Correlates of estimated lifetime cruciate ligament survival inform potential rupture risk reduction strategies: findings from the Exceptional Aging in Rottweilers Study.

Cranial cruciate ligament (CCL) rupture is one of the most commonly diagnosed orthopedic conditions of pet dogs, making estimated lifetime cruciate ligament survival an attractive endpoint for studies attempting to define clinical and genetic correlates of rupture risk reduction. Early life experiences contribute significantly to the origins of adult health outcomes, yet our current understanding of modifiable susceptibility factors that drive the high frequency of CCL rupture remains limited. We reasoned that combining lifetime medical history with standardized late-life assessment of lifetime cruciate ligament survival and detailed phenotyping of each dog for selected risk variables would provide a sensitive approach to identify factors that would differentiate between lifelong avoidance versus susceptibility to ligament rupture. Here, we report results of Kaplan-Meier analysis of estimated lifetime cruciate ligament survival and Cox proportional hazards modeling to assess risk variables in a lifetime cohort study of 123 purebred Rottweilers, a breed at high risk for veterinarian-diagnosed CCL rupture. We show that gonad removal during the 24-month developmental period is adversely associated with three measures of susceptibility-increased incidence of CCL rupture, multiplicity (bilateral rupture), and accelerated time to initial CCL failure. Our analysis reveals two other phenotypes-short adult height and the production of offspring (in females)-are associated with significant CCL rupture risk reduction. Together, the results provide clues to an early endocrine influence on lifetime cruciate ligament survival. Further, we identify two distinct clinical syndromes of CCL failure, providing a disease subtyping framework to advance future progress in genetic epidemiology, pathogenesis, and prediction. By conducting an evaluation of estimated lifetime CCL survival in dogs, we show that cruciate ligament survival may be jeopardized by gonad removal during the developmental period. Avoidance of such early environmental adversity may represent an actionable method for the control of canine CCL disease in certain breeds.

A modern pulse of ultrafast exhumation and diachronous crustal melting in the Nanga Parbat Massif.

We combine monazite petrochronology with thermal modeling to evaluate the relative roles of crustal melting, surface denudation, and tectonics in facilitating ultrafast exhumation of the Nanga Parbat Massif in the western Himalayan syntaxis. Our results reveal diachronous melting histories between samples and a pulse of ultrafast exhumation (9 to 13 mm/year) that began ~1 Ma and was preceded by several million years of slower, but still rapid, exhumation (2 to 5 mm/year). Recent studies show that an exhumation pulse of similar timing and magnitude occurred in the eastern Himalayan syntaxis. A synchronous exhumation pulse in both Himalayan syntaxes suggests that neither erosion by rivers and/or glaciers nor a pulse of crustal melting was a primary trigger for accelerated exhumation. Rather, our results, combined with those of recent studies in the eastern syntaxis, imply that larger-scale tectonic processes impose the dominant control on the current tempo of rapid exhumation in the Himalayan syntaxes.

Devising a new dialogue for nutrition science: how life course perspective, U-shaped thinking, whole organism thinking, and language precision contribute to our understanding of biological heterogeneity and forge a fresh advance toward precision medicine.

The process of designing and implementing individualized health-promoting interventions, nutritional or otherwise, is fraught with great difficulty owing to the heterogeneity inherent in factors that influence healthy longevity. This article proposes that careful attention to three principles-life course perspective, U-shaped thinking, and whole organism thinking-creates an attitudinal framework that can be used to reframe biological heterogeneity into the clinically relevant question: Who will benefit? The search for tools to cope with the complexity of this heterogeneity has been dominated by technological advances, including state-of-the-art "-omics" approaches and machine-based handling of "big data." Here, it is proposed that language precision and nuanced category usage could provide critical tools for coping with heterogeneity, thereby enabling interventionalists to design and implement strategies to promote healthy longevity with greater precision. The lack of a clear understanding of "Who will benefit?" stands as a major obstacle to the design and implementation of nutritional strategies to optimize healthy longevity. This article opens a new dialogue situating the principles of life course perspective, U-shaped thinking, and whole organism thinking, along with cultivating an attitude of language precision at the very core of accelerating creative discovery and refining practical advance in the field of nutrition science.

A pedagogical strategy addressing an unmet need: Making the biology of aging an accessible part of interdisciplinary gerontology education.

In an age of specialization, obstacles to interdisciplinary training and integrated intellectual growth are expected. One such obstacle to graduate-level training in gerontology is the challenge of making the biology of aging accessible to nonbiologists. In this article, the authors' aim is to share 15 years of experience developing a pedagogical strategy that situates the biology of aging as an accessible part of interdisciplinary gerontology education for nonbiologists and biologists alike. The approach hinges on a four-pronged learning opportunity-four course offerings-that places high priority on exactitude with language and sees development of an attitude of precision with language as essential to intellectual growth. By inspiring students to master language in the key of B-Biology of Aging-we unleash a versatile method for developing cross-disciplinary discoverers prepared for a lifetime of seeing and reporting.

Five threads: How U-shaped thinking weaves together dogs, men, selenium, and prostate cancer risk.

Prostate cancer is one of the leading causes of cancer-related mortality among men living in developed countries, making the development of safe, practical approaches to prostate cancer risk reduction a high research priority. The relationship between prostate cancer risk and selenium, an essential nutrient required for a number of metabolically important enzymes including glutathione peroxidases, has been investigated, but a satisfactory integration of results has proven elusive. Dogs, like men, naturally develop prostate cancer during aging, providing an appropriate context to study the effects of selenium supplementation on the dysregulation of homeostasis that drives cancer development within the aging prostate. In this paper, we summarize the translational significance of research results gained from dog studies on selenium and prostate cancer risk. Our discovery of a U-shaped dose-response between toenail selenium concentration and prostatic DNA damage in dogs remarkably parallels data on the relationship between selenium status and prostate cancer risk in men. Notably, the dog U-curve provides a plausible explanation for the unanticipated increase in prostate cancer incidence among men with highest baseline selenium who received selenium supplementation in the largest-ever prostate cancer prevention trial (SELECT). Moreover, the dog U-curve guided the discovery of a non-antioxidant, anti-carcinogenic mechanism of organic selenium - the preferential triggering of apoptosis in DNA damaged cells, which we have termed "homeostatic housecleaning". Taken together, the data from dogs and men indicate that increasing selenium status will not necessarily be associated with prostate cancer risk reduction. Landing in the trough of the U - achieving mid-range selenium status - is better than being too low or too high. Personalizing health promotion in a more-is-not-necessarily-better world poses distinctive challenges. Dog studies can be relied upon to contribute important insights into dose-dependent and form-dependent effects - two critical aspects of selenium biology that will have to be disentangled if the burgeoning science of selenium is to be translated into effective strategies for human disease prevention. Beyond contributing to understanding the role of selenium in biology, our work situates the concept of U-shaped thinking at the core of personalized medicine and precision nutrition.

Homeostatic housecleaning effect of selenium: evidence that noncytotoxic oxidant-induced damage sensitizes prostate cancer cells to organic selenium-triggered apoptosis.

The anti-cancer activity of organic selenium has been most consistently documented at supra-nutritional levels at which selenium-dependent, antioxidant enzymes are maximized in both expression and activity. Thus, there is a strong imperative to identify mechanisms other than antioxidant protection to account for selenium's anti-cancer activity. In vivo work in dogs showed that dietary selenium supplementation decreased DNA damage but increased apoptosis in the prostate, leading to a new hypothesis: Organic selenium exerts its cancer preventive effect by selectively increasing apoptosis in DNA-damaged cells. Here, we test whether organic selenium (methylseleninic acid; MSA) triggers more apoptosis in human and canine prostate cancer cells that have more DNA damage (strand breaks) created by hydrogen-peroxide (H2O2) at noncytotoxic doses prior to MSA exposure. Apoptosis triggered by MSA was significantly higher in H2O2-damaged cells. A supra-additive effect was observed--the extent of MSA-triggered apoptosis in H2O2-damaged cells exceeded the sum of apoptosis induced by MSA or H2O2 alone. However, neither the persistence of H2O2-induced DNA damage, nor the activation of mitogen-activated protein kinases was required to sensitize cells to MSA-triggered apoptosis. Our results document that selenium can exert a "homeostatic housecleaning" effect--a preferential elimination of DNA-damaged cells. This work introduces a new and potentially important perspective on the anti-cancer action of selenium in the aging prostate that is independent of its role in antioxidant protection.

Prostatic response to supranutritional selenium supplementation: comparison of the target tissue potency of selenomethionine vs. selenium-yeast on markers of prostatic homeostasis.

Prostate cancer is the product of dysregulated homeostasis within the aging prostate. Supplementation with selenium in the form of selenized yeast (Se-yeast) significantly reduced prostate cancer incidence in the Nutritional Prevention of Cancer Trial. Conversely, the Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed no such cancer-protective advantage using selenomethionine (SeMet). The possibility that SeMet and Se-yeast are not equipotent in promoting homeostasis and cancer risk reduction in the aging prostate has not been adequately investigated; no direct comparison has ever been reported in man or animals. Here, we analyzed data on prostatic responses to SeMet or Se-yeast from a controlled feeding trial of 49 elderly beagle dogs-the only non-human species to frequently develop prostate cancer during aging-randomized to one of five groups: control; low-dose SeMet, low-dose Se-yeast (3 µg/kg); high-dose SeMet, high-dose Se-yeast (6 µg/kg). After seven months of supplementation, we found no significant selenium form-dependent differences in toenail or intraprostatic selenium concentration. Next, we determined whether SeMet or Se-yeast acts with different potency on six markers of prostatic homeostasis that likely contribute to prostate cancer risk reduction-intraprostatic dihydrotestosterone (DHT), testosterone (T), DHT:T, and epithelial cell DNA damage, proliferation, and apoptosis. By analyzing dogs supplemented with SeMet or Se-yeast that achieved equivalent intraprostatic selenium concentration after supplementation, we showed no significant differences in potency of either selenium form on any of the six parameters over three different ranges of target tissue selenium concentration. Our findings, which represent the first direct comparison of SeMet and Se-yeast on a suite of readouts in the aging prostate that reflect flux through multiple gene networks, do not further support the notion that the null results of SELECT are attributable to differences in prostatic consequences achievable through daily supplementation with SeMet, rather than Se-yeast.

Differential responses to selenomethionine supplementation by sex and genotype in healthy adults.

A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 µg/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9-12 months and was linearly related to effective Se dose (µg/d per kg0·75). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Se(pl-target)) is: Se(in) = [(Se(pl - target) - Se(pl))/(18.2ng d kg°.75/ml per mu g)] .

On the self-renewal of teachers.

In previous issues of the Journal of Veterinary Medical Education, wide-ranging insights on how to achieve excellence in the classroom have been framed by award-winning teachers. These recipes for educational success, however, invariably lack a key ingredient-the teacher's process of self-renewal. What skills and attitudes prime the teacher for continued high performance? To stay out of the ruts of expertise, where does the teacher turn? Teachers and administrators alike recognize its great importance, yet few opportunities for the renewal of teachers are built into the educational system. In this article, we challenge teachers to see their own self-renewal as an underutilized approach to innovate education. We propose a schema for sustained self-renewal: each educator developing her own personalized, hand-picked gallery of intellectual heroes who in turn serve as the educator's life-long teachers. To illustrate the value of this activity, we introduce our own collection of 10 gifted thinkers, providing a brief encounter with each sage as a way of stimulating new thinking on the skills and attitudes that promote personal growth and transformative teaching. We conclude that the veterinary profession should work to create better opportunities for the self-renewal of teachers. By envisioning even our best teachers as unfinished and under construction, we open up a new dialogue situating the self-renewal of teachers at the very core of educational excellence.

Aging research 2011: exploring the pet dog paradigm.

Researchers are counting on comparative biologists to find alternative animal models of human aging that will foster experimental approaches to study disability-free longevity, not just the addition of years. This article presents one such alternative: the use of pet dogs living in the same environment as people to study the determinants of healthy longevity. There are both theoretical and practical reasons for this research model beyond the well-documented physiologic similarities between dogs and humans. First, a wealth of medical data--based on clinical and biochemical evaluation, medical imaging, and pathology--is available for pet dogs. Second, a vast array of phenotypic domains can be accurately assessed in dogs, ranging from cardiac contractility and glomerular integrity to the ability to climb stairs and interact with people. Moreover, studying pet dogs obviates the purchase and per diem costs typically associated with large animal research. Pet dogs may be particularly well suited for exploring (1) mechanisms of sex differences in longevity; (2) interventions to compress morbidity and enhance healthspan; (3) genomic correlates of successful aging phenotypes and endophenotypes; (4) heterogeneity in resistance to aging-related diseases, such as cancer; and (5) noninvasive biomarkers of particular target organs. Finally, between-breed differences in senescence trajectories and longevity may expand hypotheses of key genetic factors that contribute to sustained organ function and the postponement of disease. Yet the pet dog paradigm in aging research is nascent; tapping into the potential of this model will add to the existing strengths of conventional model systems.

Hydrophilic agarose macrobead cultures select for outgrowth of carcinoma cell populations that can restrict tumor growth.

Cancer cells and their associated tumors have long been considered to exhibit unregulated proliferation or growth. However, a substantial body of evidence indicates that tumor growth is subject to both positive and negative regulatory controls. Here, we describe a novel property of tumor growth regulation that is neither species nor tumor-type specific. This property, functionally a type of feedback control, is triggered by the encapsulation of neoplastic cells in a growth-restricting hydrogel composed of an agarose matrix with a second coating of agarose to form 6- to 8-mm diameter macrobeads. In a mouse cell model of renal adenocarcinoma (RENCA cells), this process resulted in selection for a stem cell-like subpopulation which together with at least one other cell subpopulation drove colony formation in the macrobeads. Cells in these colonies produced diffusible substances that markedly inhibited in vitro and in vivo proliferation of epithelial-derived tumor cells outside the macrobeads. RENCA cells in monolayer culture that were exposed to RENCA macrobead-conditioned media exhibited cell-cycle accumulation in S phase due to activation of a G(2)/M checkpoint. At least 10 proteins with known tumor suppression functions were identified by analysis of RENCA macrobead-conditioned media, the properties of which offer opportunities to further dissect the molecular basis for tumor growth control. More generally, macrobead culture may permit the isolation of cancer stem cells and other cells of the stem cell niche, perhaps providing strategies to define more effective biologically based clinical approaches to treat neoplastic disease.

Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogs.

To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine 'centenarians'--exceptionally long-lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest-old Rottweilers (age at death, > or = 13 years) were compared to a cohort of Rottweilers that had usual longevity (age at death, 8.0-10.8 years). Like women, female dogs were more likely than males to achieve exceptional longevity (OR, 95% CI = 2.0, 1.2-3.3; P = 0.006). However, removal of ovaries during the first 4 years of life erased the female survival advantage. In females, a strong positive association between ovaries and longevity persisted in multivariate analysis that considered other factors, such as height, body weight, and mother with exceptional longevity. A beneficial effect of ovaries on longevity in females could not be attributed to resistance against a particular disease or major cause of death. Our results document in dogs a female sex advantage for achieving exceptional longevity and show that lifetime ovary exposure, a factor not previously evaluated in women, is associated with exceptional longevity. This work introduces a conceptual framework for designing additional studies in pet dogs to define the ovary-sensitive biological processes that promote healthy human longevity.

Supplemental dietary racemic equol has modest benefits to bone but has mild uterotropic activity in ovariectomized rats.

Soy isoflavones and their metabolites, with estrogenic activity, have been considered candidates for reducing postmenopausal bone loss. In this study, we examined the effect of dietary equol, a bioactive metabolite of the soy isoflavone daidzein, on equol tissue distribution, bone parameters, and reproductive tissue activity using an adult ovariectomized (OVX) rat model. An 8-wk feeding study was conducted to compare 4 dietary treatments of equol (0, 50, 100, 200 mg/kg diet) in 6-mo-old OVX female Sprague-Dawley rats. A dose response increase in tissue equol concentrations was observed for serum, liver, kidney, and heart, and a plateau occurred at 100 mg equol/kg diet for intestine. In OVX rats receiving 200 mg equol/kg diet, femoral calcium concentration was greater than those receiving lower doses but was still less than SHAM (P < 0.05), and other bone measures were not improved. Tibia calcium concentrations were lower in OVX rats receiving 100 and 200 mg equol/kg diet compared with the OVX control rats. Trabecular bone mineral density of tibia was also lower in equol-fed OVX rats. At this dietary equol intake, uterine weight was higher (P < 0.05) than in other OVX groups but lower than the SHAM-operated intact rats. The 200 mg/kg diet dose of dietary equol significantly increased proliferative index in the uterine epithelium. Dietary equol had no stimulatory effect on mammary gland epithelium. We conclude that in OVX rats, a dietary equol dose that had modest effect on bone also exerts mild uterotropic effects.

Reevaluation of predictive factors for complete recovery in dogs with nonambulatory tetraparesis secondary to cervical disk herniation.

The vast majority of dogs with cervical disk herniation experience cervical pain and only mild motor deficits; therefore, not much is known about the factors that predict recovery in dogs with nonambulatory tetraparesis (NAT) secondary to cervical disk herniation. In this retrospective study, we tested the hypothesis that two previously reported prognostic factors, site of disk herniation and severity of neurological deficits, are useful predictors of complete recovery. Overall, 20 (62%) of 32 dogs with cervical disk herniation-associated NAT had complete recovery. Site of disk herniation was not a significant predictor of complete recovery; dogs with high cervical lesions (C2 to C3, C3 to C4) did not have a higher likelihood of complete recovery than other dogs. Likewise, severity of neurological deficits (i.e., intact voluntary motor function versus absent voluntary motor function) was not a significant predictor of complete recovery. Using stepwise logistic regression, two significant predictors of complete recovery were identified. Small dogs (delta15 kg body weight) were six times more likely to achieve complete recovery than larger dogs. Dogs that regained the ability to walk within 96 hours after surgery were seven times more likely to completely recover than dogs not walking 96 hours after surgery. We conclude that neither the site of disk herniation nor severity of neurological deficits assists the clinician in predicting postoperative outcome in dogs with cervical disk herniation-associated NAT. Reliable preoperative predictors of complete recovery are needed to advance current diagnostic and treatment protocols to improve overall prognosis.

Defining the Optimal Selenium Dose for Prostate Cancer Risk Reduction: Insights from the U-Shaped Relationship between Selenium Status, DNA Damage, and Apoptosis.

Our work in dogs has revealed a U-shaped dose response between selenium status and prostatic DNA damage that remarkably parallels the relationship between dietary selenium and prostate cancer risk in men, suggesting that more selenium is not necessarily better. Herein, we extend this canine work to show that the selenium dose that minimizes prostatic DNA damage also maximizes apoptosis-a cancer-suppressing death switch used by prostatic epithelial cells. These provocative findings suggest a new line of thinking about how selenium can reduce cancer risk. Mid-range selenium status (.67-.92 ppm in toenails) favors a process we call "homeostatic housecleaning"-an upregulated apoptosis that preferentially purges damaged prostatic cells. Also, the U-shaped relationship provides valuable insight into stratifying individuals as selenium-responsive or selenium-refractory, based upon the likelihood of reducing their cancer risk by additional selenium. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a robust experimental approach bridging the gap between laboratory and human studies that can help to define the optimal doses of cancer preventives for large-scale human trials. Moreover, our observations bring much needed clarity to the null results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and set a new research priority: testing whether men with low, suboptimal selenium levels less than 0.8 ppm in toenails can achieve cancer risk reduction through daily supplementation.

The art of casting nets: fishing for the prize of personalized cancer prevention.

Now, more than ever, there is great need for personalized cancer prevention. We define personalized cancer prevention as a strategy that will enable each person to reduce his or her risk for lethal cancer by matching the dose, duration, and timing of an intervention with their own cancer risk profile. Most research studies provide us with data on the average person. But who is the average person anyway? The central tenet of personalized cancer prevention is that average is overrated. In this article, we frame what are the major obstacles to developing personalized cancer-reducing interventions: the lack of validated, non-invasive stratifiers of risk; the U-shaped dose response between cancer-fighting nutrients (e.g., selenium) and DNA damage, meaning that more of a good thing is not necessarily a good thing; the relatively brief duration of interventions evaluated in human prevention trials; the challenge of finding populations in which the impact of early life interventions on the incidence of cancers affecting older adults can be studied; and the interindividual differences in gene expression that may influence a person's response to a particular nutrient. Moreover, we contend that those who study personalized cancer prevention will need a unique constellation of expertise, including an understanding of cancer and aging, a passion for prevention, and proven health communication skills. We propose that becoming cross-trained in cancer and aging and taking more responsibility for communicating health-related research to the public in the proper context are two of the most important ways scientists can move us all closer to the goal of personalized cancer prevention. Every fisherman knows that where he casts his net determines his catch. Now, we ask: When it comes to solving the cancer problem, where should we be casting our nets?

Noninvasive prediction of prostatic DNA damage by oxidative stress challenge of peripheral blood lymphocytes.

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H(2)O(2)) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H(2)O(2) were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H(2)O(2)-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk.

Preoperative prediction of multifocal prostate cancer and application of focal therapy: review 2007.

Prostate cancer is a leading malignancy among men. Early prostate cancer is most commonly treated with radical surgery and radiotherapy. In the era of prostate-specific antigen and newly emerging highly specific screening tests, a greater number of men are given a diagnosis earlier in life, and disease is more often confined. Less-invasive treatments, such as focal therapy, are becoming increasingly popular, yielding shorter hospital stays, faster recovery, and fewer complications. Potential drawbacks to focal therapy include the risk of incomplete treatment, which may result from missed cancer foci and inadequate ablation to target tissues. Furthermore, this approach is not universally applicable to all patients--for example, those who have periurethral and extraprostatic extension of the tumor may not benefit from focal treatment. This article reviews the importance of multifocal prostate cancer and the application of focal treatment.