As compared with radical cystectomy alone, the use of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin followed by radical cystectomy increases the likelihood of eliminating residual cancer in the cystectomy specimen and is associated with improved survival among patients with locally advanced bladder cancer.
Each prostate-cancer treatment was associated with a distinct pattern of change in quality-of-life domains related to urinary, sexual, bowel, and hormonal function. These changes influenced satisfaction with treatment outcomes among patients and their spouses or partners.
Purpose Long-term prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen-detected cancers and the pathological risk factors for PCSM are needed for treatment decision-making. Methods Using Fine and Gray competing risk regression analysis, the clinical and pathological data and follow-up information of 11,521 patients treated by radical prostatectomy at four academic centers from 1987 to 2005 were modeled to predict PCSM. The model was validated on 12,389 patients treated at a separate institution during the same period. Results The overall 15-year PCSM was 7%. Primary and secondary pathological Gleason grade 4–5 (P < 0.001 for both), seminal vesicle invasion (P < 0.001), and year of surgery (P = 0.002) were significant predictors of PCSM. A nomogram predicting 15-year PCSM based on standard pathological parameters was accurate and discriminating with an externally-validated concordance index of 0.92. Stratified by patient age, 15-year PCSM for Gleason score ≤ 6, 3+4, 4+3, and 8–10 ranged from 0.2–1.2%, 4.2–6.5%, 6.6–11%, and 26–37%, respectively. The 15-year PCSM risks ranged from 0.8–1.5%, 2.9–10%, 15–27%, and 22–30% for organ-confined cancer, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis, respectively. Only 3 of 9557 patients with organ-confined, Gleason score ≤ 6 cancers have died from prostate cancer. Conclusions The presence of poorly differentiated cancer and seminal vesicle invasion are the prime determinants of PCSM after radical prostatectomy. The risk of PCSM can be predicted with unprecedented accuracy once the pathological features of prostate cancer are known.
More than 1,000,000 men undergo prostate biopsy each year in the United States, most for “elevated” serum prostate specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA-screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy.
A B S T R A C T PurposeThe long-term risk of prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread prostate-specific antigen (PSA) screening. Models that predict the risk of PCSM are needed for patient counseling and clinical trial design. MethodsA multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM. Patient clinical information and treatment outcome was modeled using Fine and Gray competing risk regression analysis to predict PCSM. ResultsFifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM ranged from 5% to 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM. A nomogram predicting the 15-year risk of PCSM was developed, and the externally validated concordance index was 0.82. Neither preoperative PSA velocity nor body mass index improved the model's accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%. ConclusionFew patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screendetected cancers. Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.
Apoptosis, a genetically controlled process of cell death, plays a central role in metazoan development and homeostasis (61,74). The apoptotic program is highly conserved during evolution, and striking similarities have been observed in the cell death programs of rodents, mammalian cells, Drosophila melanogaster, and Caenorhabditis elegans (28,81,85,91). In normally proliferating cells, the apoptotic program is actively suppressed or inactivated; however, withdrawal or inhibition of the apoptosis suppressor mechanisms triggers apoptotic pathways (16,37,86). One mechanism by which apoptotic gene products may be prevented from executing their effect may involve direct interaction with specific proteins that act to attenuate the function of the apoptotic activators or effectors. The interaction between antiapoptotic protein Bcl-2 and proapoptotic protein Bax illustrates this point: whether a cell undergoes apoptosis or not is dependent upon the relative levels of these two proteins; an excess of Bax will trigger apoptosis, whereas an excess of Bcl-2 will prevent apoptosis (38,66,68,89,90). Identification of other such antiapoptotic and proapoptotic protein pairs that dictate the survival of cells should enhance our understanding of the apoptosis process.Apoptosis is characterized by cell membrane blebbing, chromatin condensation, changes in nuclear architecture, and oligonucleosome-length DNA fragmentation (87, 88). The process of apoptotic cell death is triggered by diverse stimuli such as cytokines, withdrawal of growth factors, DNA damage, expression of oncogenes or immediate-early genes, and fluctuations in the levels of Bcl-2 family members (3,13,16,37,47,48,54,71,78,86,89). Certain apoptotic stimuli can sequentially activate the basal cell death machinery composed of initiator, amplifier, and effector proteases belonging to the interleukin-1-converting enzyme (ICE) subfamily or an ICE-related family (9,17,21,41,46,91). Downstream targets of these proteases include the ICE subfamily proteases themselves; nuclear enzymes poly(ADP-ribose) polymerase and DNA-dependent protein kinase, which are involved in DNA repair; the nuclear protein U1 ribonucleoprotein and nuclear lamins; and cytoplasmic components such as protein kinase C␦ and cytoskeleton components such as actin (cited in reference 21). However, it is unclear whether any of these cellular components are directly linked to the morphological changes associated with apoptosis.Prostate tissue, which is composed of androgen-dependent and -independent cells (8, 58), provides an excellent model system for studying apoptosis. Androgen ablation in animals leads to an elevation of intracellular calcium that subsequently results in apoptosis of the androgen-dependent but not of the androgen-independent prostatic cells (11,(42)(43)(44). However, apoptosis can be induced in androgen-independent cell cultures by artificially upregulating intracellular calcium with calcium ionophores (53, 69) or with thapsigargin (TG) (22), an
Context Sexual function is the health-related quality of life (HRQOL) domain most commonly impaired after prostate cancer treatment; however, validated tools to enable personalized prediction of erectile dysfunction after prostate cancer treatment are lacking. Objective To predict long-term erectile function following prostate cancer treatment based on individual patient and treatment characteristics. Design Pretreatment patient characteristics, sexual HRQOL, and treatment details measured in a longitudinal academic multicenter cohort (Prostate Cancer Outcomes and Satisfaction With Treatment Quality Assessment; enrolled from 2003 through 2006), were used to develop models predicting erectile function 2 years after treatment. A community-based cohort (community-based Cancer of the Prostate Strategic Urologic Research Endeavor [CaPSURE]; enrolled 1995 through 2007) externally validated model performance. Patients in US academic and community-based practices whose HRQOL was measured pretreatment (N = 1201) underwent follow-up after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer. Sexual outcomes among men completing 2 years’ follow-up (n = 1027) were used to develop models predicting erectile function that were externally validated among 1913 patients in a community-based cohort. Main Outcome Measures Patient-reported functional erections suitable for intercourse 2 years following prostate cancer treatment. Results Two years after prostate cancer treatment, 368 (37% [95% CI, 34%–40%]) of all patients and 335 (48% [95% CI, 45%–52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%–56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual’s pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74–0.80] for prostatectomy; 0.87 [95% CI, 0.80–0.94] for external radiotherapy; and 0.90 [95% CI, 0.85–0.95] for brachytherapy). Conclusion Stratification by pretreatment patient characteristics and treatment details enables prediction of erectile function 2 years after prostatectomy, external radiotherapy, or brachytherapy for prostate cancer.
Heart transplant rejection is characterized pathologically by myocyte necrosis and apoptosis associated with interstitial mononuclear cell infiltration. Any one of these components can be targeted for noninvasive detection of transplant rejection. During apoptotic cell death, phosphatidylserine, a phospholipid that is normally confined to the inner leaflet of cell membrane bilayer, gets exteriorized. Technetium-99m-labeled annexin-V, an endogenous protein that has high affinity for binding to phosphatidylserine, has been administered intravenously for noninvasive identification of apoptotic cell death. In the present study of 18 cardiac allograft recipients, 13 patients had negative and five had positive myocardial uptake of annexin. These latter five demonstrated at least moderate transplant rejection and caspase-3 staining, suggesting apoptosis in their biopsy specimens. This study reveals the clinical feasibility and safety of annexin-V imaging for noninvasive detection of transplant rejection by targeting cell membrane phospholipid alterations that are commonly associated with the process of apoptosis.
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