Objective
To identify the predictors of time from initial diagnosis of metastatic castration-resistance prostate cancer (mCRPC) to all-cause death within the Shared Equal Access Regional Cancer Hospital cohort.
Patients and Methods
We performed a retrospective analysis of 205 mCRPC men. Overall survival was estimated and plotted using the Kaplan-Meier method. The uni- and multivariable overall survival predictors were evaluated with Cox proportional hazards model. A nomogram was generated to predict overall survival at 1, 2, 3, and 5 years after mCRPC. Concordance index and calibration plot were obtained.
Results
A total of 170 men (83%) died over a median follow up of 41 months. In univariable analysis, older age, more remote year of mCRPC, nonblack race, greater number of bone metastasis, higher prostate-specific antigen (PSA) levels, shorter PSA doubling time, and faster PSA velocity at mCRPC diagnosis were significantly associated with shorter overall survival (all P<.05). In multivariable analysis, older age, more remote year of mCRPC, greater number of bone metastasis, higher PSA levels and shorter PSA doubling time at mCRPC diagnosis remained significantly associated with shorter overall survival (all P<0.05). On the basis of these variables a nomogram was generated yielding a concordance index of 0.67 and good calibration.
Conclusion
The use of clinical parameter such as age, disease burden, PSA levels and kinetics can be used to estimate overall survival in mCRPC patients.
OBJECTIVE
To investigate predictors of time to metastasis among men treated with androgen deprivation therapy for nonmetastatic prostate cancer who developed castration-resistant prostate cancer (CRPC) within the Shared Equal Regional Cancer Hospital cohort.
METHODS
This is a retrospective analysis of 458 nonmetastatic CRPC men. Metastases were detected in routine bone scans or other imaging tests. Predictors of time to metastasis were analyzed using proportional hazards model with CRPC as time zero.
RESULTS
A total of 256 (56%) men were diagnosed with metastatic disease over a median follow-up of 36 months. Metastasis-free survival was 79%, 65%, 52%, 47%, and 41% at 1,2,3,4, and 5 years after CRPC, respectively. In multivariable analysis, Gleason score 8–10 (hazard ration [HR] = 1.61; P = .026), receiving primary localized treatment (HR = 1.38; P = .028), higher prostate-specific antigen (PSA) levels at CRPC diagnosis (logPSA HR = 1.64; P ≤ .001), and PSA doubling time <6 months (HR = 1.42; P = .040) were independently associated with shorter time to metastasis. Race, year of CRPC, age, and time from androgen deprivation therapy to CRPC were not associated with metastasis.
CONCLUSION
Among nonmetastatic CRPC men, nearly 60% developed metastatic disease during the 5 years, with most of the metastasis occurring within the first 3 years. Higher Gleason score, receiving primary treatment, higher PSA, and shorter PSA doubling time were independently associated with shorter time to metastasis. Therefore, these variables can be used to stratify patients according to metastasis risk.
Glycogen storage disease type Ia (GSD Ia) is caused by glucose-6-phosphatase (G6Pase) deficiency in association with severe, life-threatening hypoglycemia that necessitates lifelong dietary therapy. Here we show that use of a zinc-finger nuclease (ZFN) targeted to the ROSA26 safe harbor locus and a ROSA26-targeting vector containing a G6PC donor transgene, both delivered with adeno-associated virus (AAV) vectors, markedly improved survival of G6Pase knockout (G6Pase-KO) mice compared with mice receiving the donor vector alone (P < 0.04). Furthermore, transgene integration has been confirmed by sequencing in the majority of the mice treated with both vectors. Targeted alleles were 4.6-fold more common in livers of mice with GSD Ia, as compared with normal littermates, at 8 months following vector administration (P < 0.02). This suggests a selective advantage for vector-transduced hepatocytes following ZFN-mediated integration of the G6Pase vector. A short-term experiment also showed that 3-month-old mice receiving the ZFN had significantly-improved biochemical correction, in comparison with mice that received the donor vector alone. These data suggest that the use of ZFNs to drive integration of G6Pase at a safe harbor locus might improve vector persistence and efficacy, and lower mortality in GSD Ia.
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