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Daniel W Lin

Publications and source records attributed to Daniel W Lin.

At least 19 recordsLinked to original sources
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2026

The 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) study.

BACKGROUND: Inherited (germline) pathogenic and likely pathogenic variants (gPVs) in key genes associated with increased risk of prostate cancer (PCa) now warrant more attentive PCa screening per National Comprehensive Cancer Network (NCCN) guidelines-e.g., BRCA2, HOXB13, ATM, BRCA1, MSH2, MSH6, CHEK2 and TP53. However, the optimal early detection strategy for gPV carriers, including use of age-adjusted PSA thresholds and prostate imaging may be refined. and as a means to investigate novel biomarkers. STUDY DESIGN: 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) is a multicentre, prospective early detection study for individuals at increased risk for PCa due to carrying a gPV in a PCa risk gene. ENDPOINTS: The primary endpoint is to determine the positive predictive value of pre-defined age-directed prostate-specific antigen (PSA) level thresholds and prostate-specific imaging, e.g., multiparametric magnetic resonance imaging (MRI) for clinically significant PCa on biopsy for individuals at risk of PCa due to a gPV. Exploratory endpoints include characterising clinicopathological characteristics of PCa and patient-reported outcomes. Biospecimens will be collected to evaluate emerging clinical and research biomarkers. PATIENTS AND METHODS: Key eligibility includes: individuals aged &#x2265;40&#x2009;years who carry a gPV in an eligible gene, who have no prior diagnosis of PCa, do not have another active malignancy, and provide informed consent. Study procedures include annual physical examination and PSA. Imaging with MRI is optional at baseline and recommended if the PSA level is above the protocol-recommended PSA level threshold. Participants will be offered prostate biopsy for any clinical concern, PSA level >1.0&#x2009;ng/mL if aged <50&#x2009;years; PSA level >1.5&#x2009;ng/mL if aged 50-59&#x2009;years; PSA level >2.0&#x2009;ng/mL if aged &#x2265;60&#x2009;years. If PCa is diagnosed, clinical care is determined by the participant and treating physician. If opting for active surveillance, study procedures will be collected annually for 10&#x2009;years or until definitive treatment. If definitive treatment, study procedures will be collected for an additional 1&#x2009;year. Long-term clinical outcomes will be collected annually until the study closes.

Humans↗
PubMed2006

Incidence of primary urethral carcinoma in the United States.

OBJECTIVES: Primary urethral carcinoma is rare, and the demographic correlates of its incidence have not been examined using population-based data. METHODS: The National Cancer Institute Surveillance, Epidemiology, and End Results database was used to identify persons diagnosed with primary urethral carcinoma from 1973 to 2002. During this period, the Surveillance, Epidemiology, and End Results program included population-based tumor registries in nine geographic areas that represented approximately 10% of the U.S. population. The incidence rates were tabulated for the major histologic subtypes according to age, sex, and race. RESULTS: Primary urethral carcinoma was identified in 1075 men and 540 women, with an annual age-adjusted incidence rate of 4.3 per million and 1.5 per million, respectively. The annual incidence rate increased with age to a peak of 32 per million men and 9.5 per million women in the 75 to 84-year age group. The rate was 5.0 per million and 2.5 per million for African Americans and whites, respectively. The histologic types were transitional cell carcinoma in 888 patients (55%), squamous cell carcinoma in 348 (21.5%), and adenocarcinoma in 265 (16.4%). The incidence of the three primary histologic types varied by race and sex. CONCLUSIONS: In the United States, the incidence of urethral carcinoma is relatively higher in men and African Americans, with a histologic profile differing from that previously described.

Adenocarcinoma↗
PubMed2006

Polymorphisms in the glutathione S-transferase M1, T1, and P1 genes and prostate cancer prognosis.

BACKGROUND: Polymorphisms in glutathione S-transferase (GST) genes can increase oxidative stress, which may affect cancer prognosis. The aim of this study was to examine associations between GSTM1, T1, or P1 genetic variants and prostate cancer outcomes. METHODS: A population-based cohort of men (n = 752) from King County, Washington, diagnosed with prostate cancer in 1993-1996, and under long-term surveillance for mortality completed a follow-up survey about prostate cancer recurrence/progression. Cox PH models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for deaths from prostate cancer or other causes and prostate cancer recurrence/progression. RESULTS: There were 50 prostate cancer-specific deaths, 65 deaths from other causes, and 143 recurrence/progressions events during an average 9.6 years of follow-up. The adjusted HR for prostate cancer mortality was 3.8 (95% CI 1.6-8.9) among Caucasian men with the GSTM1-null genotype. There were no differences, however, in mortality from other causes or prostate cancer recurrence/progression between men with GSTM1-null versus not-null genotypes. The GSTT1 and GSTP1 genotypes were not associated with any of these outcomes. DISCUSSION: Results suggest that the GSTM1 genotype may be a useful biomarker to identify patients at higher risk for fatal prostate cancer.

Biomarkers, Tumor↗
PubMed2006

Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder.

BACKGROUND: Primary adenocarcinomas of the bladder and urachus are rare malignancies, and knowledge of the patient demographics, pathologic characteristics, and survival associated with these tumors is poor. The current study compares disease-specific characteristics and survival associated with urachal and nonurachal primary bladder adenocarcinomas. METHODS: Incident cases of urachal and nonurachal primary adenocarcinomas of the bladder were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Demographic and pathologic characteristics at the time of diagnosis were compared. Risks of mortality among urachal and nonurachal primary adenocarcinomas of the bladder were compared using multivariate Cox regression. RESULTS: A total of 151 urachal and 1374 nonurachal adenocarcinomas of the bladder patients were identified. Compared to those with nonurachal tumors, patients with urachal adenocarcinoma were more likely to be younger (median age, 56 vs. 69 years, P <.0001) and female (45% vs. 36%, P = .02). Urachal lesions were less likely to be high grade (35% vs. 66%, P < .001), but more likely to involve distant metastases (30% vs. 15%, P < .001). Partial cystectomy was more common in urachal tumors (66% vs. 16%, P <.001). In multivariate analysis, subjects with urachal tumors had a lower risk of all cause (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.38-0.83) and disease-specific (HR = 0.59, 95% CI: 0.35-0.98) mortality compared with patients with nonurachal tumors. CONCLUSIONS. Urachal adenocarcinomas represent 10% of all primary adenocarcinomas of the bladder. Overall and disease-specific mortality risks are improved in patients with urachal lesions, even after controlling for numerous patient and tumor characteristics.

Adenocarcinoma↗
PubMed2006

Persistent intraprostatic androgen concentrations after medical castration in healthy men.

CONTEXT: The impact of serum androgen manipulation on prostate tissue hormone levels in normal men is unknown. Studies of men with prostate cancer have suggested that prostatic androgens are preserved in the setting of castration. Tissue androgens might stimulate prostate growth, producing adverse clinical consequences. OBJECTIVE: The objective of the study was to determine the effect of serum androgen manipulation on intraprostatic androgens in normal men. DESIGN: Thirteen male volunteers ages 35-55 yr (prostate-specific antigen < 2.0 ng/ml; normal transrectal ultrasound) were randomly assigned to: 1) a long-acting GnRH-antagonist, acyline, every 2 wk; 2) acyline plus testosterone (T) gel (10 mg/d); or 3) placebo for 28 d. Serum hormones were assessed weekly. Prostate biopsies were obtained on d 28. Extracted androgens were measured by RIA, and immunohistochemistry for androgen-regulated proteins was performed. RESULTS: The mean decrease in serum T was 94%, whereas prostatic T and dihydrotestosterone levels were 70 and 80% lower, respectively, in subjects receiving acyline alone compared with controls (P < 0.05). Despite this decrease in prostate androgens, there were no detectable differences in prostate epithelial proliferation, apoptosis, prostate-specific antigen, and androgen receptor expression. CONCLUSION: In this small study of healthy subjects, despite a 94% decrease in serum T with medical castration, intraprostatic T and dihydrotestosterone levels remained 20-30% of control values, and prostate cell proliferation, apoptosis, and androgen-regulated protein expression were unaffected. Our data highlight the importance of assessing tissue hormone levels. The source of persistent prostate androgens associated with medical castration and their potential role in supporting prostate metabolism deserves further study.

Adult↗
PubMed2006

Influence of surgical manipulation on prostate gene expression: implications for molecular correlates of treatment effects and disease prognosis.

PURPOSE: Measurements of tissue gene expression are increasingly used for disease stratification, clinical trial eligibility, and assessment of neoadjuvant therapy response. However, the method of tissue acquisition alone could significantly influence the expression of specific transcripts or proteins. This study examines whether there are transcript alterations associated with surgical resection of the prostate gland by radical retropubic prostatectomy. MATERIALS AND METHODS: Twelve patients with clinically localized prostate cancer underwent immediate in situ prostate biopsy after induction of anesthesia for radical prostatectomy. Ex vivo prostate biopsies were performed immediately after surgical removal. Prostate epithelium was acquired by laser-capture microdissection, and transcript abundance levels were quantitated by cDNA microarray hybridization and confirmed by quantitative polymerase chain reaction. Data were analyzed by paired, two-sample t test using Statistical Analysis of Microarray algorithms, and linear models were fit as a function of clinical characteristics. RESULTS: Of 5,753 cDNAs with measurable expression in prostate epithelium, 88 (1.5%) were altered as a result of surgery (false-discovery rate < or = 10%), representing 62 unique genes. These included transcripts encoding acute phase response proteins, IER2 and JUNB, and regulators of cell proliferation, p21Cip1 and KLF6. Of the clinical characteristics examined, including patient age, prostate volume, serum prostate-specific antigen, blood loss, and operative time, only gland volume was significantly and negatively associated with the magnitude of gene expression difference between pre- and postsurgical specimens. CONCLUSION: Surgical manipulation results in significant gene expression changes. Molecular analyses of surgical samples should recognize that transcript alterations occur rapidly, and these results are important when designing and analyzing molecular correlates of clinical studies.

Aged↗
PubMed2006

Intermittent androgen deprivation: clinical experience and practical applications.

Prostate cancer is more frequently being diagnosed at an earlier age, men are dying of prostate cancer at an older age, and men are now treated with androgen deprivation for biochemical relapse. As a result, the amount of time that patients are potentially subjected to androgen deprivation is increasing. Intermittent androgen deprivation (IAD) has been investigated as a potential alternative to continuous androgen deprivation (CAD) in order to improve quality of life and potentially delay the progression to androgen independence. Along with the increased use of primary hormonal therapy in clinically localized prostate cancer, IAD may supplant the traditional surgical or radiotherapy options, specifically in men who have underlying co-morbidities and decreased life expectancy. There are ongoing multi-institutional, randomized trials that will lend insight into the utility, efficacy, and feasibility of IAD versus CAD. This article discusses the theoretical benefits and rationale of IAD and reviews the completed and on-going IAD trials. Finally, the controversies, practical applications, and future directions of IAD are addressed.

Androgen Antagonists↗
PubMed2006

Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000.

OBJECTIVES: The incidence of testicular cancer in white adults in the United States increased during most of the last half of the 20th century, but information on trends in the occurrence of prepubertal testicular cancer is lacking. We analyzed a population-based cohort to determine whether the incidence trends of prepubertal testicular germ cell tumors have risen similarly to those seen in adult testicular tumors. METHODS: We identified cases of histologically confirmed germ cell testicular cancer in boys aged 0 to 14 years, of all races, from 1973 to 2000, through the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. The variables analyzed included age, race, tumor histologic type, and year of diagnosis. RESULTS: A total of 131 cases of testicular germ cell cancer were diagnosed among boys of all races, with an overall incidence of 1.6 cases per 1 million person-years. Yolk sac tumor was the most common, followed by teratoma. Choriocarcinoma and seminoma were equally rare. Tumors were most common among whites during early infancy. No secular trends in incidence rates were identified. CONCLUSIONS: Prepubertal testicular cancer is rare. All tumors were more common in whites. In contrast to adult testicular cancer, no clear trend over time was found for prepubertal tumors. Whatever the reasons for the increased incidence of testicular cancer over time in men, they do not seem to bear on the risk of testicular cancer in boys.

Adolescent↗
PubMed2005

Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites.

The higher prevalence of autoimmune disease among women compared with men suggests that steroids impact immune regulation. To investigate how sex steroids modulate cellular immune function, we conducted a randomized trial in 12 healthy men aged 35-55 yr treated for 28 days with placebo, a GnRH antagonist, acyline to induce medical castration, or acyline plus daily testosterone (T) gel to replace serum T, followed by a 28-day recovery period. Serum hormones were measured weekly and peripheral blood lymphocytes (PBLs) were collected biweekly for analyses of thymus-derived lymphocyte (T cell) subtypes and natural killer (NK) cells. Compared with the other groups and to baseline throughout the drug exposure period, men receiving acyline alone had significant reductions in serum T (near or below castrate levels), dihydrotestosterone, and estradiol (P < 0.05). Medical castration significantly reduced the percentage of CD4+ CD25+ T cells (P < 0.05), decreased mitogen-induced CD8+ T cell IFN-gamma expression, and increased the percentage of NK cells without affecting the ratio of CD4+ to CD8+ T cells and the expression of NK cell-activating receptor NKG2D or homing receptor CXCR1. No changes in immune composition were observed in subjects receiving placebo or acyline with replacement T. These data suggest that T and/or its metabolites may help maintain the physiological balance of autoimmunity and protective immunity by preserving the number of regulatory T cells and the activation of CD8+ T cells. In addition, sex steroids suppress NK cell proliferation. This study supports a complex physiological role for T and/or its metabolites in immune regulation.

Adult↗
PubMed2005

Prostate cancer in men using testosterone supplementation.

PURPOSE: Although an association between testosterone supplementation and the development of prostate cancer is unproven, a recent increase in the use of this therapy has reopened the debate about its safety in men at risk for prostate cancer. To increase awareness of this risk, we report on a series of patients in whom clinically significant prostate cancer developed and was presumed to be related to exogenous testosterone use. MATERIALS AND METHODS: The medical records of 6 urology practices were reviewed to identify men undergoing testosterone supplementation for sexual dysfunction or "rejuvenation " who were found to have prostate cancer after initiation of exogenous testosterone supplementation. Cases were analyzed to determine clinical and pathological parameters characterizing the presentation of prostate cancer. RESULTS: A total of 20 men were diagnosed with prostate cancer after initiation of testosterone therapy. Prostate cancer was detected within 2 years of testosterone initiation in 11 men (55%) and from 28 months to 8 years in the remainder. The tumors were of moderate and high grade, being Gleason sum 6, 7 and 8 to 10 in 9 (45%), 6 (30%) and 5 (25%) men, respectively. Median serum prostate specific antigen (PSA) concentration at diagnosis tended to be low at 5.1 ng/ml (range 1.1 to 329.0) and digital rectal examination generally proved more sensitive than PSA assays in detecting the cancer. Patients seen by nonurologist physicians were monitored less often for prostate cancer during testosterone use than those followed by urologists. CONCLUSIONS: Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment. Digital rectal examination is particularly important in the detection of these cancers. Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.

Aged↗
PubMed2005

Tumor lysis syndrome in a patient with metastatic, androgen independent prostate cancer.

Tumor lysis syndrome (TLS) is an uncommon, but well described, clinical entity that typically occurs following chemotherapy in patients with rapidly growing hematological malignancies. It is rarely described in patients with solid tumors. We report a case of TLS in a patient with metastatic adenocarcinoma of the prostate after treatment with paclitaxel chemotherapy.

Adenocarcinoma↗
PubMed2004

Prognostic value of combined "triple"-reverse transcription-PCR analysis for prostate-specific antigen, human kallikrein 2, and prostate-specific membrane antigen mRNA in peripheral blood and lymph nodes of prostate cancer patients.

PURPOSE: We present the largest study of both peripheral blood and lymph node samples examining the utility of reverse transcription-polymerase chain reaction (RT-PCR) for established molecular markers as a diagnostic tool in the molecular staging of prostate cancer patients undergoing radical prostatectomy. EXPERIMENTAL DESIGN: Peripheral blood from 358 patients was obtained before radical prostatectomy. Corresponding obturatory lymph node samples were collected from 153 of these patients. Nested RT-PCR for prostate-specific antigen (PSA), human kallikrein 2 (hK2), and prostate-specific membrane antigen (PSMA) were performed on cDNA from peripheral blood. The lymph node cDNA was analyzed for PSA und hK2 expression. RESULTS: RT-PCR in peripheral blood was positive in 124 (34.6%) of 358 samples for PSA, 215 (60.1%) of 358 for PSMA, and 97 (27.1%) of 358 for hK2. Comparison of positive RT-PCR rates of pT(2) and pT(3) tumors in corresponding peripheral blood for PSA, PSMA, and hK2 were 31.9 and 40.0%, 58.8 and 62.5%, and 26.9 and 27.5%, respectively. Histopathologically, cancer-free lymph node samples were positive in RT-PCR for PSA and hK2 in 70 (49.6%) of 141 and 89 (63.2%) of 141 of cases. All histologically positive lymph node samples (n = 12, pN+) were positive for PSA RT-PCR. PSA RT-PCR alone, as well as combined PSA/PSMA RT-PCR evaluation, in peripheral blood showed a significant association with grading. PSA RT-PCR lymph node-negative samples were significantly less likely positive in their corresponding peripheral blood RT-PCR sample. CONCLUSIONS: Although the preoperative PSA RT-PCR in peripheral blood correlated with the grading of prostate cancer, no combination of RT-PCR results using "triple" markers (PSA, hK2, PSMA) in peripheral blood and/or lymph nodes yielded additional preoperative staging information.

Antigens, Surface↗
PubMed2003

Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy.

PURPOSE: We determined the outcome in patients who underwent urethrectomy after cystectomy followed by routine urethral wash cytology versus those not followed by urethral wash cytology who presented with bleeding or urethral discharge. We retrospectively evaluated the outcome in post-cystectomy urethrectomy cases at our institution from 1994 to 2000. MATERIALS AND METHODS: A total of 24 patients with a median age of 70.5 years underwent urethrectomy after cystectomy, including 17 due to asymptomatic, positive urethral wash cytology (group 1) and 7 who were not followed by urethral wash and presented with bleeding/urethral discharge (group 2). Median time from cystectomy to urethrectomy was 11.4 months (range 6.7 to 67.1). Median followup after cystectomy and urethrectomy was 37 and 27.7 months, respectively. RESULTS: Urethrectomy pathological evaluation showed pTis disease in cases 12 (50%), pT0 in 9 (37.5%) and pT1 in 3 (12.5%). Cystectomy pathology was organ confined (pT0, pTis and pT1-pT2b disease) in 12 cases (50%), nonorgan confined (pT3a-pT4) in 6 (25%) and pT any N1 in 5 (21%). Cystectomy pathology was unknown in 1 case. At the most recent followup there was no evidence of disease in 14 patients (58%), 5 (21%) were alive with disease, 3 (12.5%) were dead of disease, 1 (4%) was dead of other causes and disease status was unknown in 1 (4%). There was no statistical difference in survival in groups 1 and 2 when controlling for original bladder tumor stage. Cox regression analysis revealed that cystectomy pathology was the only statistically significant parameter of disease-free survival (p = 0.011), while urethrectomy pathology and followup method (urethral washing versus no washing) were not significant. There were no perioperative or postoperative complications and no patients died. CONCLUSIONS: There was no significant survival difference in patients followed and not followed with urethral washing. Longer followup and increased patient numbers are needed to determine the significance of these findings.

Aged↗