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1.  Serum 25-Hydroxy Vitamin D and Survival in Advanced Colorectal Cancer: A Retrospective Analysis 
Nutrition and cancer  2015;67(3):424-430.
Higher serum 25-hydroxy vitamin D [25(OH)D] levels are associated with decreased colorectal cancer (CRC) incidence. In this retrospective study of stage IV CRC patients, we evaluate whether 25(OH)D levels at diagnosis correlate with survival.
Stored sera from carcinoembryonic antigen (CEA) measurements obtained between February 2005 and March 2006 were screened. The first 250 patients with CEA ±30 days of stage IV CRC diagnosis were included. Serum 25(OH)D levels were determined and categorized as adequate ≥30 ng/mL, or deficient <30 ng/mL. Multivariable Cox regression models controlling for albumin and Eastern Cooperative Oncology Group performance status were used to investigate whether higher 25(OH)D levels were associated with prolonged survival.
A total of 207 patients (83%) were vitamin D-deficient (median, 21 ng/mL), with deficiencies significantly more likely among non-Hispanic black patients (P=0.009). Higher levels were associated with prolonged survival in categorical variable analysis: adequate vs deficient, hazard ratio 0.61, 95% CI 0.38–0.98, P=0.041.
A majority of newly diagnosed stage IV CRC patients are vitamin D-deficient. Our data suggest that higher 25(OH)D levels are associated with better overall survival. Clinical trials to determine whether aggressive vitamin D repletion would improve outcomes for vitamin D-deficient CRC patients are warranted.
PMCID: PMC4385477  PMID: 25646565
Colorectal cancer; Vitamin D; Epidemiological
2.  Validating Billing/Encounter Codes as Indicators of Lung, Colorectal, Breast, and Prostate Cancer Recurrence using Two Large Contemporary Cohorts 
Medical care  2014;52(10):e65-e73.
A substantial proportion of cancer-related mortality is attributable to recurrent, not de novo metastatic disease, yet we know relatively little about these patients. To fill this gap, investigators often use administrative codes for secondary malignant neoplasm or chemotherapy to identify recurrent cases in population-based datasets. However, these algorithms have not been validated in large, contemporary, routine care cohorts.
To evaluate the validity of secondary malignant neoplasm and chemotherapy codes as indicators of recurrence after definitive local therapy for stage I-III lung, colorectal, breast, and prostate cancer.
Research Design, Subjects & Measures
We assessed the sensitivity, specificity, and positive predictive value (PPV) of these codes 14- and 60-months after diagnosis using two administrative datasets linked with gold-standard recurrence status information: CanCORS/Medicare (diagnoses 2003-2005) and HMO/Cancer Research Network (diagnoses 2000-2005).
We identified 929 CanCORS/Medicare patients and 5298 HMO/CRN patients. Sensitivity, specificity, and PPV ranged widely depending on which codes were included and the type of cancer. For patients with lung, colorectal, and breast cancer, the combination of secondary malignant neoplasm and chemotherapy codes was the most sensitive (75%-85%); no code-set was highly sensitive and highly specific. For prostate cancer, no code-set offered even moderate sensitivity (≤19%).
Secondary malignant neoplasm and chemotherapy codes could not identify recurrent cancer without some risk of misclassification. Findings based on existing algorithms should be interpreted with caution. More work is needed to develop a valid algorithm that can be used to characterize outcomes and define patient cohorts for comparative effectiveness research studies.
PMCID: PMC3600389  PMID: 23222531
3.  Genetic variation in KLK2 and KLK3 is associated with levels of hK2 and PSA in seminal plasma and in serum in young men 
Clinical chemistry  2013;60(3):490-499.
Genetic variants in KLK2 and KLK3 have been associated with increased serum levels of their encoded proteins human kallikrein-related peptidase 2 (hK2) and prostate-specific antigen (PSA), and with prostate cancer in older men. Catalytic PSA, possibly activated by hK2, cleaves semenogelin I and II in semen to release motile sperm; low PSA levels in seminal plasma are associated with low sperm motility. To evaluate whether common genetic variants in KLK2 and KLK3 affect physiological prostatic secretion, we studied the association of SNPs with hK2 and PSA levels in seminal plasma and serum of young healthy men.
Leukocyte DNA was extracted from 303 male military conscripts (median age 18.1 years). Nine SNPs across KLK2-KLK3 were genotyped. PSA and hK2 were measured in seminal plasma and serum with immunofluorometric assays. The association of genotype frequencies with hK2 and PSA levels was tested using the Kruskal-Wallis test.
Four KLK2 SNPs (rs198972, rs198977, rs198978, and rs80050017) were strongly associated with hK2 levels in seminal plasma and serum, with individuals homozygous for the major alleles having 3- to 7-fold higher levels than the other homozygote and heterozygotes having intermediate levels (all P<0.001). Three of these SNPs were significantly associated with %fPSA in serum (all P<0.007). Three KLK3 SNPs showed associations with PSA in seminal plasma and the rs1058205 SNP was associated with total PSA in serum (P=0.001), and with lower %free PSA (P=0.015).
In young men without prostate disease, both the seminal plasma and serum levels of hK2 and PSA are associated with several genetic variants in KLK2 and KLK3 that could be used to refine models of PSA cut-off values in prostate cancer testing.
PMCID: PMC3943614  PMID: 24270797
prostate cancer; prostate-specific antigen; tumor markers; seminal fluid
4.  Prognostic significance of lymphovascular invasion in radical prostatectomy specimens 
BJU international  2010;108(4):502-507.
To determine whether lymphovascular invasion (LVI) in radical prostatectomy (RP) specimens has prognostic significance.
The study examined whether LVI is associated with clinicopathological characteristics and biochemical recurrence (BCR).
LVI was evaluated based on routine pathology reports on 1298 patients treated with RP for clinically localized prostate cancer between 2004 and 2007.
LVI was defined as the unequivocal presence of tumour cells within an endothelium-lined space.
The association between LVI and clinicopathological features was assessed with univariate logistic regression. Cox regression was used to test the association between LVI and BCR.
LVI was identified in 10% (129/1298) of patients.
The presence of LVI increased with advancing pathological stage: 2% (20/820) in pT2N0 patients, 16% (58/363) in pT3N0 patients and 17% (2/12) in pT4N0 patients; and was highest in patients with pN1 disease (52%; 49/94).
Univariate analysis showed an association between LVI and higher preoperative prostate-specific antigen levels and Gleason scores, and a greater likelihood of extraprostatic extension, seminal vesicle invasion, lymph node metastasis and positive surgical margins (all P < 0.001).
With a median follow-up of 27 months, LVI was significantly associated with an increased risk of BCR after RP on univariate (P < 0.001) and multivariate analysis (hazard ratio, 1.77; 95% confidence interval, 1.11–2.82; P = 0.017).
As a result of the relatively short follow-up, the predictive accuracy of the standard clinicopathological features was high (concordance index, 0.880), and inclusion of LVI only marginally improved the predictive accuracy (0.884).
Although associated with features of aggressive disease and BCR, LVI added minimally to established predictors on short follow-up.
Further study of cohorts with longer follow-up is warranted to help determine its prognostic significance.
PMCID: PMC4319653  PMID: 21050364
prostate; prostatic neoplasms; prostatectomy; disease progression; lymphovascular invasion
5.  Clinical Outcomes of Primary Bladder Carcinoma in Situ in a Contemporary Series 
The Journal of urology  2010;184(1):74-80.
The natural history of primary bladder carcinoma in situ (CIS) has not been well described. We describe patterns of disease recurrence and progression and identify clinical-outcome predictors for primary CIS after BCG therapy.
Materials and Methods
A retrospective analysis of 155 patients diagnosed with isolated primary high-grade CIS in a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical BCG therapy. The endpoints included time to disease recurrence, time to progression to invasive disease (≥cT1) or to muscle-invasive disease (≥cT2), or early radical cystectomy (RC). Predictors included gender, age, race, smoking history, presenting symptoms, CIS pattern (focal, multiple or diffuse), and response to BCG.
In total, 155 patients received BCG therapy within 6 mo. Five-yr cumulative incidence of progression to ≥cT1 was 45% (95% CI, 37%–55%), to ≥cT2 was 17% (95% CI, 12%–25%), adjusting for the competing risk of RC. Of 130 patients evaluated for response to BCG, 81 (62%) were considered responders. Response to BCG was significantly associated with progression to ≥cT1/RC (HR: 0.59; 95% CI, 0.36–0.95; p=0.029) and to ≥cT2/RC (HR: 0.53; 95% CI, 0.32–0.88; p=0.015). This association was largely driven by the higher rate of early RC among non-responders.
Despite BCG therapy and early RC, patients with primary CIS had a high rate of disease progression. Response to BCG was significantly associated with a lower rate of disease progression or early RC.
PMCID: PMC4226045  PMID: 20546806
Bladder Cancer; Carcinoma in Situ; BCG
6.  Complications After Radical and Partial Nephrectomy as a Function of Age 
The Journal of urology  2010;183(5):1725-1730.
Partial nephrectomy may be underutilized in elderly patients due to concerns of higher complication rates compared with radical nephrectomy. We sought to determine if the association between age and perioperative outcomes differed between types of nephrectomy.
Materials and Methods
We identified patients who underwent radical or partial nephrectomy between January 2000 and October 2008. Using multivariable methods, we determined whether the relationship between age and risk of postoperative complications, estimated blood loss, or operative time differed by type of nephrectomy.
Of 1,712 patients, 651 (38%) underwent radical nephrectomy and 1061 (62%) underwent partial nephrectomy. Patients treated with partial nephrectomy had higher complication rates than those treated with radical nephrectomy (20% vs 14%). In a multivariable model, age was significantly associated with a small increased risk of having a complication (OR for 10-year age increase: 1.17; 95% CI, 1.04-1.32; p = 0.009). When including an interaction term between age and procedure type, the interaction term was not significant (p = 0.09), indicating there was no evidence the risk of complications associated with a partial versus a radical nephrectomy increased with advancing age. We found no evidence that age was significantly associated with estimated blood loss or operative time.
We found no evidence that elderly patients experience a proportionally higher rate of complications, longer operative times, or higher estimated blood loss from partial nephrectomy than do younger patients. Given the advantages of renal function preservation, we should expand the use of nephron-sparing treatment for renal tumors in elderly patients.
PMCID: PMC4179201  PMID: 20299040
Carcinoma, renal cell; Kidney neoplasms; Nephrectomy; Urologic surgical procedures; Postoperative complications
7.  Developments in the surgical management of sporadic synchronous bilateral renal tumours 
BJU international  2009;105(8):1093-1097.
To examine our experience with managing sporadic bilateral renal masses, focusing on trends in surgical management over time, because as loss of renal function is associated with adverse cardiovascular outcomes, nephron-sparing approaches are increasingly emphasized in the treatment of kidney tumours, creating new challenges for the treatment of bilateral tumours.
Patients and Methods
We identified all patients who underwent partial or radical nephrectomy (PN or RN) at Memorial Sloan-Kettering Cancer Center (MSKCC) during 1989-2008. We compared patients presenting with synchronous bilateral renal masses with those with unilateral tumour and evaluated trends in management using logistic regression.
Of the 2777 patients studied, 73 (3%) presented with synchronous bilateral disease. The overall survival and clinical/pathologica features between groups were similar. Of those patients receiving bilateral operations for synchronous tumours, three had bilatera RN (all before 2003), 28 (38%) had an RN followed by a PN, 10 (14%) had a PN then an RN, and 32 (44%) had bilateral PN. Over time, the proportion of patients receiving bilateral PN increased (P < 0.001); 13 of 14 patients after 2005 had bilateral PN, compared with only 34% (16 of 45) between 1995 and 2004. Forty-five patients (62%) had the larger tumour removed during the first operation. The concordance rate between tumours in a specific histological subtype was 70% (51/73), and concordance for benign vs malignant disease was 90% (66/73).
The use of PN in the management of synchronous bilateral renal masses has increased over time. The contemporary treatment of synchronous bilateral renal masses at MSKCC involves staged PN when feasible, with the more involved kidney (often larger tumour) operated on first.
PMCID: PMC4179200  PMID: 19751262
carcinoma; renal cell; kidney; nephrectomy; urological surgery
8.  Comparison Between Laparoscopic and Open Radical Nephroureterectomy in a Contemporary Group of Patients: Are Recurrence and Disease-Specific Survival Associated with Surgical Technique? 
European urology  2010;58(5):645-651.
Open radical nephroureterectomy (ORN) is the current standard of care for upper tract urothelial carcinoma (UTUC), but laparoscopic radical nephroureterectomy (LRN) is emerging as a minimally invasive alternative. Questions remain regarding the oncologic safety of LRN and its relative equivalence to ORN.
Our aim was to compare recurrence-free and disease-specific survival between ORN and LRN.
Design, setting, and participants
We retrospectively analyzed data from 324 consecutive patients treated with radical nephroureterectomy (RN) between 1995 and 2008 at a major cancer center. Patients with previous invasive bladder cancer or contralateral UTUC were excluded. Descriptive data are provided for 112 patients who underwent ORN from 1995 to 2001 (pre-LRN era). Comparative analyses were restricted to patients who underwent ORN (n = 109) or LRN (n = 53) from 2002 to 2008. Median follow-up for patients without disease recurrence was 23 mo.
All patients underwent RN.
Recurrence was categorized as bladder-only recurrence or any recurrence (bladder, contralateral kidney, operative site, regional lymph nodes, or distant metastasis). Recurrence-free probabilities were estimated using Kaplan-Meier methods. A multivariable Cox model was used to evaluate the association between surgical approach and disease recurrence. The probability of disease-specific death was estimated using the cumulative incidence function.
Results and limitations
Clinical and pathologic characteristics were similar for all patients. The recurrence-free probabilities were similar between ORN and LRN (2-yr estimates: 38% and 42%, respectively; p = 0.9 by log-rank test). On multivariable analysis, the surgical approach was not significantly associated with disease recurrence (hazard ratio [HR]: 0.88 for LRN vs ORN; 95% confidence interval [CI], 0.57–1.38; p = 0.6). There was no significant difference in bladder-only recurrence (HR: 0.78 for LRN vs ORN; 95% CI, 0.46–1.34; p = 0.4) or disease-specific mortality (p = 0.9). This study is limited by its retrospective nature.
Based on the results of this retrospective study, no evidence indicates that oncologic control is compromised for patients treated with LRN in comparison with ORN.
PMCID: PMC4167427  PMID: 20724065
Laparoscopy; Nephroureterectomy; Recurrence; Survival; Transitional cell carcinoma; Urothelial carcinoma
9.  Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years 
Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long-term follow in young persons. Our cohort included 33,346 subjects, aged 26–61 years at baseline, in a representative, population-based study enrolling subjects from 1974 to 1992. Median follow-up time was 28 years. Plasma creatinine was analysed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40–52), 7,498 older women (age 47–57) and 1,688 younger women (age 35–43). Glomerular filtration rate (GFR) was estimated using the CKD-EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR≥60 mL/min/1.73m2), or moderate kidney dysfunction (eGFR<60 mL/min/1.73m2). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; P=0.004). However, we found no association with overall long-term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high-risk groups and biological mechanisms.
PMCID: PMC3707943  PMID: 23463659
Cancer; chronic kidney disease; kidney cancer; renal function
10.  A simple decision analytic solution to the comparison of two binary diagnostic tests 
Statistics in medicine  2012;32(11):1865-1876.
One of the most basic biostatistical problems is the comparison of two binary diagnostic tests. Commonly, one test will have greater sensitivity and the other greater specificity. In this case, the choice of the optimal test generally requires a qualitative judgment as to whether gains in sensitivity are offset by losses in specificity. Here we propose a simple decision-analytic solution in which sensitivity and specificity are weighted by an intuitive parameter, the threshold probability of disease at which a patient will opt for treatment. This gives a net benefit that can be used to determine which of two diagnostic tests will give better clinical results at a given threshold probability, and whether either is superior to the strategy of assuming that all or no patients have disease. We derive a simple formula for the relative diagnostic value, which is the difference in sensitivities of two tests divided by the difference in the specificities. We show that multiplying relative diagnostic value by the odds at the prevalence gives the odds of the threshold probability below which the more sensitive test is preferable, and above which the more specific test should be chosen. The methodology is easily extended to incorporate combination of tests, and the risk or side-effects of a test.
PMCID: PMC3531575  PMID: 22975863
diagnostic tests; decision analysis; combination tests; sequential testing; prostate cancer; molecular markers
11.  Comparison of Transperineal Mapping Biopsy Results with Whole-Mount Radical Prostatectomy Pathology in Patients with Localized Prostate Cancer 
Prostate Cancer  2014;2014:781438.
Objective. We sought to evaluate the accuracy of transperineal mapping biopsy (TMB) by comparing it to the pathology specimen of patients who underwent radical prostatectomy (RP) for localized prostate cancer. Methods. From March 2007 to September 2009, 78 men at a single center underwent TMB; 17 of 78 subsequently underwent RP. TMB cores were grouped into four quadrants and matched to data from RP whole-mount slides. Gleason score, tumor location and volume, cross-sectional area, and maximal diameter were measured; sensitivity and specificity were assessed. Results. For the 17 patients who underwent RP, TMB revealed 12 (71%) had biopsy Gleason grades ≥ 3 + 4 and 13 (76%) had bilateral disease. RP specimens showed 14 (82%) had Gleason scores ≥ 3 + 4 and 13 (76%) had bilateral disease. Sensitivity and specificity of TMB for prostate cancer detection were 86% (95% confidence interval [CI] 72%–94%) and 83% (95% CI 62%–95%), respectively. Four quadrants negative for cancer on TMB were positive on prostatectomy, and six positive on TMB were negative on prostatectomy. Conclusion. TMB is a highly invasive procedure that can accurately detect and localize prostate cancer. These findings help establish baseline performance characteristics for TMB and its utility for organ-sparing strategies.
PMCID: PMC4037573  PMID: 24900923
12.  Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer 
BJU international  2011;109(5):713-719.
To investigate the relationship between BRCA mutation status and response to taxane-based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non-carriers and docetaxel improves survival in patients with castration-resistant prostate cancer.
Patients and Methods
We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration-resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review.
Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations.
Response to taxane-based therapy was defined by the prostate-specific antigen nadir within 12 weeks of therapy.
In all, 88 men received taxane-based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non-carriers.
Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non-carriers (72%) (absolute difference 15%; 95% confidence interval −23% to 53%; P = 0.4).
Among patients with an initial response, the median change in prostate-specific antigen was similar for BRCA carriers (−63%, interquartile range −71% to −57%) and non-carriers (−60%, interquartile range −78% to −35%) (P = 0.6).
At last follow-up, all seven BRCA carriers and 49 non-carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months.
In this small, hypothesis-generating study approximately half of BRCA carriers had a prostate-specific antigen response to taxane-based chemotherapy, suggesting that it is an active therapy in these individuals.
PMCID: PMC3971723  PMID: 21756279
castration-resistant prostate cancer; BRCA1; BRCA2; taxane; docetaxel; response
World journal of urology  2012;32(1):185-191.
To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade ≥ 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations.
25,512 biopsies from 10 cohorts (6 European, 1 UK, and 3 US) were included; 4 implemented 6-core biopsies and the remaining had 10- or higher schemes; 8 were screening cohorts and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen (PSA), digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC), and net benefit curves.
The median AUC of the PCPTHG for high grade disease detection in the 10- and higher-core cohorts was 73.5% (range 63.9% to 76.7%) compared to a median of 78.1 (range = 72.0 to 87.6) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15%. The PCPTHG demonstrated higher clinical net benefit in higher- compared to six-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts.
The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20%, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making.
PMCID: PMC3702682  PMID: 22527674
Calibration; Discrimination; Net Benefit; High Grade Prostate Cancer; Risk; Prostate Cancer Prevention Trial
14.  Acupuncture for chronic pain: individual patient data meta-analysis 
Archives of internal medicine  2012;172(19):1444-1453.
Although acupuncture is widely used for chronic pain, there remains considerable controversy as to its value. We aimed to determine the effect size of acupuncture for four chronic pain conditions: back and neck pain, osteoarthritis, chronic headache, and shoulder pain.
We conducted a systematic review to identify randomized trials of acupuncture for chronic pain where allocation concealment was determined unambiguously to be adequate. Individual patient data meta-analyses were conducted using data from 29 of 31 eligible trials, with a total of 17,922 patients analyzed.
In the primary analysis including all eligible trials, acupuncture was superior to both sham and no acupuncture control for each pain condition (all p<0.001). After exclusion of an outlying set of trials that strongly favored acupuncture, the effect sizes were similar across pain conditions. Patients receiving acupuncture had less pain, with scores 0.23 (95% C.I. 0.13, 0.33), 0.16 (95% C.I. 0.07, 0.25) and 0.15 (95% C.I. 0.07, 0.24) standard deviations lower than sham controls for back and neck pain, osteoarthritis, and chronic headache respectively; the effect sizes in comparison to no acupuncture controls were 0.55 (95% C.I. 0.51, 0.58), 0.57 (95% C.I. 0.50, 0.64) and 0.42 (95% C.I. 0.37, 0.46). These results were robust to a variety of sensitivity analyses, including those related to publication bias.
Acupuncture is effective for the treatment of chronic pain and is therefore a reasonable referral option. Significant differences between true and sham acupuncture indicate that acupuncture is more than a placebo. However, these differences are relatively modest, suggesting that factors in addition to the specific effects of needling are important contributors to the therapeutic effects of acupuncture.
PMCID: PMC3658605  PMID: 22965186
15.  Susceptibility Loci Associated with Prostate Cancer Progression and Mortality 
Prostate cancer is a heterogenous disease with a variable natural history that is not accurately predicted by currently used prognostic tools.
Experimental Design
We genotyped 798 prostate cancer cases of Ashkenazi Jewish ancestry treated for localized prostate cancer between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to clinical data. The survival analysis was adjusted for Gleason score and PSA. We investigated associations between 29 single nucleotide polymorphisms (SNPs) and biochemical recurrence, castration-resistant metastasis, and prostate cancer-specific survival. Subsequently, we performed an independent analysis using a high resolution panel of 13 SNPs.
On univariate analysis, 2 SNPs were associated (p<0.05) with biochemical recurrence; 3 SNPs were associated with clinical metastases; and 1 SNP was associated with prostate cancer-specific mortality. Applying a Bonferroni correction (p<0.0017), one association with biochemical recurrence (p=0.0007) was significant. Three SNPs showed associations on multivariable analysis, although not after correcting for multiple testing. The secondary analysis identified an additional association with prostate cancer-specific mortality in KLK3 (p<0.0005 by both univariate and multivariable analysis).
We identified associations between prostate cancer susceptibility SNPs and clinical endpoints. The rs61752561 in KLK3 and rs2735839 in the KLK2-KLK3 intergenic region associated strongly with prostate cancer-specific survival, and rs10486567 in 7JAZF1 gene associated with biochemical recurrence. A larger study will be required to independently validate these findings and determine the role of these SNPs in prognostic models.
PMCID: PMC3732009  PMID: 20460480
Single nucleotide polymorphisms; Prostate cancer; Prognosis
The Journal of urology  2009;182(3):949-955.
We sought to assess the impact of prostate size on operative difficulty as measured by estimated blood loss (EBL), operating room (OR) time and positive surgical margins (SM) and secondarily to assess the impact on biochemical recurrence (BCR) and the functional outcomes of potency and continence at one year following radical prostatectomy (RP) as well as postoperative bladder neck contracture (BNC).
Materials and Methods
During 1998–2007, 3067 men underwent RP by one of 5 dedicated prostate surgeons with no neoadjuvant or adjuvant therapy. Pathologic specimen weight was used as a measure of prostate size. Cox proportional hazards and logistic regression analysis was used to study the association between specimen weight and biochemical recurrence (BCR) and SM status, respectively, controlling for adverse pathologic features. Continence and potency were analyzed controlling for age, nerve-sparing status, and surgical approach.
With increasing prostate size, there was increased EBL (p=0.013) and OR time (p=0.004) and a decrease in positive SM (84/632 (14%) for ≤40g, 99/862 (12%) for 41–50g, 78/842 (10%) for 51–65g, 68/731 (10%) for >65g (p<0.001)). BCR was observed in 186 of 2882 patients followed postoperatively and was not significantly associated with specimen weight (p=0.3). Complete continence was observed in 1165/1422 (82%) and potency in 425/827 (51%) at one year. Specimen weight was not significantly associated with potency (p=0.8), continence (p=0.08) or BNC (p=0.22).
Prostate size does not appear to affect biochemical recurrence or one-year functional results. However, EBL and OR time increased with larger prostate size and positive SM are more often observed in smaller glands.
PMCID: PMC2885288  PMID: 19616260
organ volume; outcome assessment (health care); penile erection; prostatectomy; urinary incontinence
17.  The Total Number of Retroperitoneal Lymph Nodes Resected Impacts Clinical Outcome Following Chemotherapy for Metastatic Testicular Cancer 
Urology  2010;75(6):1431-1435.
Following the multidisciplinary management of metastatic germ cell tumor, approximately 10 to 15% of patients with the histologic finding of fibrosis or teratoma will suffer disease recurrence. We evaluated the prognostic significance of the total number of lymph nodes obtained at post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Materials and Methods
From 1989 to 2006, a total of 628 patients underwent PC-RPLND and were found to have either fibrosis or teratoma. Following Institutional Review Board approval, complete clinical and pathologic data were obtained from our prospective testis cancer surgical database. A Cox proportional hazards regression model was constructed to evaluate the association of the total number of lymph nodes obtained at PC-RPLND on disease recurrence.
On pathologic evaluation, 248 (57%) patients had fibrosis and 184 (43%) patients had teratoma. The median number of lymph nodes resected was 25 (IQ range 15, 37). On multivariable analysis, increasing post-chemotherapy nodal size and decreasing lymph node counts were significant predictors of disease recurrence (p=0.01, 0.04, respectively). For patients with 10 nodes removed, the predicted 2 year relapse free probability was 90%, compared to 97% when 50 nodes were removed.
Our data suggests that the total number of lymph nodes removed and analyzed is an independent predictor of disease recurrence following PC-RPLND. This has implications both for the urologist to assure completeness of resection and for the pathologist to meticulously assess the pathologic specimens.
PMCID: PMC3654386  PMID: 20299079
testis cancer; surgery; chemotherapy; lymph node count
18.  Focal Treatment or Observation of Prostate Cancer: Pretreatment Accuracy of TRUS Biopsy and T2-Weighted MRI 
Urology  2009;75(2):472-477.
Focal treatment is a curative option for localized prostate cancer (PCA), but appropriate selection of patients hasn’t been established. We analyzed patients who had undergone radical prostatectomy (RP), with preoperative disease features considered favorable for focal treatment, to test the hypothesis that they would be accurately characterized with transrectal biopsy and prostate MRI.
202 patients with PCA who had preoperative MRI and low-risk biopsy criteria (no Gleason grade 4/5, one involved core, < 2 mm, PSA density ≤ 0.10, clinical stage ≤ T2a). Indolent RP pathology was defined as no Gleason 4/5, organ confined, tumor volume < 0.5cc, negative surgical margins. MRI ability to locate and determine the tumor extent was assessed.
After RP, 101 men (50%) had non-indolent cancer. Multifocal and bilateral tumors were present in 81% and 68% of patients, respectively. MRI indicated extensive disease in 16 (8%). MRI sensitivity to locate PCA ranged from 2–20%, and specificity from 91–95%. On univariate analysis, MRI evidence of extracapsular extension (ECE) (P = 0.027) and extensive disease (P = 0.001) were associated with non-indolent cancer. On multivariate analysis, only the later remained as significant predictor (P = 0.0018).
Transrectal biopsy identified men with indolent tumors favorable for focal treatment in 50% of cases. MRI findings of ECE and extensive tumor involving more than half of the gland are associated with unfavorable features, and may be useful excluding patients from focal treatment. According to these data, endorectal MRI isn’t sufficient to localize small tumors for focal treatment.
PMCID: PMC3651887  PMID: 19643467
Focal therapy; Prostate biopsy; Prostate cancer; Prostate MRI
19.  Evaluating The PCPT Risk Calculator in Ten International Biopsy Cohorts: Results from the Prostate Biopsy Collaborative Group 
World journal of urology  2011;30(2):181-187.
To evaluate the discrimination, calibration and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European Randomized study of Screening for Prostate Cancer (ERSPC), 1 United Kingdom, 1 Austrian and 3 US biopsy cohorts.
PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history and history of prior biopsy, and single imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves.
AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort, and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well-calibrated in the SABOR, Tyrol and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts.
External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.
PMCID: PMC3616370  PMID: 22210512
receiver operating characteristic curve; risk; prostate cancer; calibration; net benefit
20.  Intra-individual short-term variability of prostate-specific antigen and other kallikrein markers in a serial collection of blood from men under evaluation for prostate cancer 
BJU international  2010;107(11):1769-1774.
To assess variation of total prostate-specific antigen (tPSA), free PSA (fPSA), percent fPSA, human glandular kallikrein 2 (hK2), and intact PSA measured three times within two weeks. Knowledge of the variation in an individual’s PSA level is important for clinical decision-making.
Patients and Methods
Study participants were 149 patients referred for prostate biopsy, of which 97 had benign disease and 52 had prostate cancer. Three blood samples were drawn with a median of four hours between first and second samples and 12 days between first and third samples. Variability was described by absolute differences, ratios and intra-individual coefficients of variation. Total PSA, fPSA, hK2, and intact PSA were measured in anti-coagulated blood plasma.
At baseline, the median tPSA was 6.8 (IQR 4.5, 9.6) ng/mL. The intra-individual variation was low for all biomarkers, and lowest for tPSA. For 80% of participants, the ratio between first and second time points for tPSA was between 0.91 and 1.09 and the ratio for percent fPSA was between 0.89 and 1.15. Total coefficients of variation between time 1 and 2 for tPSA, fPSA, percent fPSA, hK2 and intact PSA were 4.0%, 6.6%, 6.0%, 9.2%, and 9.5%, respectively. The measurements taken several days apart varied more than those taken on the same day, but the variation between both time points were not large.
The intra-individual variation for all the kallikrein-like markers studied was relatively small, especially for samples drawn the same day. Few cases are reclassified between the time points. This indicates high short-term biological and technical reproducibility of the tests in clinical use.
PMCID: PMC3572723  PMID: 20955263
Free PSA; Prostate cancer; PSA; Screening; Variation
21.  PSA velocity does not aid the detection of prostate cancer in men with a prior negative biopsy: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden and Rotterdam, Netherlands 
The Journal of urology  2010;184(3):907-912.
Prostate specific antigen (PSA) velocity has been proposed as a marker to aid detection of prostate cancer. We sought to determine whether PSA velocity could predict the results of repeat biopsy in men with persistently elevated PSA after initial negative biopsy.
Materials and Methods
We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer (ERSPC), and who had one or more subsequent prostate biopsies after an initial negative finding. We evaluated whether PSA velocity improved predictive accuracy beyond that of PSA alone.
There were a total of 2579 repeat biopsies, of which 363 (14%) were positive for prostate cancer, and 44 (1.7%) were high grade (Gleason score ≥7). Although PSA velocity was statistically associated with cancer risk (p<0.001), it had very low predictive accuracy (area-under-the-curve [AUC] of 0.55). There was some evidence that PSA velocity improved AUC compared to PSA for high grade cancer. However, the small increase in risk associated with high PSA velocity – from 1.7 % to 2.8% as velocity increased from 0 to 1 ng / ml / year - is of questionable clinical relevance.
Men with a prior negative biopsy have a lower risk for prostate cancer at subsequent biopsies, with high grade disease particularly rare. We found little evidence to support the use of PSA velocity to aid decisions about repeat biopsy for prostate cancer.
PMCID: PMC3412428  PMID: 20643434
22.  Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50 
Cancer  2010;117(6):1210-1219.
We previously reported that a single prostate-specific antigen (PSA) measured at age 44–50 was highly predictive of subsequent prostate cancer diagnosis in an unscreened population. Here we report an additional seven years of follow-up. This provides a replication on an independent data set, and allows estimates of the association between early PSA and subsequent advanced cancer (clinical stage ≥T3 or metastases at diagnosis).
Blood was collected from 21,277 men in a Swedish city (74% participation rate) during 1974–1986 at age 33–50. Through 2006, prostate cancer was diagnosed in 1408 participants; we measured PSA in archived plasma for 1312 (93%) of these cases and for 3728 controls.
At a median follow-up of 23 years, baseline PSA was strongly associated with subsequent prostate cancer (area-under-the-curve 0.72; 95% CI 0.70, 0.74; for advanced cancer 0.75; 95% CI 0.72, 0.78). Associations between PSA and prostate cancer were virtually identical for the initial and replication data sets with 81% (95% CI 77%, 86%) of advanced cases found in men with PSA above the median (0.63 ng/ml at age 44 – 50).
A single PSA at or before age 50 predicts advanced prostate cancer diagnosed up to 30 years later. Use of early PSA to stratify risk would allow a large group of men to be screened less often but increase frequency of testing on a more limited number of high-risk men. This is likely to improve the ratio of benefits to harms for screening.
PMCID: PMC3412541  PMID: 20960520
prostate cancer; prostate-specific antigen; human kallikrein 2; risk factors; case-control study
23.  Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer: A Multi-institutional Collaboration 
European urology  2011;60(2):205-210.
Oncologic outcomes in men with radiation-recurrent prostate cancer (PCa) treated with salvage radical prostatectomy (SRP) are poorly defined.
To identify predictors of biochemical recurrence (BCR), metastasis, and death following SRP to help select patients who may benefit from SRP.
Design, setting, and participants
This is a retrospective, international, multi-institutional cohort analysis. There was a median follow-up of 4.4 yr following SRP performed on 404 men with radiation-recurrent PCa from 1985 to 2009 in tertiary centers.
Open SRP.
BCR after SRP was defined as a serum prostate-specific antigen (PSA) ≥0.1 or ≥0.2 ng/ml (depending on the institution). Secondary end points included progression to metastasis and cancer-specific death.
Results and limitations
Median age at SRP was 65 yr of age, and median pre-SRP PSA was 4.5 ng/ml. Following SRP, 195 patients experienced BCR, 64 developed metastases, and 40 died from PCa. At 10 yr after SRP, BCR-free survival, metastasis-free survival, and cancer-specific survival (CSS) probabilities were 37% (95% confidence interval [CI], 31–43), 77% (95% CI, 71–82), and 83% (95% CI, 76–88), respectively. On preoperative multivariable analysis, pre-SRP PSA and Gleason score at postradiation prostate biopsy predicted BCR (p = 0.022; global p < 0.001) and metastasis (p = 0.022; global p < 0.001). On postoperative multivariable analysis, pre-SRP PSA and pathologic Gleason score at SRP predicted BCR (p = 0.014; global p < 0.001) and metastasis (p < 0.001; global p < 0.001). Lymph node involvement (LNI) also predicted metastasis (p = 0.017). The main limitations of this study are its retrospective design and the follow-up period.
In a select group of patients who underwent SRP for radiation-recurrent PCa, freedom from clinical metastasis was observed in >75% of patients 10 yr after surgery. Patients with lower pre-SRP PSA levels and lower postradiation prostate biopsy Gleason score have the highest probability of cure from SRP.
PMCID: PMC3124574  PMID: 21420229
Prostate cancer; Radiation therapy; Salvage therapy
24.  Preoperative and Postoperative Nomograms Incorporating Surgeon Experience for Clinically Localized Prostate Cancer 
Cancer  2009;115(5):1005-1010.
Accurate preoperative and postoperative risk assessment has been critical for counseling patients regarding radical prostatectomy for clinically localized prostate cancer. In addition to other treatment modalities, neoadjuvant or adjuvant therapies have been considered. The growing literature suggested that the experience of the surgeon may affect the risk of prostate cancer recurrence. The purpose of this study was to develop and internally validate nomograms to predict the probability of recurrence, both preoperatively and postoperatively, with adjustment for standard parameters plus surgeon experience.
The study cohort included 7724 eligible prostate cancer patients treated with radical prostatectomy by 1 of 72 surgeons. For each patient, surgeon experience was coded as the total number of cases conducted by the surgeon before the patient’s operation. Multivariable Cox proportional hazards regression models were developed to predict recurrence. Discrimination and calibration of the models was assessed following bootstrapping methods, and the models were presented as nomograms.
In this combined series, the 10-year probability of recurrence was 23.9%. The nomograms were quite discriminating (preoperative concordance index, 0.767; postoperative concordance index, 0.812). Calibration appeared to be very good for each. Surgeon experience seemed to have a quite modest effect, especially postoperatively.
Nomograms have been developed that consider the surgeon’s experience as a predictor. The tools appeared to predict reasonably well but were somewhat little improved with the addition of surgeon experience as a predictor variable.
PMCID: PMC3391599  PMID: 19156928
prostate cancer; surgeon experience; recurrence; predictive value; nomogram
25.  Evaluation of Prediagnostic Prostate-Specific Antigen Dynamics as Predictors of Death from Prostate Cancer in Patients Treated Conservatively 
Prostate-specific antigen (PSA) dynamics have been proposed to predict outcome in men with prostate cancer. We assessed the value of PSA velocity (PSAV) and doubling time (PSADT) for predicting prostate-cancer–specific mortality (PCSM) in men with clinically localized prostate cancer undergoing conservative management or early hormonal therapy. From 1990 to 1996, 2333 patients were identified, of whom 594 had two or more PSA values before diagnosis. We examined 12 definitions for PSADT and 10 for PSAV. Because each definition required PSA measurements at particular intervals, the number of patients eligible for each definition varied from 40 to 594 and number of events from 10 to 119. Four PSAV definitions, but no PSADT, were significantly associated with PCSM after adjustment for PSA in multivariable Cox proportional hazards regression. All 4 could be calculated only for a proportion of events, and the enhancements in predictive accuracy associated with PSAV had very wide confidence intervals. There was no clear benefit of PSAV in men with low PSA and Gleason grade 6 or less. Although evidence that certain PSAV definitions help predict PCSM in the cohort exist, the value of incorporating PSAV in predictive models to assist in determining eligibility for conservative management is, at best, uncertain.
PMCID: PMC2988082  PMID: 20658531
prostate-specific antigen; prostate-specific antigen velocity; prostate-specific antigen doubling time; watchful waiting; prediction

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