of patients who have had the surgery than of patients for whom only the eyedrop treatment was prescribed.5. Which of following, if true, most helps to explain the low rate glaucoma-related blindness among patients who had the surgery? [单选题] *A. Glaucoma-related blindness is no more common among patients who have had only the surgery than it is among patients who had the surgery after using the eyedropsB. Doctors rarely recommend the surgery for glaucoma patients who have already started the traditional course of treatmentC. There is no known physiological cause of glaucoma other than increase in pressure inside the eyeD. A significant percentage of the people for whom the eyedrop treatment has been prescribed fail to follow the prescribed daily regimen, because the eyedrops have unpleasant side effects.(正确答案)E. The eyedrops traditionally prescribed to treat glaucoma are normally prescribed to treat other disease of the eye.GRE阅读题【4】In 1998 the United States Department of Transportation received nearly 10,000 consumer complaints about airlines; in 1999 it received over 20,000. Moreover, the number of complaints per 100,000 passengers also more than doubled. In both years the vast majority of complaints concerned flight delays, cancellations, mishandled baggage, and customer service. Clearly, therefore, despite the United States airline industry’s serious efforts to improve performance in these areas, passenger dissatisfaction with airline service increased significantly in 1999.1. Which of the following, if true, most seriously weakens the argument? [单选题] *A. Although the percentage of flights that arrived on time dropped slightly overall, from77 percent in 1998 to 76 percent in 1999, some United States airlines’ 1999 on-time rate was actually better than their 1998 on-time rate.B. The number of passengers flying on United States airlines was significantly higher in 1999 than in 1998.C. Fewer bags per 1,000 passengers flying on United States airlines were lost or delayed in 1999 than in 1998.D. The appearance in 1999 of many new Internet sites that relay complaints directly to the Department of Transportation has made filing a complaint about airlines much easier for consumers than ever before.(正确答案)E. Although the number of consumer complaints increased for every major United States airline in 1999, for some airlines the extent of the increase was substantial, whereas for others it was extremely small.。

A biomedical engineering approach to mitigate the errors of prostate biopsy

IntroductionThe current diagnostic pathway that is employed to both detect and rule out pros-tate cancer involves serum PSA testing and transrectal ultrasonography (TRUS)-guided biopsy. The role of PSA screening in the underdetection of clinically significant prostate cancer, overdiagnosis of clinically insignificant disease and limitations in risk stratification has been discussed in great detail, but little has been written regarding the contribution of TRUS-guided biopsy to these errors.1,2We believe that the inherent limitations of TRUS-guided biopsy confer most of the error that has hitherto been attributed to PSA testing. Indeed, the blind spot we have for TRUS-guided biopsy is even reflected in the terms that we use to describe it: it is often referred to as ‘systematic’ or ‘random’.However, as a method of sampling a volumeof tissue, the reality is that it is neither trulyrandom nor reliably systematic in nature.Randomness is not achieved because ofoperator preferences for certain parts ofthe prostate and the accessibility of someparts of the organ compared with others—a systematic sampling of the whole prostateis a near impossibility, owing to anatomicalconstraints if the point of access is trans-rectal. The result is oversampling of someareas and undersampling of others.Ultimately, TRUS-guided biopsy per-forms poorly because it is conductedwithout knowledge of the cancer l o cation—ultrasonography is used simply to deter-mine that the needle has targeted prostatetissue. Until novel imaging modalities,such as multiparametric MRI or ultrasono-graphic tissue characterization, are shownto be reproducible outside single expertcenters, we continue to seek improvementsto the traditional TRUS-guided biopsy. Wehave started this search with a bio m edicalengineering evaluation of the currentassumptions that underlie TRUS-guidedbiopsy, leading to the modeling of a strat-egy that could address the short c omings.We propose corrections to the protocolthat could reduce the types of error result-ing from a procedure that is undertakenalmost a million times per year in the USA.This plethora of biopsies, which are oftenperformed on men only nominally at risk,materially affect patient welfare, introduceadded morbidity, and substantially increasesocietal costs.Current biopsy strategy is flawedCurrently, a man with an unexplained risein PSA is advised to undergo TRUS-guidedbiopsy, and 10 or 12 core samples are col-lected from throughout the peripheral zoneof the prostate. The results of such biop-sies are most often negative and, therefore,inconclusive. One in five men with a nega-tive biopsy will have clinically significantprostate cancer if verified using a more accu-rate test such as template prostate mappingbiopsy, which samples the gland every5 mm.3 Even when the results are positive,biopsy performs poorly as a histological testto rule in or rule out clinically significantprostate cancer. Given this poor attributionof status, it follows that the process of riskstratification is also compromised by the testperformance. About half of those men whoare diagnosed as “low-risk” following biopsyare shown to harbor a cancer of either highergrade or higher burden than originallydetermined when the sample is subjectedto some method of reclassification.3 Thisattribu t ion error will result in inappropriatetreat m ent al l ocation—men with high-riskdis e ase will be recommended conservativemanagement in contrast to radical therapyand men with low-risk disease are recom-mended radical therapy ‘just in case’.4,5 Theburden of overtreatment has always beenrecognized in prostate cancer therapy buthas only recently been quantified. Large-scale randomized studies have generatedmetrics such as ‘number needed to treat’(NNT)—the number of patients who mustbe treated in order to save one life. For a manin a screened versus nonscreened popu-lation, the NNT for prostate cancer rangesfrom 12 to 48.6,7The stability of the negative biopsy statuswas tested formally in the Reduction byOPINIONA biomedical engineering approachto mitigate the errors of prostate biopsyHashim Uddin Ahmed, Mark Emberton, Gordon Kepner and Jeremy KepnerAbstract | The current protocol for detecting and ruling out prostate cancer involvesserum PSA testing followed by sampling of the prostate using a transrectalultrasonography (TRUS)-guided biopsy. Many specialists have discussed how PSAscreening has contributed to underdetection of clinically significant prostate cancer,overdiagnosis of clinically insignificant disease and poor risk stratification; however,little consideration has been given to the role of TRUS-guided biopsy in these errors.The performance of TRUS-guided biopsy is constrained by the biomechanical attributesof the sampling strategy, resulting in suboptimal detection efficiency of each core. Byusing a biomedical engineering approach, a uniform grid sampling strategy could beused to improve the detection efficiency of prostate biopsy. Moreover, the calibrationof the sampling can be adjusted by altering the distance between needle deployments.Our model shows that for any given number of needle trajectories, a uniform gridapproach will be superior to a divergent, nonuniform strategy for the detection ofclinically important disease. This is an important message that should result in a moveaway from divergent sampling to a uniform grid approach for prostate biopsy.Ahmed, H. U. et al.Nat. Rev. Urol.9, 227–231 (2012); published online 7 February 2012;doi:10.1038/nrurol.2012.3Competing interestsH. U. Ahmed and M. Emberton declareassociations with the following companies:Advanced Medical Diagnostics, GSK, Oncura,Steba Biotech, USHIFU, and USHIFU/FocusedSurgery/Misonix Inc. See the article online for fulldetails of the relationships. The other authorsdeclare no competing interests.PERSPECTIVESDutasteride of Prostate Cancer Events (REDUCE) study,8 in which men with a nega t ive biopsy were eligible for randomiza-tion to receive either dutasteride or placebo. Men underwent two planned, protocol-directed biopsies and a for-cause biopsy if indicated. At the end of the study, one-quar-ter of men in the placebo group had tested positive for cancer. The sobering implication of this result is that men who are classified as ‘at risk’ prior to TRUS-guided biopsy have about a one-in-four chance of the result being positive. A negative biopsy result does little to change this risk if men undergo another TRUS-guided biopsy using the same protocol on two further occasions. In other words, the probability of being diagnosed with prostate cancer is the same for a man awaiting biopsy as it is for a man who has just been informed that his biopsy is negative. The true extent of the errors generated by TRUS-guided biopsy and the costs and harms that result from them are, at present, impossible to quantify because of the effects of selection and verification biases. These biases occur as a result of several practices. The first, and probably most important, is the management of the man with a nega-tive biopsy result. Men who test negative for prostate cancer are either discharged to the community for yearly PSA testing or kept under review for planned repeat biopsies triggered by subsequent PSA rises.The second form of bias relates to the most commonly used reference test (radical prostatectomy specimens), which are used to validate the accuracy of TRUS-guided biopsy. In other words, only men who are diagnosed with prostate cancer who then choose to have extirpative surgery (as opposed to radiation therapy or active surveil l ance) are used to validate the accu-racy of TRUS-guided biopsy. Consequently, the false-negative rate of TRUS biopsy is never tested and the positive is verified in a very select population, inviting the influ-ence of spectrum bias when the results are inevit a bly generalized.Evolution of TRUS biopsyThe current protocol for placing TRUS-guided biopsy needles is based on a series of clinical studies demonstrating that 10 or 12 tissue cores were better at detecting prostate cancer than six and that needle trajectories directed obliquely to the prostate were again better at detecting prostate cancer than those directed perpendicular to the posterior surface of the prostate.9 Biopsy studies claim-ing that the frequency of tumors is greater in one part of the peripheral compared toanother conflict with data showing a homo-geneous distribution of tumors within azone.10,11 Nonetheless, the probability ofdetection is not necessarily the same at everypoint in a prostatic zone because tumors atthe periphery of the prostate, especi a lly inthe apex, are more easily detected owing tothe ‘edge effect’, which means that these areasare more easily sampled, because the periph-eral zone at these points has less volume soa tumor is more likely to be detected by abiopsy needle.12Furthermore, the current samplingapproach limits comparison betweenstudies, as it is not known precisely wherebiopsy needles were placed nor the distri-bution and risk stratification of cancer indifferent cohorts.Multifocality of prostate cancerProstate cancer is often multifocal with twoor three tumors of different volumes beingpresent in a single patient.13 Most men withprostate cancer will have a dominant tumorthat has the greatest volume and the highestgrade. Evidence sug g ests that this dominanttumor is the index lesion—the lesion thathas the immediate potential to pro g ress andmetastasize within the patient’s remain-ing lifetime—and the smaller, lower gradelesions are deemed indolent or clinicallyinsignificant.14,15 It has also been arguedthat the index lesion must meet a thresholdvolume for this potential to be realized,16 butthe exact value for this threshold remainsthe sub j ect of con s ider a ble disagreementand uncer t ainty.17 Values of 0.2 cm3, 0.5 cm3and 1.3 cm3 have been pro p osed.18 However,such a thres h old is unlikely to be absoluteand might differ from one man to the nextdepending on comor b idity, age and esti-mates of life expec t ancy. Thus, the role ofthe biopsy may not necessarily be to findevery lesion. Instead, when positive, itshould be used to locate and characterizethe index lesion grade and volume. Whennegative, it should pro v ide an estimate,bounded by known levels of certainty, ofthe largest volume of any lesion that couldhave escaped detection. This knowledgewould confer some clinical utility to a nega-tive test result, where currently none exists.So, instead of the rather glib—and factu-ally incorrect—‘all clear’, clinicians couldtell their patients that the biopsy resultis negative, mean i ng that there is a 95%chance that they do not have any clinicallysignificant prostate cancer. It is likely thatthe patient would walk away just as relievedand the clini c ian would feel considerablyless anxious than they would having toldtheir patients something that has a one-in-three chance of not being true if based onthe result of a TRUS-guided biopsy.Modeling a new biopsy strategyThe ideal biopsy strategy should detectcancer greater than a specified volume with95% certainty and rule out prostate cancervolumes that are greater than a specifiedthreshold volume with 95% certainty.19,20Studies of radical prostatectomy specimenshave shown that the great majority of bothperipheral and transition zone tumors areless than 2 cm3 in volume and are confinedto their zone of origin, whereas a smallfraction of tumors are 2–4 cm3 in volume,found in both zones, and are confined tothe prostate.21,22 Assume for one momentthat the radical prostatectomy specimensinvestigated are representative of othermen diagnosed and treated for presumedorgan-confined disease. Using the distribu-tion of cancers within removed prostates asthe reference standard, we can begin to testsome sampling theories. Thus, one methodfor evaluating the effectiveness of a biopsystrategy would be to assess how effectivelyit detects prostate tumor foci within thesetwo volume ranges (<2 cm3 and 2–4 cm3)and how well it rules them out if the biopsyresult is negative.Tumor model assumptionsIn order to develop the model we requireone other assumption—that tumor foci<4 cm3 conform to a sphere.12 However, weknow that many tumor foci are not spheri-cal when viewed in cross section on whole-mount specimens—some are curvilinear,others are fusiform. Despite this, for thepurposes of modeling, the assumption of asphere works well for generating samplingprobabilities, in that certain geometries willbe over-represented on any detection strat-egy and others will be under-represented.As the sphere has the lowest surface:volumeratio, its morphology is, therefore, hardestto detect per unit volume. Thus, by usingspheres the modeling we describe is a‘worst-case scenario’. In addition, thedetection of a sphere should be orientation-independent to any sampling regimen—transrectal or transperineal. Tumors withdiameters of 1–2 cm yield tumor volumesbetween 0.5 and 4.0 cm3, suggesting that theprimary focus of a biopsy approach shouldbe to detect tumors 1–2 cm in diameter,while minimizing the detection of tumorsPERSPECTIVES<1.0 cm in diameter, as very few men are likely to benefit from the detection and treatment of such small tumors.Uniform grid of coresImagine, instead of the currently used random location of the biopsy cores, a 3D perspective on the relationship between a uniform grid of cores and its ability to detect a spherical tumor volume (Figure 1). The unit grid is four parallel biopsy cores placed S cm apart (Figure 2). The unit grid uses four parallel point cores to create the detection square, with sides of length S cm. The circumscribed circle of diameter D rep-resents the model spherical tumor in cross-section. It is the largest tumor that just fits inside the detection square cores. There is a set volume for the largest spherical tumor that could, theoretically, be positioned pre-cisely inside these four points without being detected. This is calculated in the following way: first, sphere dia m eter, D, is the product of S and √2. Second, sphere volume is the product of π/6 and D3. In this way, if S is known, the maximum tumor volume that could avoid detection (by fitting into the space delineated by S) can be derived. Forexample, if the core spacing S is 1.0 cm and D is 1.41 cm, then V is 1.46 cm3. There are hundreds of different positions, all equally likely, for the center point of this tumor within the unit grid of four cores. At every one of these positions (except the position shown in Figure 2) the tumor would inter-sect at least one core. Effectively, the prob-ability of detection for this tumor volume is almost 100%. A detailed analysis on the probability of detection for spherical tumors by the unit grid of cores was pre-viously summarized for different values of S.12 Decreasing S decreases the size of the largest tumor that could go undetected. To do so requires increasing the sampling intensity, in other words increasing the number of cores. This uniform grid analysis has many useful attributes. It is independent of the number of tumors within each zone that is sampled. It is also independent of tumor location because a uniformly spaced biopsy strategy will sample the whole gland as opposed to preferentially sampling a particular zone or area of the prostate. For instance, TRUS-guided biopsy has one par-ticular area that is always avoided (called the ‘no-fly zone’). This is the midline in which the urethra is positioned. By sampling either side of the urethra, the operator will have an estimate of what volume tumor, if any, might lie behind the urethra.Negative biopsy limits tumor sizeWhen a biopsy conducted with the uniformgrid approach is negative, the cliniciancan estimate the largest spherical tumorvolume that could escape detection with, forexample, 95% or 99% probability.12 In theidealized setting, if S is 1.0 cm, then thereis a 99% probability of detecting a 1.0 cm3tumor. In real-life practice the small needledeviations that take place will be randomand over many deployments should canceleach other out. The swelling of the prostatethat occurs during any sampling proce-dure will have the effect of systematicallyclustering some needle deployments as aresult of tissue swelling on a fixed samp-ling frame, but this error should be smallover the 10 min or so that is required tocomplete the sampling.Uniform grid versus TRUS-guided biopsyVarious nonuniform TRUS-guided biopsyprotocols involving 6–20 cores, or some-times more, have been reported.23–25 Forease of visualization, a 14-core patternis used for the example presented here(Figure 3). In the TRUS-guided biopsysetting, one can see the difficulty of placingthe second biopsy needle deployments inoptimal positions, given the uncertaintyof the needle placements during the firstround of sampling. Furthermore, the place-ment of biopsies inevitably leads to unsam-pled areas, which could allow larger tumorsto escape detection (Figure 3).Figure 1 | Relation of the spherical tumor model volume to the detection grid formed by the four parallel cores. a | A 3D cut-out view of the prostate shows the maximum size of a spherical tumor that can avoid detection in a uniform grid of cores with spacing, S, between core centers.b | Gray quarter-cylinders denote the volume in which a small spherical tumor of diameter DT would be detected. The volume of the four quarter-cylinders (one cylinder of diameter D2Tand height h), is (π/4)(DT)2h. When divided by the total volume of the sampling space, S2h, it calculates the probability of detection.12 This figure was modified from Kepner, G. & Kepner, J. Theor. Biol. Med. Model.7, 23 (2010), which is published under an open-access license by Biomed Central.SFigure 2 | Four evenly spaced parallel pointcores spaced S cm apart, with thecircumscribed circle of diameter Drepresenting the model spherical tumor incross-section. It is the largest tumor that justfits inside the detection square cores. Thereis a set volume for the largest sphericaltumor that could, theoretically, be positionedprecisely inside these four points withoutbeing detected.PERSPECTIVESBy contrast, needles deployed as part of a uniform grid approach sample tissue volumes that are essentially equal, with uniform and minimal overlap (Figure 4). This approach maximizes detection effi-ciency because the value of S is constant throughout the entire prostate volume sampled and is minimized to produce a higher probability of detection for the volume of cancer lesion that would be important in a particular man.12DiscussionTRUS biopsy performs poorly.26,27 Its perfor-mance is constrained by the bio m echanical attributes of the sampling strategy, resulting in suboptimal detection efficiency of each core. Greater detection efficiencies can be gained by using a uniform grid sampling strategy, which can be calibrated according to the specific risk of a particular man har-boring clinically significant cancer and the volume of tumor that defines clinical sig-nificance for his particular situation, taking into account preoperative biomarker levels and competing risks of mortality.Methodological limitationsMuch of the theory supporting these con-clusions is derived from idealized models that are unlikely to exactly replicate the real-life situation. In creating biomedical engineering models we have been careful not to underestimate the performance of the standard test, TRUS-guided biopsy. If anything, the performance of TRUS-guided biopsy has been overestimated in our model, by assuming that it samples the whole prostate—most clinicians are aware that the needle trajectories employed duringTRUS-guided biopsy mean that parts of the prostate such as the apex and the anterior prostate are difficult to sample effectively. We have assumed otherwise. Our aim was to develop a new strategy that maximized the detection efficiency of each needle.We accept that tumor grade is not evalu a ted within our model. In order to inform models of the grade within indivi-dual lesions, whole-mount specimens are required in order to map Gleason grade within the whole tumor, as areas of vary-ing grade are heterogeneously distrib-uted through o ut the lesion. We have not been able to obtain such datasets. How-ever, there is a strong correlation between tumor volume and grade. Only 5% of lesions <0.2 cm 3 in volume have elements of Gleason pattern 4. In other words, our assump t ion is that if one detects a lesion of volume above a clinically acceptable volume threshold, then the highest grade will also have been detected in the majority of cases.Clinical implicationsOur modeling shows that for any given number of needle trajectories, a uniform grid approach will be superior to a diver-gent, nonuniform strategy for the detec-tion of clinically important disease. This is an important message that we hope will prompt a move away from divergent sam-pling to a uniform grid approach. Moreover, the uniform grid approach is amenable to a user-defined calibration for detecting, or ruling out, cancer foci of a given volume. In other words, the distance between needles can be altered and set to rule out a tumor focus with a volume above what the clini-cian would consider significant for a par-ticular man, taking into account all other clinical parameters such as age, serum PSA level, family history of prostate cancer and rectal examination findings. The 5 mm needle distance, advocated by Barzell 28 for transperineal sampling is the most accurate biopsy test we have, and could be adjusted to 10 mm or 15 mm for any revised defi-nition of tumor volume significance, or for biopsy in the older man. Our use of the term ‘uniform grid’ might imply that the parallel sampling strategy requires a transperineal approach.12 This is not the case. Novel, commercially available needle tracking and biopsy guidance platforms mean that optimal sampling strategies can be constructed independent of the point of access to the prostate. As well as construct-ing a needle-by-needle sampling strategy, unlike a fixed template, the biopsy protocolcan be adjusted to account for random needle deflection and for gland swelling.29,30 Although the expert user might be able to carry out such uniform grid sampling trans-rectally, it is unlikely that the average user will be able to do so without a commercial platform. Thus, for the average user and in order to facilitate dissemination of uni-form grid sampling, either a transperineal approach will have to be adopted or such software platforms will be needed. Either way, such a change in the biopsy protocol is likely to transform the diagnostic pathway, while also providing the necessary correc-tions to the problems of risk stratification and treatment allocation that are inherent in TRUS-guided biopsy.In addition, our biopsy modeling does not take into account progress being made in imaging and detection and measurement of biomarkers in the blood and urine. For instance, multiparametric MRI incorpo-rates T2-weighted, diffusion-weighted, and dynamic-contrast-enhanced imaging and spectroscopy to obtain detailed anatomical and functional information. Early studies using multiparametric MRI for prostate cancer diagnosis demonstrate promising results in detecting and ruling out clinically significant lesions.31 In addition, tissue bio-markers such as PCA3, serum kallikrein and single nucleotide polymorphism panels might have utility as triage tests.32Future researchThe optimal biopsy strategies can only be designed once the urological communitydecides what they hope to detect in termsFigure 3 | A typical TRUS-guided biopsyapproach, showing the 14-core sample sites (pink dots) in the initial biopsy and the 14-core rebiopsy sites (blue dots). A largespherical tumor could just escape detection (dashed circle), even after two biopsies whenthis “random systematic” approach is used.Figure 4 | A potential uniform grid pattern for the 28 cores—biopsy and rebiopsy—distributed throughout the entire prostatevolume. The largest spherical tumor that could just escape detection by the uniform gridpattern (dashed circle) is substantially smaller than that which could escape detection using a TRUS-guided biopsy. The dotted partial circle illustrates the edge effect.PERSPECTIVESof cancer volume and grade and, more importantly given the near universality of prostate cancer in the older man, what it is in terms of tumor volume and grade that we are content for our tests to overlook. Once optimal strategies are in place and refined, the next challenge will focus on the role of triage tests to assist in identifying which man should undergo biopsy, and on exploit-ing the negative predictive value of imaging in order to deploy fewer needles in those who do.Division of Surgery and Interventional Science, 4th Floor, Medical School Building, University College London, 74 Huntley Street, London WC1E 6AU, UK (H. U. Ahmed, M. Emberton). Membrane Studies Project, PO Box 14180, Minneapolis, MN 55414, USA (G. Kepner). MIT Computer Science and Artificial Intelligence Laboratory, The Stata Center, Building 32,32 Vassar Street, Cambridge, MA 02139, USA (J. Kepner).Correspondence to: H. U. Ahmedhashim.ahmed@1. Strope, S. A. & Andriole, G. L. Prostate cancerscreening: current status and futureperspectives. Nat.Rev.Urol.7, 487–493(2010).2. Esserman, L. & Thompson, I. Solving theoverdiagnosis dilemma. J.Natl Cancer Inst.102, 582–583 (2010).3. Onik, G., Miessau, M. & Bostwick, D. G. Three-dimensional prostate mapping biopsy has apotentially significant impact on prostatecancer management. J.Clin.Oncol.27,4321–4326 (2009).4. Taira, A. V. et al. Performance of transperinealtemplate-guided mapping biopsy in detectingprostate cancer in the initial and repeat biopsysetting. Prostate Cancer Prostatic Dis. 13,71–77 (2010).5. Barqawi, A. B. et al. The role of 3-dimensionalmapping biopsy in decision making fortreatment of apparent early stage prostatecancer. J.Urol.186, 80–85 (2011).6. Schröder, F. H. et al. ERSPC Investigators.Screening and prostate-cancer mortality in arandomized European study. N.Engl.J.Med.360, 1320–1328 (2009).7. Hugosson, J. et al. Mortality results from theGöteborg randomised population-basedprostate-cancer screening trial. Lancet Oncol.11, 725–732 (2010).8. Andriole, G. L. et al. REDUCE Study Group.Effect of dutasteride on the risk of prostatecancer. N.Engl.J.Med.362, 1192–1202(2010).9. Heidenreich, A. et al. EAU guidelines onprostate cancer. Part 1: screening, diagnosis,and treatment of clinically localised disease.Eur.Urol.59, 61–71 (2011).10. Brossner, C. et al. Distribution of prostatecarcinoma foci within the peripheral zone:analysis of 8062 prostate biopsy cores. WorldJ.Urol.21, 163–166 (2003).11. Djavan, B. & Margreiter, M. Biopsy standardsfor detection of prostate cancer. World J.Urol.25, 11–17 (2007).12. Kepner, G. & Kepner, J. Transperineal biopsy:analysis of a uniform core sampling patternthat yields data on tumor volume limits innegative biopsies. Theor.Biol.Med.Model.7,23 (2010).13. Wise, A. M., Stamey, T. A., McNeal, J. E. &Clayton, J. L. Morphologic and clinicalsignificance of multifocal prostate cancers inradical prostatectomy specimens. Urology60,264–269 (2002).14. Ahmed, H. U. The index lesion and the origin ofprostate cancer. N.Engl.J.Med.361,1704–1706 (2009).15. Liu, W. et al. Copy number analysis indicatesmonoclonal origin of lethal metastatic prostatecancer. Nat. Med.15, 559–565 (2009).16. Netto, G. Tumor volume threshold ofinsignificant prostate cancer—was Dr. Stameyright all along? J.Urol.185, 10–11 (2011).17. Ploussard, G. et al. The contemporary conceptof significant versus insignificant prostatecancer. Eur.Urol.60, 291–303 (2011).18. Stamey, T. et al. Localized prostate cancer.Relationship of tumor volume to clinicalsignificance for treatment of prostate cancer.Cancer71, 933–938 (1993).19. Karavitakis, M., Ahmed, H. U., Abel, P. D.,Hazell, S. & Winkler, M. H. Tumor focality inprostate cancer: implications for focal therapy.Nat.Rev.Clin.Oncol.8, 48–55 (2011).20. Ahmed, H. U. et al. Characterizing clinicallysignificant prostate cancer using templateprostate mapping biopsy. J.Urol.186, 458–464(2011).21. Bouye, S. et al. Transition zone and anteriorstromal prostate cancers: zone of origin andintraprostatic patterns of spread athistopathology. Prostate69, 105–113 (2009).22. Haffner, J. et al. Peripheral zone prostatecancers: location and intraprostatic patterns ofspread at histopathology. Prostate69,276–282 (2009).23. Delongchamps, N. & Hass, G. Saturationbiopsies for prostate cancer: current usesand future prospects. Nat.Rev.Urol.6,645–652 (2009).24. Patel, A. & Jones, S. Optimal biopsystrategies for the diagnosis and staging ofprostate cancer. Curr.Opin.Urol.19,232–237 (2009).25. Scattoni, V. et al. Biopsy schemes with thefewest cores for detecting 95% of theprostate cancers detected by a 24-corebiopsy. Eur.Urol.57, 1–8 (2010).26. Singh, P., Ahmed, H. U. & Emberton, M. Activesurveillance: Is there a need for better riskstratification at the outset? J.Clin.Oncol.28,e513 (2010).27. Wei, J. Limitations of a contemporary prostatebiopsy: The blind march forward. Urol.Oncol.28, 546–549 (2010).28. Barzell, W. E. & Melamed, M. R. Appropriatepatient selection in the focal treatment ofprostate cancer: the role of transperineal3-dimensional pathologic mapping of theprostate--a 4-year experience. Urology70(Suppl. 6), 27–35 (2007).29. Megwalu, I. I. et al. Evaluation of a novelprecision template-guided biopsy system fordetecting prostate cancer. BJU Int.102,546–550 (2008).30. Ukimura, O., Hung, A. & Gill, I. Innovations inprostate biopsy strategies for activesurveillance and focal therapy. Curr.Opin.Urol.21, 115–120 (2011).31. Ahmed, H. U. et al. Is it time to consider a rolefor MRI before prostate biopsy? Nat.Rev.Clin.Oncol.6, 197–206 (2009).32. Mikolajczyk, S. D., Song, Y., Wong, J. R.,Matson, R. S. & Rittenhouse, H. G. Aremultiple markers the future of prostatecancer diagnostics? Clin.Biochem.37,519–528 (2004).AcknowledgmentsH. U. Ahmed and M. Emberton receive funding fromthe Medical Research Council, National Institute ofHealth Research-Health Technology Assessmentprogramme, Pelican Cancer Foundation, ProstateAction, St Peter’s Trust, Prostate Cancer ResearchFoundation, Prostate Cancer Charity and ProstateCancer Research Centre. Mark Emberton receivesfunding in part from the UK National Institute ofHealth Research UCLH/UCL ComprehensiveBiomedical Research Centre.Author contributionsH. U. Ahmed and G. Kepner researched data for thearticle. All authors contributed to discussion ofcontent, writing the manuscript, and review andediting of the article before submission.PERSPECTIVES。

优质护理在脑梗死患者护理中的应用效果评价

review[J].Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub,2012,156:186-199.[12] Lubiński J,Lener MR,Marciniak W,et al.Serum essential elements andsurvival after cancer diagnosis[J].Nutrients,2023,15(11):2611.[13] Schenk JM,Till C,Neuhouser M,et al.Differential biopsy patternsinfluence associations between multivitamin use and prostate cancer risk in the selenium and vitamin e cancer prevention trial[J].Cancer Epidemiol Biomarkers Prev,2022,31:2063-2069.[14] Crowe FL,Appleby PN,Travis RC,et al.Endogenous hormones,nutritionalbiomarkers and prostate cancer collaborative group. Circulating fatty acids and prostate cancer risk: Individual participant meta-analysis of prospective studies[J].J Natl Cancer Inst,2014,106(9):dju240.[15] Parra-SS,Ahumada D,Petermann-Rocha F,et al.Association ofmeat,vegetarian,pescatarian and fish-poultry diets with risk of 19 cancer sites and all cancer:findings from the UK Biobank prospective cohort study and meta-analysis[J].BMC Med,2022,20:79.[16] Birney E.Mendelian randomization[J].Cold Spring Harb PerspectMed,2022,12(4):a041302.[17] Davey SG,Hemani G.Mendelian randomization:genetic anchors for causalinference in epidemiological studies[J].Hum Mol Genet,2014,23:89-98.[18] Dong H,Kong X,Wang X,et al.The causal effect of dietary compositionon the risk of breast cancer: A mendelian randomization study[J].Nutrients,2023,15(11):2586.[19] Yan H,Jin X,Zhang C,et al.Associations between diet and incidencerisk of lung cancer: A Mendelian randomization study[J].Front Nutr,2023,10:1149317.[20] Yin L,Yan H,Chen K,et al.Diet-derived circulating antioxidants andrisk of digestive system tumors: A mendelian randomization study[J].Nutrients,2022,14(16):3274.[21] Brasky TM,Darke AK,Song X,et al.Plasma phospholipid fatty acidsand prostate cancer risk in the SELECT trial[J].J Natl Cancer Inst,2013,105:1132-1141.[22] Outzen M,Tj ønneland A,Christensen J,et al.Fish consumption andprostate cancer risk and mortality in a Danish cohort study[J].Eur J Cancer Prev,2018,27:355-360.[23] Fu YQ,Zheng JS,Yang B,et al.Effect of individual omega-3 fatty acids onthe risk of prostate cancer: A systematic review and dose-response meta-analysis of prospective cohort studies[J].J Epidemiol,2015,25:261-274.[24] Burgess S,Swanson SA,Labrecque JA.are mendelian randomizationinvestigations immune from bias due to reverse causation[J].Eur J Epidemiol,2021,36:253-257.[25] Guo JZ,Xiao Q,Gao S,et al.Review of Mendelian Randomization Studieson Ovarian Cancer[J].Front Oncol,2021,11:681396.[2024-01-07收稿]脑血管疾病是指脑血管病变所引起的脑功能障碍。

前列腺癌靶向超声造影剂的研究进展

前列腺癌（PCa ）是男性泌尿生殖系统最常见的恶性肿瘤之一，在西方国家发病率极高，在美国和欧洲的癌症死因中位居第2［1］。

据美国癌症协会统计，2020年新诊断的PCa 患者超过190000人，因PCa 死亡的人数高达3万人以上［2］。

近年来PCa 的发病率在大多数亚洲国家呈上升趋势［3］。

随着我国居民生活习惯的改变，检查技术的提高以及人口进入老龄化，PCa 的发病率也逐年升高，故对于高危群体进行及时干预具有非常重要的意义。

超声分子成像技术使用特定抗体或配体标记成像化合物，生成能够结合特定组织或病变的靶向超声造影剂，静脉给药后，这些分子探针通过血液循环在靶组织中特异性聚集，经超声检查可在分子或细胞水平上对病变区域进行特异性成像。

本文就靶向超声造影技术在PCa 的诊断与治疗方面的研究进展进行综述。

1靶向超声造影剂在PCa 诊断方面的研究进展靶向超声造影剂是将靶向生物标记物添加到分子显像剂中的一种技术，配体被设计成黏附在外壳上的内皮生物标志物［4］。

靶向造影剂将通过配体-受体黏附到靶组织，在微血管中积累。

给药几分钟后进行影像学检查，大部分游离造影剂通过呼吸道排出，靶区的造影剂将会显影，信号强度与生物标志物的表达程度成正比［5］。

目前在超声造影剂中常用的PCa 靶向配体有以下几种。

1.1前列腺素1（STEAP-1）STEAP-1是一种细胞表面蛋白，具有组织特异性，在原发性PCa 细胞中高表达，与细胞之间的通讯有关［6］。

该抗原有339个氨基酸残基，并以蛇形方式折叠成2个Advances in targeted ultrasound contrast agents for prostate cancerWANG Huijie 1,2,HONG Hua 2,LIANG Danyan 21Inner Mongolia Clinical College,Inner Mongolia Medical University,Hohhot 010110,China;2Department of Ultrasound Medicine,People's Hospital of Inner Mongolia Autonomous Region,Hohhot 010017,China摘要：前列腺癌是泌尿系统常见的恶性肿瘤之一，在我国前列腺癌的发病率逐年升高。

RECSIT1[1].1中英文对照全文

New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)新版实体瘤疗效评价标准：修订的RECIST指南（1.1版本）Abstract摘要Background背景介绍Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews.临床上评价肿瘤治疗效果最重要的一点就是对肿瘤负荷变化的评估：瘤体皱缩（目标疗效）和病情恶化在临床试验中都是有意义的判断终点。

Advances in biomarkers for the early diagnosis of prostate cancer

窑Review 窑Prostate cancer(PCa)is a common tumor that poses a significant threat to men's health.Currently,serum prostate specific antigen(PSA)is the most important marker for screening patients for PCa.However,the sensitivity and specificity of PSA in the early detection of PCa are not satisfactory 1,2 ,particularly when PSA falls within the range of410ng/mL.The detection rate of PCa is merely25%,while the rate of negative biopsy was about70%80% 2 .Some studies have demonstrated that negative biopsy results could not completely exclude the possibility of malignant tumors 3 .In addition,not only do inappropriate needle biopsies put patients at risk for prostate complications and increase their mental burden,but also it increases medical cost. Therefore,there is urgent demand for early diagnostic evidence of PCa,so that we can identify significant PCa to the extent possible,reduce the detection of latent and clinically insignificant tumors,and avoid inappropriate clinical treatment.Recently,numerous molecular markers have been reported to be useful for early diagnosis of PCa or prognostic prediction in PCapatients.Tumor biomarkers often signal the existence of tumors before other detection approaches,and thereby contribute to the diagnosis of tumors at early stages.That makes them an effective method to diagnose PCa earlier and is also a critical step in improving prognosis.At present,among studies that are exploring for more specific tumor biomarkers than PSA to improve the early diagnosis capacity of PCa,the most interesting tumor markers are PSA derivatives,hereditary prostate cancer1 (HPC1),prostate cancer antigen3(PCA3),the TMPRSS2:ETS fusion gene,glutathione stransferase π 1(GSTP1), α methylacylCoA racemase(AMACR),Golgi phosphoprotein2 (GOLPH2),early prostate cancer antigen(EPCA),andsarcosine.The PSA gene is located on chromosome19(19q13.41)and encodes a261aminoacid preprotein.When a leader sequence at the end of the amino acid chain is cleaved,it becomes a proenzyme without catalyzing activity(ProPSA).When another 7aminoacid leader sequence is cleaved from the terminal of ProPSA,it becomes a237aminoacid enzyme with catalyzing activity(PSA).There are various forms of PSA in the bloodstream,including free PSA(fPSA)and complex PSA (cPSA).Furthermore,fPSA includes nicked PSA,intact PSA,and ProPSA,while cPSA mostly refers to the PSA binding to琢 1 antichymotrypsin(PSAACT)and less frequently the PSA binding to琢 2 macroglobulin(PSAA2M)and琢 1protease inhibitorAdvances in biomarkers for the early diagnosis ofprostate cancerDaLong Cao 1,2 ,XuDong Yao 1,21 Department of Urology,Cancer Hospital,Fudan University,Shanghai200032,P.R.China;2 Department of Oncology,Shanghai Medical College, Fudan University,Shanghai200032,P.R.China揖Abstract铱Key words:Correspondence to:Xu鄄Dong Yao;Tel:+86013817811836;Email: yaoxudong67@This paper was translated from Chinese into English by Guangzhou Liheng Medical Translation and edited by Hope fferty on 20091030.The Chinese version of this paper is avaiable at /cn/article .asp?id=16207.Received:20090520;Accepted:20090908(PSAAPI).A recent metaanalysis including66studies showed that% fPSA[fPSA/total PSA(tPSA)]and cPSA had better diagnostic capacity than tPSA 4 .However,Bratslavsky . 5 expanded the biopsy scope in their study but failed to reveal any statistically significant difference between the diagnostic capacity of%fPSA, tPSA,and cPSA.The reasons for this may be that fPSA in the bloodstream is unstable,that PSA is not specific to PCa,and that a prostate with a larger volume may dilute tPSA.Benign PSA(BPSA)is formed when the internal peptide bonds between145and146amino acids and between182and 183amino acids are ruptured.It is mainly related to the volume of the transition zone in the prostate.As cleavaged by human kallikrein2(hk2),ProPSAs with leader peptides of2,4,5,and7 amino acids were named[2]ProPSA,[4]ProPSA,[5]ProPSA, and[7]ProPSA,respectively.Sokoll . 6 illuminated the practical value of this change in a confirmative study in the Early Detection Research Network by the United States National Cancer Institute(NCI).When PSA fell within the range of2 ng/mL10ng/mL,the areas under the curve(AUCs)of%[2] ProPSA([2]ProPSA/fPSA),a logistic regression model(with the combination of PSA,BPSA,%fPSA,%[2]ProPSA,[2] ProPSA/BPSA,and testosterone),and%fPSA were0.73,0.73, and0.53,respectively.All these findings indicate that the substantially altered PSA metabolic pathway in the occurrence and development of PCa,as well as relevant PSA mathematical models,may aid in the early recognition of PCa.Currently,the kinetic parameters of PSA,such as PSA velocity(PSAV),PSA doubling time(PSADT),and PSA halflife (PSAHL),are mainly used in monitoring treatment response and disease progression and prognosis 7 .Their significance in the early detection of PCa has yet to be developed.For the time being,serum PSA is still the most important parameter in PCa diagnosis and posttreatment followup.Therefore,it is extremely necessary to further study the metabolic pathway of PSA, relevant mathematical models for PSA,and PSA kinetics and their relationships with other tumor biomarkers,to optimize the early detection ofPCa.Hereditary prostate cancer1(HPC1),an important andsusceptible gene in PCa,is located on chromosome1(1q2425).The RNASEL(25Adependent ribonuclease)gene is located atthe lq25site.RNASEL interferes with the antiviral andantiproliferative activities mediated by the25A pathway,which,alternately,is regulated by interferon.The E265X mutation inRNASEL results in significantly reduced activity of RNASEL.Therefore,based on the linkage and segregation phenomenaidentified between PCa and the deletion mutation(E265X)andthe mutation in the initiation code(M1I)in two families carryingHPC1,RNASEL is considered a candidate allele for HPC1 8 .Inaddition,Rokman . 9 revealed in their study that deletionmutation E265X and missense mutation R462Q in RNASEL wereassociated with an increased risk for PCa.HPC1is probablyinvolved in the initiation of hereditary PCa.Yet,Rennet . 10failed to identify the association between the mutations of theRNASEL gene and PCa risk in Asian(Indian)patients with PCa.Such inconsistency may derive from the heterogeneity ofhereditary factors.Despite all this,the significance of thesestudies is not limited to illustrating the important role of geneticfactors in hereditary PCa;they also provide evidence for revealingthe complicated biologic features of PCa and for exploring newdiagnostic and treatmentstrategies.The DD3PCA3encoding gene is located on chromosome9(9q2122).The gene includes four exons and three introns.InPCa,the most frequent mutation is the selective splicing of thesecond exon.At present,there is a vast body of ongoing studieson PCA3.Hopefully they can further confirm the role of PCA3inthe occurrence and the development of PCa and provide newtreatment targets for patients with PCa.Hessels . 11 suggestedthat using quantitative reverse transcriptase polymerase chainreaction(RTPCR)for the detection of urine DD3PCA3was avaluable molecular detection method in patients with PCa andcould help reduce unnecessary biopsies.In a multicenter studydesigned to examine the diagnostic capacity of urine PCA3detection,the AUC of urine PCA3detection was0.66,while theAUC of serum PCA3detection was merely0.57.The sensitivityand specificity of PCA3detection were65%and66%,respectively 12 .Recently,researchers have suggested that serumPSA level plus PCA3detection was the most promisingdiagnostic method for PCa 13 .All these studies show that PCA3isprobably an important urine marker for PCa.It also provides anew clue for developing noninvasive detection methods for PCa.Hence,PCA3may have considerable significance in multipletumormarker screening of patients for PCa in thefuture.TMPRSS2encodes an androgendependent transmembraneserine protease.The ETS transcription factor regulates thosegenes related to cancerous biologic processes(such as cellgrowth,differentiation,and transformation).Numerous publishedstudies have already revealed the fusion of the TMPRSS2gene(which is located on21q22.3)and the ETS transcription factorfamily(such as ERG[21q22.2],ETV1[7p21.2],ETV4[17q21],and ETV5[3q28])in PCa 14 .The TMPRSS2:ETS fusion geneenables the ETS gene to be activated by the promoter of theTMPRSS2gene,and thus launches the effects of the ETStranscription factor in cancerous biologic processes.The latestresearch also revealed that the TMPRSS2:ETS fusion gene is in50%or more of earlyor middlestage localized PCa andhormoneresistant metastatic PCa,while in highgrade prostaticintraepithelial neoplasia,such gene fusion was rarely seen 15 .Furusato . 16 used RTPCR and found the TMPRSS2:ETSgene fusion in at least one tumor site in30out of45patients.In80tumor sites,39patients presented such gene fusion.Moreimportantly,the sensitivity,specificity,negative predictive value,and positive predictive value of the detection of the TMPRSS2:ETS fusion gene in urine samples were37%,93%,36%,and94%,respectively 17 .This provides evidence for developing andoptimizing urine detection for PCa in the future.Gene fusion isone of the mechanisms that initiates tumor occurrence.It isnecessary to further study the potential value of the TMPRSS2: ETS fusion gene in the early detection,targeted treatment, response evaluation,and prognostic prediction ofPCa.GSTP1is an important multifunctional detoxicating enzyme in the glutathioneStransferase family.By catalyzing the binding of electrophilic carcinogens to glutathione,glutathioneStransferase deactivates the carcinogens.The GSTP1gene methylation can silence this gene and thus disable its expression.Available studies have demonstrated that GSTP1expression was rarely seen in most ing methylationspecific PCR,methylation of the deoxycytidine in the CpG island at the5'terminal of GSTP1could be identified in intraepithelial neoplasia and PCa and in the body fluids of patients with PCa(plasma,serum, semen,and urine),but such methylation was not found in benign prostate epithelial cells 18 .Subsequently,Thompson . 19 used genomic DNA chips to compare seminal vesicles(seminal vesicles share much homogeneity with the prostate,but seminal vesicle tumors are rare),normal prostate tissue,and PCa,and also reported significantly decreased expression of GSTP1in PCa.Recent studies also showed that hypermethylation of GSTP1had statistically significant sensitivity and specificity in distinguishing PCa and benign prostatic hyperplasia 20 .Apparently, GSTP1gene methylation has deprived normal cells of protection by GSTP1and thus made them susceptible to damage by oxidation and electrophilic substances and subsequent malignant transformation.Likewise,cancerous cells may also be susceptible to attack due to the lack of GSTP1protection.Since absent or decreased GSTP1in normal cells may be related to carcinogenesis,but may be also related to better prognosis in cancer cells,the role of GSTP1changes before and after cell carcinogenesis in cancers needs to beclarified.AMACR is an enzyme that is encoded by the P504S gene (which is located on5p13)and contains382amino acids.Its main roles are to participate in the β oxidation in branched chain fatty acids and in the transformation from Risomer to Lisomer in fatty acids.For common prostate adenocarcinoma,the sensitivity of immunohistochemical staining for P504S/AMACR is80% 100% 21 .Particularly when PSA falls within the range of410 ng/mL,increased concentrations of the antiAMACR antibody can become the clue to distinguishing patients with PCa from healthy individuals.Its diagnostic sensitivity and specificity were62%and 72%,respectively 22 .However,the main shortcoming of AMACR as a biomarker for early PCa detection is that AMACR 21,23 is also expressed both in other normal tissue and in malignant tumor tissue.As a result,the specificity of AMACR as a screening approach for PCa will certainly be impaired.It is possible that AMACR is a common molecular basis for cancer occurrence, therefore it may have an important role in revealing common cancerous molecular mechanisms and common anticancertargets.GOLPH2,also known as GOLM1or GP73,is a type II Golgimembrane protein.Studies have demonstrated elevated levels ofGOLPH2mRNA expression in PCa tissue 24 .Since proteins andlipids synthesized in the endoplasmic reticulum will be furtherprocessed,modified,and classified in the Golgi apparatus andthen partially excreted out of the cells and partially transferred intothe cytomembrane and the endosome,changes in the structureand function of the Golgi apparatus may impact the structures,functions,and characteristics of the cells.Wei . 25 usedrealtime RTPCR,Western blot,and tissue microarraytechniques and further confirmed that the expression level ofGOLPH2was elevated in PCa.It was also demonstrated by thesemiquantitative evaluation system for staining intensity that theexpression level of GOLPH2was higher in PCa than in normaltissue( <0.001).The GOLPH2expression level was upregulated in567out of614tumor tissue specimens;elevatedGOLPH2expression was seen in26out of31AMACRnegativePCa specimens 26 .These findings suggest that changes in thestructures and functions of subcellular structure(Golgi apparatus,nucleus,mitochondria,and so forth)may also have an importantrole in the occurrence ofcancer.EPCA is a nuclear matrix ingimmunohistochemical staining,the staining intensity of EPCA wassignificantly different between patients with PCa and controls( <0.001),with sensitivity and specificity of84%and85%,respectively.It was also found that men with negative results onpathology but positive results for antiEPCA antibody staining inbiopsy tissue would be diagnosed with PCa within or after5years 27 .Fundamental research showed that some nuclear matrix proteinscould be seen in all types of cells and physiologic status andothers are tissuespecific or vary with cell status.In various cells,different nuclear matrix proteins maintain diverse cell nuclearshape,function,and elements.Changes in nuclear matrixproteins may be an early event in tumor occurrence.Paul . 28used ELISA(with a prespecified absorbance threshold of1.7at540nm)to compare study subjects,including patients with PCa,other tumors,or spinal cord injury,and healthy individuals,andfound that only those with PCa had serum EPCA levels above thethreshold.The EPCA level was significantly different betweenpatients with PCa and other groups,particularly healthyindividuals( <0.001),patients with bladder cancer( <0.003),and patients with spinal cord injury( <0.001),with thesensitivity and specificity of EPCA detection for PCa at92%and94%,respectively.An recent study suggested that the sensitivityand specificity of serum EPCA2in recognizing PCa were94%and92%,respectively.Moreover,it could distinguish localizedand metastatic PCa(AUC=0.89,95%CI0.820.97; <0.001) 29 .EPCA probably precedes microscopic pathologic changes and isthus a potential tumor marker that can actually detect early signsof cancer.Hence,further investigation is needed to reveal its rolein disease development and thereby provide evidence fordesigning highly sensitive and specific PCa screening methods inthefuture.In2009,Sreekumar . 30 reported the value of sarcosine inPCa.In an independent subset containing89tissue specimens,the sarcosine level was significantly elevated in localized PCa as compared to adjacent benign prostate specimens.When compared to localized PCa,the sarcosine level in metastatic specimens was even higher.When compared to a control group with negative biopsy results,the sarcosine level was significantly higher in urine sediments and urine supernatants obtained from patients with positive biopsy.The sarcosine level was markedly increased in PCa cell lines as compared to benign cell lines. Since a large number of current studies are exploring changes in genetic and protein profiles of tumors,changes in the metabolic profiles of tumors is poorly understood.Highlighting the metabolic features of tumors may help us understand tumors in a more comprehensive way and discover new diagnostic strategies and treatment targets for tumors.Therefore,this study is valuable in that it provides new directions for futurestudies.Currently,studies regarding prostatespecific membrane antigen(PSMA)are mainly focusing on investigating the value of PSMA as a treatment target by using antiPSMA dendritic cells and antiPSMA antibodies carrying radioactive isotopes or toxins, while studies with prostate stem cell antigen(PSCA)are mainly concentrating on the correlations between PSCA and the risk factors,high Gleason scores,later stage,frequent metastasis, and treatment targets of PCa.Whether they can become diagnostic or treatment tools has yet to be explored.Other tumor markers of interest include kallikreinrelated peptidase2(KLK2), urokinase plasminogen activator and receptor(uPA and uPAR), Hepsin,Annexin A3(ANAXA3),insulinlike growth factors and binding proteins(IGFs and IGFBPs),transforming growth factor 茁 1(TGF茁 1),enhancer of zeste homolog2(EZH2),prostate secretory protein94(PSP94),and cysteinerich secretory protein 3(CRISP3) 31.Environmental factors,genetic factors,or the interactionbetween the two initiate the molecular mechanisms underlyingPCa occurrence and development.So far,numerous moleculesrelated to PCa have been found,,which might derive fromdifferent stages and different molecular pathways in PCaoccurrence and development.This explains why the combinationof multiple tumor markers may improve the accuracy of PCadiagnosis.Hessels . 17 demonstrated in their study that theconcomitant detection of urine TMPRSS2:ERG fusion gene andPCA3could improve the sensitivity in diagnosing bineddetections of GOLPH2,serine peptidase inhibitor,Kazal type1(SPINK1),PCA3,and TMPRSS2:ERG fusion gene transcript inurine sediments was also better at identifying PCa than detectingPSA or PCA3alone 32 .Vener . 33 used quantitative methylationspecific PCR to measure urine GSTP1,retinoic acid receptorbeta(RARB),and adenomatous polyposis coli(APC)as earlydetectors for PCa.They reported that the sensitivity,specificity,and AUC of the combined detections of these three markers inthe first group of121patients were55%,80%,and0.69,respectively,and in the second group of113patients,thesensitivity,specificity,and AU C were53%,76%,and0.65,respectively.Schostak . 34 also reported that PSA plus urineAnnexin A3(ANAXA3)detection was better than the detection ofeither parameter alone.AUC was0.82when tPSA fell within therange of26ng/mL and was0.83when tPSA was410ng/mL.For all patients,AUC was0.81.In addition,they also foundexcellent detection capacity for the combination in the subgroupsof patients with negative results on digital rectal exam(DRE)andlow tPSA levels.Apparently,the combination of multiple tumormarkers can significantly improve diagnostic accuracy,representing an important future direction in the screening ofpatients forPCa.The studies mentioned above explored the screening of PCaon different levels(metabolic pathway,genetic,transcriptional,protein,subcellular,and metabolic),but the clinical value of thetumor biomarkers selected in these studies has not been fullyconfirmed yet,so multicenter and largescale studies areneeded.With the progress in high throughput techniques includingPCR,gene microarray,protein microarray,and the combinationof chromatogram/mass spectrogram,our ability to detect tumorbiomarkers has been greatly improved.If we can achieve thedetection of multiple tumor markers in urine to screen patients forPCa in the future,we will enjoy the convenience in just one singlesample while both reducing detection costs and avoiding thedamage from invasive procedures for patients.Negative markers(those with absent or decreased expressionin tumor tissue)may improve the specificity of detection.Thecombination of positive(those with increased expression in tumortissue)and negative markers may help optimize the multipletumormarker screening of PCa in the future.However,theproblem with the combination of multiple tumor markers is that,with a parallel combination of multiple tumor markers,thesensitivity will definitely be impaired,and when they are combinedserially,the specificity will be decreased.Therefore,in futurestudies on tumor screening and early detection,it is veryimportant to optimize a group of tumor markers with highsensitivity and specificity and to establish a perfectly sensitiveand specific detection model that can effectively integrate(ratherthan simple parallel or serial combinations)selected tumormarkers.At present,a number of studies are still centering on thechanges in one gene or one protein.However,tumor occurrenceand development is a dynamic and interrelated process.It istherefore extremely significant to establish genomic,transcriptomic,proteomic,metabonomic,and subcellular(Golgiapparatus,mitochondria,nucleus,ribosome,and so forth)information that covers the dynamic transformation from normalto abnormal cells on genetic,transcriptional,protein,metabolic,and subcellular levels.Since those information take intoconsideration the relationships among the various componentsand the interactions between the various components and cellsand are capable of revealing relevant biologic networks and咱员暂咱圆暂咱猿暂咱源暂咱缘暂咱远暂咱苑暂咱愿暂咱怨暂咱员园暂咱员员暂咱员圆暂咱员 3暂 relationships between abnormal expression and abnormal function,they will definitely be helpful in fully understanding the complicated biologic features of PCa and in establishing and optimizing the multiple tumormarker screening models for PCa.So far,most studies have selected patients with highrisk PCa as rated by existing clinical standards.Therefore,the sensitivity and specificity of tumor markers for screening the general population may be impacted and those tumor markers that can actually recognize early signs of cancer are probably neglected. On the other hand,the gold standard for diagnosis of PCa in existing clinical settings is that cancerous cells have been detected in the tissue samples,which may lag behind the progress in tumor ing this criteria in future studies may thus decrease the sensitivity of some tumor markers. Hence,study methods need to be further optimized.Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostatecancer among men with a prostate鄄 specific antigen level < or =4.0 ng per milliliter [J]. N Engl J Med, 2004, 350(22):2239-2246.Stamey TA, Johnstone IM, McNeal JE, et al. Preoperative serum prostatespecific antigen levels between 2 and 22ng/mL correlate poorly with post鄄 radical prostatectomy cancer morphology: prostate specific antigen curerates appear constant between 2 and 9 ng/mL [J]. J Urol, 2002,167(1):103-111.Scattoni V, Zlotta A, Montironi R, et al. Extended and saturation prostaticbiopsy in the diagnosis and characterisation of prostate cancer: a criticalanalysis of the literature [J]. Eur Urol, 2007,52(5):1309-1322.Roddam AW, Duffy MJ, Hamdy FC, et al. Use of prostate鄄 specific antigen(PSA) isoforms for the detection of prostate cancer in men with a PSAlevel of 2-10 ng/mL: systematic review and meta鄄 analysis [J]. Eur Urol, 2005,48(3):386-399.Bratslavsky G, Fisher HA, Kaufman RP Jr, et al. PSA鄄 related markers inthe detection of prostate cancer and high鄄 grade disease in thecontemporary era with extended biopsy [J]. Urol Oncol, 2008,26(2):166- 170.Sokoll LJ, Wang Y, Feng Z, et al. [-2]proenzyme prostate specificantigen for prostate cancer detection: a national cancer institute early detection research network validation study [J]. J Urol, 2008,180(2):539-543.Fitzpatrick JM, Banu E, Oudard S. Prostate鄄 specific antigen kinetics inlocalized and advanced prostate cancer [J]. 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Clin Cancer Res, 2007,13(3):939-943.Neves AF, Ara俨 jo TG, Biase WK, et al. Combined analysis of multiplemRNA markers by RT鄄 PCR assay for prostate cancer diagnosis [J]. ClinBiochem, 2008,41(14-15):1191-1198.Yoshimoto M, Joshua AM, Cunha IW, et al. Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome [J]. Mod Pathol, 2008,21(12):1451-1460.Mehra R, Tomlins SA, Yu J, et al. Characterization of TMPRSS2鄄 ETS gene aberrations in androgen鄄 independent metastatic prostate cancer [J]. Cancer Res, 2008,68(10):3584-3590.Furusato B, Gao CL, Ravindranath L, et al. Mapping of TMPRSS2鄄 ERG fusions in the context of multi鄄 focal prostate cancer [J]. Mod Pathol, 2008,21(2):67-75.Hessels D, Smit FP, Verhaegh GW, et al. Detection of TMPRSS2鄄 ERG fusion transcripts and prostate cancer antigen 3 in urinary sediments may improve diagnosis of prostate cancer [J]. Clin Cancer Res, 2007,13(17): 5103-5108.Meiers I, Shanks JH,Bostwick DG. 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EPCA鄄 2: A highly specific serum marker for prostate cancer [J]. Urology, 2007,69(4):714-720.Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression [J]. Nature, 2009, 457(7231): 910-914.Sardana G,Dowell B, Diamandis EP. Emerging biomarkers for the diagnosis and prognosis of prostate cancer [J]. Clin Chem, 2008, 54(12): 1951-1960.Laxman B, Morris DS, Yu J, et al. A first generation multiplex biomarker analysis of urine for the early detection of prostate cancer [J]. Cancer Res, 2008,68(3):645-649.Vener T, Derecho C, Baden J, et al. Development of a multiplexed urine assay for prostate cancer diagnosis [J]. Clin Chem, 2008,54(5):874-882. Schostak M, Schwall GP, Poznanovic S, et al. Annexin A3 in urine: a highly specific noninvasive marker for prostate cancer early detection [J]. J Urol, 2009,181(1):343-353.咱14暂咱15暂咱16暂咱17暂咱18暂咱19暂咱20暂咱21暂咱22暂咱23暂咱24暂咱25暂咱26暂咱27暂咱28暂咱29暂咱30暂咱31暂咱32暂咱33暂咱34暂。

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ORIGINAL ARTICLEThe new insight of prostate-speciﬁc antigen reduction during ﬁnasteride therapy in aging menDing Xu 1•Jie Ding 1•Yunkai Zhu 2•Xiaoqiang Qian 1•Liujian Duan 1•Jun Qi 1Received:24November 2015/Accepted:26November 2015ÓSpringer International Publishing Switzerland 2016AbstractObjective To evaluate the effect of ﬁnasteride on pros-tate-speciﬁc antigen (PSA)in Chinese population.Materials and methods From Feb 2011to Jan 2012,83benign prostatic hyperplasia (BPH)patients with prostate volume (PV)[30mL were enrolled in our study.All the patients were older than 50years and all of them received combined therapy (ﬁnasteride ?doxazosin).All the patients were required for 1-year follow-up.PSA level and PV was measured at the start,6and 12months,respectively.Results 79patients completed the follow up.PSA level reduced by approximately 40%during ﬁnasteride therapy.We deﬁned baseline PSA as PSA1,PSA at 6months as PSA2,PSA at 12months as PSA3.PSA1was signiﬁcantly correlated with PSA2/PSA1and PSA3/PSA1.However,prostate volume was not correlated with PSA1.We divided the patients into three groups according to PSA level.Groups 1,2,3represented the patients with PSA less than 2ng/mL,between 2and 4ng/mL and greater than 4ng/mL,respectively.Both the PSA2/PSA1and the PSA3/PSA1had signiﬁcant difference among three groups.Fur-thermore,group 1and group 2both showed the fairly large data variance.Conclusions When baseline PSA level was greater than 4ng/mL,the doubling rule could be used for screening.When baseline PSA level was less than 4ng/Ml,the dou-bling rule might not be an accurate predictor.We can use the PSA rise from nadir or proPSA to predict prostate cancer.Keywords Benign prostatic hyperplasia ÁProstate-speciﬁc antigen ÁFinasterideIntroductionBenign prostate hyperplasia (BPH),manifesting with lower urinary tract symptoms (LUTS),such as frequency,urgency,nocturia and dysuria,is one of the most common urological diseases among elderly men.The incidence of BPH increases from 50%in 60-year-old men to almost 100%in 80-year-old men [1].And the cost of BPH treatment ranges from $5824to $50,000per quality adjusted life year (QALY)[2].Furthermore,BPH can also be progressive,with a risk of urinary retention,bladder infection,hematuria,bladder stone,hydronephrosis and renal failure [3–5].Finasteride,a selective inhibitor of 5a -reductase,acts chemically by blocking dihydrotestosterone production and shrinking prostate volume [6,7]which ﬁrstly identiﬁed in 1984by Rasmusson et al.[8],is one of the ﬁrst medication used in treatment of BPH.From PLESS study,after 4-year follow-up,the prostate volume of ﬁnasteride group shrinked by 18%.On the contrary,the prostate volume of placebo group enlarged by 14%[9].Nowadays ﬁnasteride remains one of the most important drugs in BPH treatment.Prostate-speciﬁc antigen (PSA)testing,which was introduced into clinical use as a biochemical marker ofD.Xu and J.Ding contributed equally to this article.&Jun Qilisterdingzai@;jasonqi@1Department of Urology,XinHua Hospital Afﬁliate to Shanghai Jiao Tong University School of Medicine,1665Kongjiang Rd,Shanghai 200092,China2Department of Ultrasound,XinHua Hospital Afﬁliate to Shanghai Jiao Tong University School of Medicine,Shanghai,ChinaAging Clin Exp ResDOI 10.1007/s40520-015-0512-3recurrence in the mid-1980s,has become one of the stan-dard diagnostic and followup tools for prostate cancer[10]. In countries where the use of PSA for screening is wide-spread,it has contributed to an increased rate of prostate cancer diagnosis in the last decade[11],especially for early detection of this disease[12].Sinceﬁnasteride was widely used in the world,doctors found that PSA level could be suppressed duringﬁnasteride therapy.PCPT and other articles reported that PSA were reduced by approximately50%after several months of treatment[10,13].To keep the initial sensitivity and speciﬁcity of PSA test,Gormley et al.have proposed that the‘‘true’’PSA level inﬁnasteride treated men can be obtained by multiplying the observed level by a factor of2 [14].Thus,by doubling the PSA level,PSA could still be useful theoretically as a screening test for prostate cancer in men undergoingﬁnasteride treatment for BPH[15].However,most of the studies were carried out in developed countries,such as America and Europe.While several studies in other areas reached different conclusions.A study from Korea found that PSA decreased by only about36%after1-yearﬁnasteride taking[16].The aim of our study was to evaluate the effect ofﬁnasteride on PSA in aging men.Patients and methodsFrom Feb2011to Jan2012,83BPH patients older than 50years old,who visited our BPH outpatient department with prostate volume(PV)[30mL,were enrolled in our study.All the patients were diagnosed BPH on the basis of history,symptoms,physicalﬁndings and ultrasound.All the enrolled patients were evaluated by the digital rectal examination(DRE),height(cm),weight(kg),Body mass index(BMI),serum tPSA level(ng/mL)and PV(mL) when they initially visited our department.All of them signed their consents on a written form of information with guarantees of conﬁdentiality and received combined ther-apy[ﬁnasteride(Proscar,provided by MSD)5mg qd po?doxazosin(Cardura,provided by Pﬁzer)4mg qn po] for1year,for doxazosin had no impact on PSA[17].If PSA was greater than4ng/mL of abnormal DRE was found,a prostate biopsy is required to conﬁrm whether it was benign or not.Criteria for inclusion were age C50years,BPH which were conﬁrmed by the ultrasound or prostate biopsy.Cri-teria for exclusion were age\50years,previous bladder, prostate or urethral operation,previous treatment for BPH, prostate or bladder malignant tumor,urethral stricture, bladder stone,neurogenic bladder dysfunction,chronic urinary tract infection,chronic renal insufﬁciency and diabetes mellitus.All the patients were required for1-year follow-up.PSA level was measured at the start,6and12months,respec-tively.And we also measured PV at the start,6and 12months.After the follow-up,all the patients need to receive the prostate biopsy.The blood sample was drawn in the clinical laboratory in our hospital before any prostatic manipulations that might cause a transient increase of tPSA.The sample was preserved in4°refrigerator and then sent for analysis in 4h,using Hybritech calibrated Access tPSA assays.The ultrasound machine made by Siemens sequoia512(Linear array probe15L8W,frequency3–8MHz)was used to estimate prostate volume(mL).The parameters of prostate volume were measured by transrectal ultrasound(TRUS), which were all done by one experienced radiologist(Yun-kai Zhu).Images were obtained with the patient in the left decubitus position.PV were calculated using the formula of volume estimation of an ellipsoid:vol-ume=0.529transverse diameter(mm)9anteroposte-rior diameter(mm)9superoinferior diameter(mm).The 10-cores prostate biopsy was taken by two experienced radiologist guided by the TRUS.Specimens were pro-cessed and evaluated by a single experienced genitourinary pathologist.Statistical package for social science(SPSS),version 19.0was used for our statistic analysis.The data were presented as the mean±SD.Bivariate correlation was used toﬁnd the correlation between PSA and the other parameters.One-way ANOVA test was used to compare the delining rate of PSA among groups with different baseline PSA levels.For all statistic tests,a P value\0.05 was considered to be statistically signiﬁcant.ResultsFinally,79patients completed the follow up.Four patients withdrew from study,two patients lost the contact and two patients refused to continue the combined therapy and follow up.All the patients had negative DRE result and no patient was conﬁrmed prostate cancer according to the prostate biopsy.Characteristics of enrolled patients are shown in Table1.We deﬁned baseline PSA as PSA1,PSA at6months as PSA2,PSA at12months as PSA3.Accordingly,we also deﬁned PV1,PV2,PV3.Figure1showed the change of PSA and PV.PSA level reduced by approximately40%duringﬁnasteride therapy. PV shrinked by about13%after1year,which seemed a little weaker than that in PLESS study.Table2showed that PSA1was signiﬁcantly correlated with PSA2/PSA1and PSA3/PSA1.The higher the PSA1, the lower PSA2/PSA1and PSA3/PSA1,which means theAging Clin Exp Resgreater the declining rate.However,PSA1was not corre-lated with PV,height,weight and BMI.Similarly,PSA2/PSA1and PSA3/PSA1were both not correlated with PV2/PV1,PV3/PV1,height,weight and BMI.We divided the patients into three groups according to PSA level.Groups 1,2,3represented the patients with PSA less than 2ng/mL,between 2and 4ng/mL and greater than 4ng/mL,respectively.Table 3indicates that both the PSA2/PSA1and the PSA3/PSA1had signiﬁcant difference among three groups.Furthermore,group 1and group 2from Table 3both showed the fairly large data variance.DiscussionAs a result,our study suggested that PSA decreased 36.71%after 1year of ﬁnasteride taking,which was similar with the result of the study from Korea [16].After dividing the patients into three groups according to the baseline PSA,it is found that PSA decreased approxi-mately 50%during ﬁnasteride therapy when baseline PSA was greater than 4ng/mL and only about 30%when baseline PSA was less than 2ng/mL,indicating that the widely used doubled PSA rule may not always beappropriate for prostate cancer screening in men received ﬁnasteride treatment in Chinese population,especially in the group of men with baseline PSA was less than 2ng/mL.Serum PSA is a product of prostate epithelial cells that receives direct stimulation from intracellular dihy-drotestosterone [18]via inhibition of 5a-reductase,ﬁnas-teride blocks the conversion of testosterone to dihydrotestosterone in these cells and,thus,reduces the level of dihydrotestosterone.In other words,ﬁnasteride deprives prostate epithelial cells of a major trophic stim-ulus [19].As a result,PSA secretion by prostate epithelialTable 1The characteristics of enrolled patients (n =79)Mean SD Age 70.708.287Height (cm)174.89 5.294Weight (kg)70.7810.94BMI 23.03 2.54PSA (ng/mL) 3.40 2.33PV (mL)45.8015.34BMI body mass index,PSA prostate-speciﬁc antigen,PV prostatevolumeFig.1The change of PSA level and prostate volume during ﬁnasteride therapy.PSA level reduced by 39.33±14.86%after 6months and 35.91±25.13%after 12months.Prostate volume shrinked by 13.58%after 1yearTable 2Correlation among PSA and other parameters Parameter 1Parameter 2r value P value PSA1PSA2/PSA1-0.541\0.001*PSA1PSA3/PSA1-0.492\0.001*PSA1PV10.1580.164PSA1PV2/PV10.0710.537PSA1PV3/PV10.0610.591PSA1Height -0.0270.812PSA1Weight -0.0800.483PSA1BMI -0.0190.867PSA2/PSA1PV2/PV1-0.1060.351PSA2/PSA1Height 0.1710.131PSA2/PSA1Weight 0.0680.552PSA2/PSA1BMI 0.0270.813PSA3/PSA1PV3/PV10.0420.714PSA3/PSA1Height 0.1990.079PSA3/PSA1Weight 0.1460.198PSA3/PSA1BMI0.1850.102PSA1baseline PSA,PSA2PSA at 6months,PSA3PSA at 12months PV1baseline PV,PV2PV at 6months,PV3PV at 12months *P \0.01Aging Clin Exp Rescells is reduced and serum PSA levels fall in men treated withﬁnasteride[20].How these drug induced changes affect the value of PSA as a screening test for prostate cancer is still unknown.Low level of dihydrotestosterone causes the elevation of stromal-to-epithelial ratio.Based on histological examina-tion of prostate tissue from men with BPH before and after 6months ofﬁnasteride treatment,Montironi et al. demonstrated that the percent epithelium in the transitional zone was reduced from13.5to6%,the stromal-to-ep-ithelial ratio increased from4.4to10.3%and the total prostate volume decreased by more than25%in ten of26 treated men[21].After6months of treatment withﬁnas-teride overall prostate tissue composition in the peripheral zone,however,was not signiﬁcantly changed[22].In another study on prostate of hamster Mesocricetus auratus,after90days ofﬁnasteride taking,it is found a remarkable decrease in the acinous area as well as the area of the acinous epithelium occurred in the animals that receivedﬁnasteride.AgNORs were less expressed in ﬁnasteride treated animals and apoptosis was more intense in the experimental group.However,there was no statis-tical difference in the cellularity between both groups, maybe suggested that90days of treatment was not long enough to reduce the number of cells in the acinous of these animals[23].Why the declining rate of PSA in our study is different from other studies?Maybe the effect ofﬁnasteride on prostate is not the same among different races.In PLESS study,prostate volume shrinked by18%after1year of ﬁnasteride treatment.However,in our study,prostate vol-ume shrinked only by about13%.Genetic polymorphisms on type II5a-reductase genes may affect enzyme activity and,thus,lead to individual variability in drug efﬁcacy. Previous studies demonstrated that several mutations on the SRD5A2gene changed the type II5a-reductase expression level[24].A comprehensive association study of SNPs on the SRD5A2gene in a Chinese population showed that rs523349and rs612224on SRD5A2were signiﬁcantly associated with the change in IPSS and PSA afterﬁnasteride treatment[25].The SNP rs523349is also known as V89L(the89th amino acid changes from valine to leucine),which is a missense(or nonsynonymous) variant located in exon1of the SRD5A2gene[26].A pooled analysis of SRD5A2genotype frequencies in control populations demonstrated variation among racial/ ethnic groups[27].Frequency of the L allele at codon89 was highest among Asians(54.8%),followed by whites (30.4%)and African Americans(23.1%);Africans were least likely to carry this variant(18.8%)[28].This may explain why the declining rate of PSA and the effect of ﬁnasteride are both different in different races.Further-more,rs523349and rs612224were both not correlated with the change of PV[24],which was consistent with the result in our study.In our study,PSA level in the patients with PSA level less than4ng/ml showed the fairly large data variance, maybe due to the individual variability in drug efﬁcacy. Leonard et al.propose that a PSA increase from nadir of 0.3ng/mL or greater should be used as an additional biopsy trigger in men receiving a5ARI for BPH[10].The PSA increase from nadir appears to be a more accurate harbinger of cancer than a doubling rule in some patients, but it still should be conﬁrmed by further data from large clinical trials.Our study also had some limitations.The current study has fairly low sample volume and has no data of the blood dihydrotestosterone level and the information of SNPs. What’s more,the study lacks long-time follow-up to fur-ther conﬁrm ourﬁnding.Therefore,in the further study,we will expand our sample volume and extend the time of follow-up.Meanwhile,we will study the declining con-sistence between PSA and dihydrotestosterone in order to increase the diagnostic accuracy of prostate cancer.We could also further study the correlation between SNPs and PSA declining rate in different baseline PSA group.In addition,we will study the effect ofﬁnasteride on proPSA to evaluate the diagnostic accurary of prostate cancer in the patients receivedﬁnasteride treatment.ConclusionTo make a brief conclusion of ourﬁnding,when baseline PSA level was greater than4ng/mL,PSA level decreased by approximately50%,as reported by earlier documents. In such cases,the doubling rule could be used for screening in China.While,when baseline PSA level was less than 4ng/mL,PSA delinced by less than50%,the doubling rule might not be an accurate predictor.On the other hand,greatTable3The effect ofﬁnasteride on PSA in different PSA levelGroup1(n=28)(%)Group2(n=26)(%)Group3(n=25)(%)P valuePSA2/PSA10.7100±18.990.5596±13.410.5368±6.76\0.001* PSA3/PSA10.7633±33.380.5658±15.750.5137±8.71\0.001* PSA1baseline PSA,PSA2PSA at6months,PSA3PSA at12months*P\0.01Aging Clin Exp Resvariance in data might also affect the accuracy of predic-tion.Our study result is beneﬁt for us to use the doubling rule to predict prostate cancer.Acknowledgments The authors wish to thank all patients for their ongoing participation in this study.The authors also wish to thank Wen-bin Guan for his contribution of specimen procession and evaluation to this article.Funding This study was funded by a grant from Science and Technology Commission of Shanghai Municipality(CN)(No. 134119a0600and14430720800).Compliance with ethical standardsConﬂict of interest The authors declare that they have no conﬂict of interest.Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of Xinhua Hospital Afﬁliated to Shanghai University School of Medicine and with the1964Helsinki declaration and its later amendments or comparable ethical standards. 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