Maternal Prenatal Infections and Biliary Atresia in Offspring.

Importance: Investigations into the association of antepartum maternal infections with the pathogenesis of biliary atresia (BA) in human offspring are insufficient. Objective: To examine the association between prenatal infections in mothers and the development of BA in their offspring. Design, Setting, and Participants: This population-based case-control study obtained administrative data from the Taiwan National Health Insurance Research Database with linkage to the Taiwan Maternal and Child Health Database, capturing demographic and medical information on nearly all 23 million of the Taiwan population. The cohort comprised 2 905 978 singleton live births among mother-infant dyads between January 1, 2004, and December 31, 2020, in Taiwan. The case group of infants with BA was identified from use of International Classification of Diseases diagnostic codes for BA and subsequent Kasai procedure or liver transplant. The control group was randomly selected from infants without BA, representing approximately 1 in 1000 study population. Data analyses were performed from May 1 to October 31, 2023. Exposure: Prenatal maternal infections, including intestinal infection, influenza, upper airway infection, pneumonia, soft-tissue infection, and genitourinary tract infection. Main Outcomes and Measures: The main outcome was exposure to prenatal maternal infections. Inverse probability weighting analysis was performed by building a logistic regression model to estimate the probability of the exposure observed for a particular infant and using the estimated probability as a weight in subsequent analyses. The weighted odds ratio (OR) estimated by logistic regressions was then used to assess the risk of BA in offspring after prenatal maternal infections. Results: Among the mother-infant dyads included, 447 infants with BA were cases (232 females [51.9%]) and 2912 infants without BA were controls (1514 males [52.0%]). The mean (SD) maternal age at childbirth was 30.7 (4.9) years. Offspring exposed to prenatal intestinal infection (weighted OR, 1.46; 95% CI, 1.17-1.82) and genitourinary tract infection (weighted OR, 1.22; 95% CI, 1.05-1.41) in mothers exhibited a significantly higher risk of BA. Furthermore, maternal intestinal infection (weighted OR, 6.05; 95% CI, 3.80-9.63) and genitourinary tract infection (weighted OR, 1.55; 95% CI, 1.13-2.11) that occurred during the third trimester were associated with an increased risk of BA in offspring. Conclusions and Relevance: Results of this case-control study indicate an association between prenatal intestinal infection and genitourinary tract infection in mothers and BA occurrence in their offspring. Further studies are warranted to explore the underlying mechanisms of this association.

Parental autoimmunity and offspring risks of rheumatic diseases: a nationwide population-based study.

OBJECTIVE: Familial aggregation of systemic autoimmune diseases is frequently reported, but little is known about how fathers and mothers differentially contribute to the development of autoimmune diseases in their offspring. This study aimed to investigate the impact of maternal and paternal autoimmunity on the risk of offspring rheumatic diseases. METHODS: We constructed a nationwide population-based cohort using data from the Maternal and Child Health Database and the Taiwan National Health Insurance Research Data (NHIRD) from 2004 to 2019. The outcome was an autoimmune disease in the offspring. Inverse probability of treatment-weighted Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for autoimmune diseases. RESULTS: Births with a father or mother with an autoimmune disease demonstrated respective risks of 1.22 times and 1.38 times the risk of developing an autoimmune disease compared to their counterparts. Maternal autoimmunity substantially contributed to SLE (aHR = 5.46, 95% CI: 5.28∼5.66), and paternal autoimmunity contributed to JIA (aHR = 1.76, 95% CI: 1.71∼1.81), and type 1 DM (aHR = 1.59, 95% CI: 1.39∼1.81) of their offspring. The contribution of mothers to the development of SLE (HR = 8.55, 95% CI: 8.10∼9.02) and inflammatory myopathy (HR = 2.08, 95% CI: 1.72∼2.51) were exacerbated in boys. Births with both parents with an autoimmune disease showed a 1.39-fold risk of developing an autoimmune disease. The maternal effect is stronger in preterm than full term births. CONCLUSIONS: This study demonstrated the landscape of how autoimmune diseases pass from parents to infants of both genders and quantified the maternal and paternal contribution to disease separately.

Risks of leukemia, intracranial tumours and lymphomas in childhood and early adulthood after pediatric radiation exposure from computed tomography.

BACKGROUND: Children are more susceptible to radiation-induced damage than adults, but little research has compared the risk of cancer after exposure to radiation during computed tomography (CT) among children at different ages. We aimed to explore the risk of intracranial tumours, leukemia or lymphoma among children, adolescents and young adults (aged < 25 yr) after radiation exposure from CT at or before the age of 18 years. METHODS: We conducted a nested, population-based case-control study using data from Taiwan's publicly funded health care system. We identified participants younger than 25 years with newly diagnosed intracranial tumours, leukemia or lymphoma, from Jan. 1, 2000, to Dec. 31, 2013. We assigned 10 non-cancer controls for each case, matching by sex, date of birth and day of entry to the cohort. We considered CT scans received at or before the age of 18 years and 3 or more years before the index date (the date of cancer diagnosis for cases) as exposure. We used conditional logistic regression models and incidence rate ratios (IRRs) to estimate the relationship between risk of these cancers and CT radiation exposure. RESULTS: We identified 7807 cases and matched to 78 057 controls. Compared with no exposure, exposure to a single pediatric CT scan did not increase risk of intracranial tumours, leukemia or lymphoma. However, participants exposed to 4 or more CT scans had an elevated incidence (IRR 2.30, 95% confidence interval 1.43-3.71) of one of the cancer outcomes of interest. Receiving 4 or more CT scans at or before 6 years of age was associated with the highest risks of cancer, followed by ages 7-12 years and 13-18 years (p for trend < 0.001). INTERPRETATION: Exposure to a single CT scan was not associated with increased risks of subsequent intracranial tumours, leukemia or lymphoma among children; however, we observed increased cancer risks among those with 4 or more CT scans, especially among younger children. Although these cancers are uncommon, the findings of this study underscore the importance of prudent use of CT in the pediatric population.

Cardiovascular risk of gonadotropin-releasing hormone antagonist versus agonist in men with prostate cancer: an observational study in Taiwan.

BACKGROUND: The impact of gonadotropin-releasing hormone (GnRH) antagonist and agonist (GnRHa) treatment on cardiovascular disease (CVD) risk in prostate cancer (PCa) remains inconclusive due to conflicting findings. We compared the effects of GnRH antagonist and GnRHa treatments on CVD risk in patients with PCa and pre-existing CVD, in a Taiwan population-based database. METHODS: We assessed the risk of major adverse CV events (MACE: ischemic heart disease [IHD], stroke, congestive heart failure [CHF] or all cause deaths) and composite CV events (IHD, stroke, CHF or CV deaths) occurring ≥90 days after androgen deprivation therapy (ADT) initiation in patients with PCa after 90 days of treatment with either GnRH antagonist (degarelix; n = 499) or GnRHa (goserelin, leuprolide, triptorelin; n = 15,127). Patients identified with pre-existing CVD had received cardiac therapy for IHD, reported a stroke or CHF within a year before ADT initiation. Adjusted hazard ratios (aHR) and 95% confidence interval (CI) were obtained for MACE and composite CV events risk after adjusting for age, baseline status of diabetes, hypertension and treatments received. RESULTS: All GnRH antagonist-treated patients showed lower risk of composite CV events than the GnRHa-treated patients. The lower composite CV events risk associated with GnRH antagonist was also observed in patients with metastasis at diagnosis (aHR 0.16; 95% CI, 0.04-0.38; p = 0.013) and those receiving ADT for more than six months (aHR 0.30; 95% CI, 0.16-0.54; p < 0.0001). In patients with pre-existing CVD, the MACE risk was 33% lower (aHR 0.67; 95% CI, 0.46-0.96; p = 0.0299) and composite CV events risk was 84% lower (aHR 0.16; 95% CI, 0.05-0.50; p = 0.0017) in GnRH antagonist-treated than the GnRHa-treated patients. CONCLUSIONS: In patients with PCa and pre-existing CVD, GnRH antagonist use was associated with lower risks for composite CV events and MACE compared with GnRHa.

Radiation Exposure and Lifetime Attributable Risk of Cancer Incidence and Mortality from Low- and Standard-Dose CT Chest: Implications for COVID-19 Pneumonia Subjects.

Since the novel coronavirus disease 2019 (COVID-19) outbreak, there has been an unprecedented increase in the acquisition of chest computed tomography (CT) scans. Nearly 616 million people have been infected by COVID-19 worldwide to date, of whom many were subjected to CT scanning. CT exposes the patients to hazardous ionizing radiation, which can damage the genetic material in the cells, leading to stochastic health effects in the form of heritable genetic mutations and increased cancer risk. These probabilistic, long-term carcinogenic effects of radiation can be seen over a lifetime and may sometimes take several decades to manifest. This review briefly describes what is known about the health effects of radiation, the lowest dose for which there exists compelling evidence about increased radiation-induced cancer risk and the evidence regarding this risk at typical CT doses. The lifetime attributable risk (LAR) of cancer from low- and standard-dose chest CT scans performed in COVID-19 subjects is also discussed along with the projected number of future cancers that could be related to chest CT scans performed during the COVID-19 pandemic. The LAR of cancer Incidence from chest CT has also been compared with those from other radiation sources, daily life risks and lifetime baseline risk.

Long-term Outcomes of Early Use of Long-Acting Injectable Antipsychotics in Schizophrenia.

Background: Long-acting injectable antipsychotics (LAIs) may potentially benefit patients requiring psychiatric hospitalization during the early stages of schizophrenia. However, few studies have compared the long-term effectiveness between patients who switched to LAIs and those who remained on oral antipsychotics (OAPs).Methods: Using the Taiwan National Health Insurance Research Database, we constructed a population-based cohort with 19,813 new OAP users with ICD-9-CM-defined schizophrenia who were hospitalized from 2002 to 2005. Within this cohort, 678 patients who switched to LAIs during their hospitalization were identified. The LAI group was matched to patients who remained on OAPs (n = 678). The LAI cohort was further subdivided for analysis into patients who switched to LAIs within 3 years of OAP initiation ("an early stage") and those who switched after 3 years ("a late stage"). Conditional Cox regressions and conditional negative binomial regressions were used to estimate the risk of death and the number of hospital visits between the two groups.Results: During the 13-year study period, 312 patients switched to LAIs within the first 3 years of OAP initiation. All- and natural-cause mortalities in these patients were significantly lower than in those who remained on OAPs. The hazard ratios (HRs) for all- and natural-cause mortalities were 0.49 (95% confidence interval [CI], 0.27-0.87) and 0.30 (95% CI, 0.15-0.60), respectively. No significant decrease associated with LAIs was observed in unnatural-cause mortality. Patients receiving LAIs had lower risks of rehospitalization (incidence rate ratio [IRR] = 0.56, 95% CI, 0.45-0.69), psychiatric hospitalization (IRR = 0.63, 95% CI, 0.50-0.81), and psychiatric emergency room visits (IRR = 0.58, 95% CI, 0.45-0.75) compared to patients who remained on OAPs. Use of LAIs in the late stage of treatment did not decrease the risk of relapse or mortality.Conclusions: Switching to LAIs during the first 3 years of treatment improved antipsychotic adherence, decreased relapses, and reduced long-term mortality. Our results provide evidence to support the benefits of early LAI treatment in schizophrenia.

A Novel Quality-Control Procedure to Improve the Accuracy of Rare Variant Calling in SNP Arrays.

Background: Single-nucleotide polymorphism (SNP) arrays are an ideal technology for genotyping genetic variants in mass screening. However, using SNP arrays to detect rare variants [with a minor allele frequency (MAF) of <1%] is still a challenge because of noise signals and batch effects. An approach that improves the genotyping quality is needed for clinical applications. Methods: We developed a quality-control procedure for rare variants which integrates different algorithms, filters, and experiments to increase the accuracy of variant calling. Using data from the TWB 2.0 custom Axiom array, we adopted an advanced normalization adjustment to prevent false calls caused by splitting the cluster and a rare het adjustment which decreases false calls in rare variants. The concordance of allelic frequencies from array data was compared to those from sequencing datasets of Taiwanese. Finally, genotyping results were used to detect familial hypercholesterolemia (FH), thrombophilia (TH), and maturity-onset diabetes of the young (MODY) to assess the performance in disease screening. All heterozygous calls were verified by Sanger sequencing or qPCR. The positive predictive value (PPV) of each step was estimated to evaluate the performance of our procedure. Results: We analyzed SNP array data from 43,433 individuals, which interrogated 267,247 rare variants. The advanced normalization and rare het adjustment methods adjusted genotyping calling of 168,134 variants (96.49%). We further removed 3916 probesets which were discordant in MAFs between the SNP array and sequencing data. The PPV for detecting pathogenic variants with 0.01%10,000 are available. The results demonstrated our procedure could perform correct genotype calling of rare variants. It provides a solution of pathogenic variant detection through SNP array. The approach brings tremendous promise for implementing precision medicine in medical practice.

Comparison of Long-Acting Injectable Antipsychotics With Oral Antipsychotics and Suicide and All-Cause Mortality in Patients With Newly Diagnosed Schizophrenia.

Importance: Schizophrenia is generally considered to be among the most severe psychiatric disorders because of the excessive mortality associated with it. Research to find means to reduce this excessive mortality is warranted. Objective: To investigate associations of long-acting injectable antipsychotics (LAIs) with all-cause, natural-cause, and suicide mortality risks as well as the impacts of early use of LAIs in patients with newly diagnosed schizophrenia. Design, Setting, and Participants: This cohort study used data from the Taiwan National Health Insurance Research Database to construct a population-based cohort of patients with schizophrenia who received oral antipsychotics (OAPs) from January 1, 2002, to December 31, 2017. Within this cohort, the LAI group was defined as patients who switched to LAIs and were prescribed LAIs at least 4 times within 1 year. The LAI group was propensity matched 1:1 to patients who continued receiving OAPs of the same compounds. All patients were followed up until switching the antipsychotic administration route, death, or the end of the study (December 31, 2018), whichever occurred first. Data analysis was performed from January 2002 to December 2018. Main Outcomes and Measures: All-cause mortality, natural-cause mortality, suicide mortality, and suicide attempts. Results: In total, 2614 patients who switched to LAIs (median [interquartile range] {IQR} age, 30 [23-39] years) and 2614 who received OAPs (median [IQR] age, 30 [23-39] years) were included (1333 male patients [51.0%] in each group). During the 16-year follow-up period (median [IQR] follow-up of 14 [10-17] years), patients who switched to LAIs had lower risks of all-cause mortality (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.54-0.81), natural-cause mortality (aHR, 0.63; 95% CI, 0.52-0.76), and suicide attempts (incidence rate ratio, 0.72; 95% CI, 0.55-0.93) compared with patients who received the corresponding OAPs. A 47% lower suicide mortality risk (aHR, 0.53; 95% CI, 0.30-0.92) was observed in patients who switched to LAIs within the first 2 years of OAP initiation. Conclusions and Relevance: These findings suggest that LAI use in patients with newly diagnosed schizophrenia is associated with decreased all-cause mortality and suicide risk. Furthermore, early treatment with LAIs within the first 2 years of OAP initiation was associated with a decrease in suicide mortality risk. Thus, LAI use in the early stage of treatment should be actively considered for patients with newly diagnosed schizophrenia.

Influence of Baseline Cardiovascular Comorbidities on Mortality after Androgen Deprivation Therapy for Metastatic Prostate Cancer.

Few studies have assessed the benefits of androgen deprivation therapy (ADT) in men with metastatic prostate cancer (PC; mPC) at an old age or with major cardiovascular conditions. A retrospective cohort consisted of 3835 men with newly diagnosed mPC from the Taiwan Cancer Registry of 2008-2014. Among them, 2692 patients received only ADT in the first year after the cancer diagnosis, and 1143 patients were on watchful waiting. The inverse probability of treatment-weighted Cox model was used to estimate the effects of ADT on all-cause mortality and PC-specific mortality according to age, and the status of congestive heart failure (CHF), coronary arterial diseases (CADs), and stroke at the baseline. After a median follow-up of 2.65 years, 1650 men had died. ADT was associated with a 17-22% risk reduction in all-cause and PC-specific mortality in men without stroke, CAD, or CHF in the 65-79-year group. The survival benefit diminished in men with any of these preexisting conditions. In contrast, ADT was not found to be associated with any survival benefit in the ≥80-year group, even though they did not present with any major cardiovascular disease at the baseline. Patients who had CHF, CAD, or stroke at the baseline did not show a survival benefit following ADT in any of the age groups. Men who have preexisting major cardiovascular diseases or are ≥80 years do not demonstrate a survival benefit from ADT for mPC. The risk-benefit ratio should be considered when using ADT for mPC in older men especially those with major cardiovascular comorbidities.

Associations among antipsychotics, metabolism-related diseases, and cataracts in patients with schizophrenia: A retrospective cohort study.

BACKGROUND: Long-term cataract risks associated with first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), and their associations with metabolism-related diseases are not yet elucidated. METHODS: Using Taiwan National Health Insurance data, we conducted a propensity score matched population-based cohort study consisting of 10,014 patients with newly diagnosed schizophrenia from 2005 to 2009 and followed them until the end of 2013. A Cox hazard model with metabolism-related diseases as time-dependent covariates was adapted to estimate the hazard ratio (HR) of cataracts between SGAs and FGAs groups. RESULTS: During the 8-year follow-up, patients receiving SGAs were associated with a higher risk of cataract than those receiving FGAs with an adjusted HR of 1.59 (95% confidence interval [CI] = 1.06-2.36). Patients receiving high-metabolic-risk SGAs (clozapine and olanzapine) showed the highest risk of cataracts among SGAs when compared with those receiving FGAs (aHR = 2.57, 95% CI: 1.35-4.88). SGAs demonstrated a stronger contribution in the risk of cataract in patients without diabetes mellitus (DM) and hyperlipidemia than in those developed these diseases. Patients who developed DM or hyperlipidemia after receiving antipsychotics had an approximately 2.5-fold increased cataract risk over those who did not develop these diseases. CONCLUSIONS: Regardless of the condition of metabolic-related diseases, SGAs were independently associated with an increased risk of cataract. DM and hyperlipidemia developed after antipsychotics contributed to the risk of cataract risk.

Mortality associated with statins in men with advanced prostate cancer treated with androgen deprivation therapy.

OBJECTIVES: Before launching large clinical trials to confirm the effects of statins in improving outcomes among men with prostate cancer (PC), the most appropriate target patient population and the type of statins need to be clearly identified. PATIENTS AND METHODS: A retrospective cohort study was conducted using the Taiwan Cancer Registry of 2008-2014. This study included 5749 men with locally advanced and metastatic PC who received only androgen deprivation therapy (ADT) in the first year after their cancer diagnosis. Statin users were defined as anyone who was prescribed statins for >28 days. An inverse probability of treatment-weighted Cox model was used to estimate the effects of statin use on all-cause mortality and PC-specific mortality (PCSM) while treating the statin status as a time-dependent variable. RESULTS: Overall, 2259 patients died, and 1495 of them died of PC during a median follow-up of 3.6 years from 1 year after their diagnosis. Statin use was associated with significant reductions in all-cause mortality (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.70-0.86) and PCSM (HR = 0.76, 95% CI: 0.68-0.86) for metastatic disease and all-cause mortality (HR = 0.66, 95% CI: 0.54-0.81) for locally advanced disease. Patients who received atorvastatin, pravastatin, rosuvastatin or pitavastatin showed a stronger reduction in mortality than those who received other statins. Benefits of statins were consistently observed in men who received post-diagnostic statins, even in those with high comorbidities or an old age. CONCLUSIONS: Our results suggest that only atorvastatin, pravastatin and rosuvastatin were associated with improved survival in advanced PC patients receiving ADT.

Multi-omics analysis reveals the BRCA1 mutation and mismatch repair gene signatures associated with survival, protein expression, and copy number alterations in prostate cancer.

BACKGROUND: Recent genomic analysis reveals that DNA repair gene mutations can be detected in 15-30% of patients in metastatic castration resistant prostate cancer depending on the population and clinical setting when comparing to a very small fraction in those with indolent localized diseases. The discovery and characterization of function associated with DNA repair gene mutations in prostate cancer patients may increase therapeutic options and lead to improved clinical outcomes. METHODS: To understand the role of DNA repair genes associated with other genomic alteration and signaling pathway, we applied an integrative analysis of multi-omics to The Cancer Genome Atlas (TCGA) prostate cancer dataset which contains 498 patients. We concurrently analyzed gene expression profiles, reverse phase protein lysate microarray (RPPA) data, and copy number alterations to examine the potential genomic mechanisms. RESULTS: We identified the signature of "chromosome condensation", "BRCA1 mutation", and "mismatch repair" were associated with disease-free survival in prostate cancer. Through the concurrent analysis of gene expression profiles, reverse RPPA data, and copy number alterations, we found the three signatures are associated with cell cycle and DNA repair pathway and also most events of copy number gains. CONCLUSIONS: This study presents a unique extension from DNA mutations to expressional functions, proteomic activities, and copy numbers of DNA repair genes in prostate cancer. Our findings revealed crucial prognostic markers and candidates for further biological and clinical investigations.

scdNet: a computational tool for single-cell differential network analysis.

BACKGROUND: Single-cell RNA sequencing (scRNA-Seq) is an emerging technology that has revolutionized the research of the tumor heterogeneity. However, the highly sparse data matrices generated by the technology have posed an obstacle to the analysis of differential gene regulatory networks. RESULTS: Addressing the challenges, this study presents, as far as we know, the first bioinformatics tool for scRNA-Seq-based differential network analysis (scdNet). The tool features a sample size adjustment of gene-gene correlation, comparison of inter-state correlations, and construction of differential networks. A simulation analysis demonstrated the power of scdNet in the analyses of sparse scRNA-Seq data matrices, with low requirement on the sample size, high computation efficiency, and tolerance of sequencing noises. Applying the tool to analyze two datasets of single circulating tumor cells (CTCs) of prostate cancer and early mouse embryos, our data demonstrated that differential gene regulation plays crucial roles in anti-androgen resistance and early embryonic development. CONCLUSIONS: Overall, the tool is widely applicable to datasets generated by the emerging technology to bring biological insights into tumor heterogeneity and other studies. MATLAB implementation of scdNet is available at https://github.com/ChenLabGCCRI/scdNet .

Proton pump inhibitors and risk of periampullary cancers--A nested case-control study.

Considerable attention has been focused on long-term use of proton pump inhibitor (PPI) medications in relation to increased risk of cancer via stimulation of DNA-damaged cells. The aim of this study is to examine the dose-dependent effect of PPI on periampullary cancers in a national population-based cohort. A nested case-control analysis was constructed based on Taiwan's National Health Insurance Research Database and the Taiwan Cancer Registry between the years 2000 and 2010. Cases involving patients diagnosed with periampullary cancers were selected and controls were matched to cases according to age, sex and observational period. A "PPI user" was defined as any patient receiving more than 28 cumulative defined daily doses as measured by prescription drug claims. Conditional logistic regression analysis was conducted to calculate odds ratios (ORs) and 95% confidence intervals (CIs) according to the level of PPI exposure. A total of 7,681 cases and 76,762 matched controls were included with a mean follow-up period of 6.6 years (SD: 2.0). The odds of PPI exposure in patients with periampullary cancers were higher than that of control patients with an adjusted OR of 1.35 (95% CIs: 1.16-1.57). Our results also showed that PPI exposure was slightly linked to periampullary cancers in dose-dependent manner. A similar association was observed in patients who solely took PPI but no eradication therapy for Helicobacter pylori infection. Long-term PPI use was associated with an increased risk of periampullary cancers in the current population-based study. Physicians must weigh potential risks of long-term maintenance against therapeutic benefit.

Risk of autism associated with general anesthesia during cesarean delivery: a population-based birth-cohort analysis.

The rates of Cesarean delivery (C-section) have risen to >30% in numerous countries. Increased risk of autism has been shown in neonates delivered by C-section. This study examined the incidence of autism in neonates delivered vaginally, by C-section with regional anesthesia (RA), and by C-section with general anesthesia (GA) to evaluate the risk of autism associated with C-section and obstetric anesthesia. During a mean follow-up of 4.3 years, the incidence of autism was higher in neonates delivered by C-section with GA than in neonates delivered vaginally, with an adjusted risk of 1.52 (95% confidence interval 1.18-1.94). However, the adjusted risk of autism in neonates delivered by C-section with RA and in neonates delivered vaginally was nonsignificantly different.

Cancer-specific survival after metastasis following primary radical prostatectomy compared with radiation therapy in prostate cancer patients: results of a population-based, propensity score-matched analysis.

BACKGROUND: Data regarding the difference in the clinical course from metastasis to prostate cancer-specific mortality (PCSM) following radical prostatectomy (RP) compared with radiation therapy (RT) are lacking. OBJECTIVE: To examine the association between primary treatment modality and prostate cancer-specific survival (PCSS) after metastasis. DESIGN, SETTING, AND PARTICIPANTS: We used the Surveillance Epidemiology and End Results-Medicare linked database from 1994 to 2007 for patients diagnosed with localized prostate cancer (PCa). We used cancer stage and Gleason score to stratify patients into low and intermediate-high risks. INTERVENTION: Radical prostatectomy or radiation therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Our outcome is time from onset of metastases to PCSM. Propensity score matching and Cox regression were used to analyze the PCSM hazard for the RP group compared with the RT group. RESULTS AND LIMITATIONS: Our study consisted of 66,492 men diagnosed with PCa, 51,337 men receiving RT, and 15,155 men undergoing RP within 1 yr of cancer diagnosis. During the study period, 2802 men were diagnosed as having metastatic disease. A total of 916 men with metastases were included in the propensity-matched cohort; of these men, 186 died from PCa. During the follow-up, for the low-risk patients, the adjusted PCSS after metastasis was 86.2% and 79.3% in the RP and RT groups, respectively; for the intermediate-high-risk patients, the PCSS after metastasis was 76.3% and 63.3% in the RP and RT groups, respectively. The hazard ratios estimating the risk of PCSM between the RP and RT groups were 0.64 (95% confidence interval [CI], 0.36-1.16) and 0.55 (95% CI, 0.39-0.77) for the low- and intermediate-high-risk groups, respectively. Because of the nature of observational studies, the results may be affected by residual confounders and treatment indication. CONCLUSIONS: Following the development of metastases, men who received primary RP have a longer PCSS than men who received primary RT. Our results may have implications for the timing and nature of local PCa treatment.