Eric J. Bergstralh

Papillary thyroid carcinoma managed at the Mayo Clinic during six decades (1940-1999): Temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients

It is uncertain whether more extensive primary surgery and increasing use of radioiodine remnant ablation (RRA) for papillary thyroid carcinoma (PTC) have resulted in improved rates of cause-specific mortality (CSM) and tumor recurrence (TR). Details of the initial presentation, therapy, and outcome of 2444 PTC patients consecutively treated during 1940–1999 were recorded in a computerized database. Patients were followed for more than 43,000 patient-years. The 25-year rates for CSM and TR were 5% and 14%, respectively. Temporal trends were analyzed for six decades. During the six decades, the proportion with initial MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores <6 were 77%, 82%, 84%, 86%, 85%, and 82%, respectively (p = 0.06). Lobectomy accounted for 70% of initial procedures during 1940–1949 and 22% during 1950–1959; during 1960–1999 bilateral lobar resection (BLR) accounted for 91% of surgeries (p <0.001). RRA after BLR was performed during 1950–1969 in 3% but increased to 18%, 57%, and 46% in successive decades (p <0.001). The 40-year rates for CSM and TR during 1940–1949 were significantly higher (p = 0.002) than during 1950–1999. During the last 50 years the 10-year CSM and TR rates for the 2286 cases did not significantly change with successive decades. Moreover, the 10-year rates for CSM and TR were not significantly improved during the last five decades of the study, either for the 1917 MACIS <6 patients or the 369 MACIS ? 6 patients. Increasing use of RRA has not apparently improved the already excellent outcome, achieved before 1970, in low risk (MACIS <6) PTC patients managed by near-total thyroidectomy and conservative nodal excision.

Radical prostatectomy for prostatic adenocarcinoma: a matched comparison of open retropubic and robot-assisted techniques

To assess the perioperative complications and early oncological results in a comparative study matching open radical retropubic (RRP) and robot‐assisted radical prostatectomy (RARP) groups.

Discovery and Validation of a Prostate Cancer Genomic Classifier that Predicts Early Metastasis Following Radical Prostatectomy

Purpose Clinicopathologic features and biochemical recurrence are sensitive, but not specific, predictors of metastatic disease and lethal prostate cancer. We hypothesize that a genomic expression signature detected in the primary tumor represents true biological potential of aggressive disease and provides improved prediction of early prostate cancer metastasis. Methods A nested case-control design was used to select 639 patients from the Mayo Clinic tumor registry who underwent radical prostatectomy between 1987 and 2001. A genomic classifier (GC) was developed by modeling differential RNA expression using 1.4 million feature high-density expression arrays of men enriched for rising PSA after prostatectomy, including 213 who experienced early clinical metastasis after biochemical recurrence. A training set was used to develop a random forest classifier of 22 markers to predict for cases - men with early clinical metastasis after rising PSA. Performance of GC was compared to prognostic factors such as Gleason score and previous gene expression signatures in a withheld validation set. Results Expression profiles were generated from 545 unique patient samples, with median follow-up of 16.9 years. GC achieved an area under the receiver operating characteristic curve of 0.75 (0.67–0.83) in validation, outperforming clinical variables and gene signatures. GC was the only significant prognostic factor in multivariable analyses. Within Gleason score groups, cases with high GC scores experienced earlier death from prostate cancer and reduced overall survival. The markers in the classifier were found to be associated with a number of key biological processes in prostate cancer metastatic disease progression. Conclusion A genomic classifier was developed and validated in a large patient cohort enriched with prostate cancer metastasis patients and a rising PSA that went on to experience metastatic disease. This early metastasis prediction model based on genomic expression in the primary tumor may be useful for identification of aggressive prostate cancer.

PD-L1 (B7-h1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: Associations with localized stage progression

PD‐L1 (programmed death ligand 1, B7‐H1) is a cell surface glycoprotein that can impair T‐cell function. PD‐L1 is aberrantly expressed by multiple human malignancies and has been shown to carry a highly unfavorable prognosis in patients with kidney cancer. The role of PD‐L1 was evaluated as a mechanism for local stage progression in urothelial carcinoma (UC) of the bladder.

Randomized Clinical Trial of Long-Acting Somatostatin for Autosomal Dominant Polycystic Kidney and Liver Disease

There are no proven, effective therapies for polycystic kidney disease (PKD) or polycystic liver disease (PLD). We enrolled 42 patients with severe PLD resulting from autosomal dominant PKD (ADPKD) or autosomal dominant PLD (ADPLD) in a randomized, double-blind, placebo-controlled trial of octreotide, a long-acting somatostatin analogue. We randomly assigned 42 patients in a 2:1 ratio to octreotide LAR depot (up to 40 mg every 28+/-5 days) or placebo for 1 year. The primary end point was percent change in liver volume from baseline to 1 year, measured by MRI. Secondary end points were changes in total kidney volume, GFR, quality of life, safety, vital signs, and clinical laboratory tests. Thirty-four patients had ADPKD, and eight had ADPLD. Liver volume decreased by 4.95%+/-6.77% in the octreotide group but remained practically unchanged (+0.92%+/-8.33%) in the placebo group (P=0.048). Among patients with ADPKD, total kidney volume remained practically unchanged (+0.25%+/-7.53%) in the octreotide group but increased by 8.61%+/-10.07% in the placebo group (P=0.045). Changes in GFR were similar in both groups. Octreotide was well tolerated; treated individuals reported an improved perception of bodily pain and physical activity. In summary, octreotide slowed the progressive increase in liver volume and total kidney volume, improved health perception among patients with PLD, and had an acceptable side effect profile.

Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer.

The long‐term survival of patients with high‐risk prostate cancer was compared after radical prostatectomy (RRP) and after external beam radiation therapy (EBRT) with or without adjuvant androgen‐deprivation therapy (ADT).

Kidney stones and the risk for chronic kidney disease.

BACKGROUND AND OBJECTIVES Kidney stones lead to chronic kidney disease (CKD) in people with rare hereditary disorders (e.g., primary hyperoxaluria, cystinuria), but it is unknown whether kidney stones are an important risk factor for CKD in the general population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Among Olmsted County, MN, residents, all stone formers (n = 4774) whose condition was diagnosed in 1986 through 2003 were matched 1:3 to control subjects (n = 12,975). Cox proportional hazards models adjusted for age, gender, and comorbidities (hypertension, diabetes, obesity, dyslipidemia, gout, alcohol abuse, tobacco use, coronary artery disease, heart failure, cerebral infarct, and peripheral vascular disease) were used to assess the risk for incident CKD defined as a clinical diagnosis (diagnostic codes), ESRD or death with CKD, sustained (>90 d) elevated serum creatinine (>1.3 mg/dl in men, >1.1 mg/dl in women), or sustained estimated GFR <60 ml/min per 1.73 m(2). RESULTS During a mean of 8.6 yr of follow-up, stone formers were at increased risk for a clinical diagnosis of CKD, but an increased risk for ESRD or death with CKD was NS. Among patients with follow-up serum creatinine levels, stone formers were at increased risk for a sustained elevated serum creatinine and a sustained reduced GFR. CONCLUSIONS Kidney stones are a risk factor for CKD, and studies are warranted to assess screening and preventive measures for CKD in stone formers.

Validation of a Genomic Classifier that Predicts Metastasis Following Radical Prostatectomy in an At Risk Patient Population

PURPOSE Patients with locally advanced prostate cancer after radical prostatectomy are candidates for secondary therapy. However, this higher risk population is heterogeneous. Many cases do not metastasize even when conservatively managed. Given the limited specificity of pathological features to predict metastasis, newer risk prediction models are needed. We report a validation study of a genomic classifier that predicts metastasis after radical prostatectomy in a high risk population. MATERIALS AND METHODS A case-cohort design was used to sample 1,010 patients after radical prostatectomy at high risk for recurrence who were treated from 2000 to 2006. Patients had preoperative prostate specific antigen greater than 20 ng/ml, Gleason 8 or greater, pT3b or a Mayo Clinic nomogram score of 10 or greater. Patients with metastasis at diagnosis or any prior treatment for prostate cancer were excluded from analysis. A 20% random sampling created a subcohort that included all patients with metastasis. We generated 22-marker genomic classifier scores for 219 patients with available genomic data. ROC and decision curves, competing risk and weighted regression models were used to assess genomic classifier performance. RESULTS The genomic classifier AUC was 0.79 for predicting 5-year metastasis after radical prostatectomy. Decision curves showed that the genomic classifier net benefit exceeded that of clinical only models. The genomic classifier was the predominant predictor of metastasis on multivariable analysis. The cumulative incidence of metastasis 5 years after radical prostatectomy was 2.4%, 6.0% and 22.5% in patients with low (60%), intermediate (21%) and high (19%) genomic classifier scores, respectively (p<0.001). CONCLUSIONS Results indicate that genomic information from the primary tumor can identify patients with adverse pathological features who are most at risk for metastasis and potentially lethal prostate cancer.

Long-Term Risk of Clinical Progression After Biochemical Recurrence Following Radical Prostatectomy: The Impact of Time from Surgery to Recurrence

BACKGROUND The natural history of biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP) is variable and does not always translate into systemic progression or prostate cancer (PCa) death. OBJECTIVE To evaluate long-term clinical outcomes of patients with BCR and to determine predictors of disease progression and mortality in these men. DESIGN, SETTING, AND PARTICIPANTS We reviewed our institutional registry of 14 632 patients who underwent RRP between 1990 and 2006 to identify 2426 men with BCR (prostate-specific antigen [PSA] levels ≥ 0.4 ng/ml) who did not receive neoadjuvant or adjuvant therapy. Median follow-up was 11.5 yr after RRP and 6.6 yr after BCR. INTERVENTION RRP. MEASUREMENTS Patients were grouped into quartiles according to time from RRP to BCR. Survival after BCR was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression models were used to analyze clinicopathologic variables associated with systemic progression and death from PCa. RESULTS AND LIMITATIONS Median systemic progression-free survival (PFS) and cancer-specific survival (CSS) had not been reached after 15 yr of follow-up after BCR. Cancer-specific mortality 10 yr after BCR was 9.9%, 9.3%, 7.8%, and 4.7% for patients who experienced BCR <1.2 yr, 1.2-3.1 yr, 3.1-5.9 yr, and >5.9 yr after RRP, respectively (p=0.10). On multivariate analysis, time from RRP to BCR was not significantly associated with the risk of systemic progression (p=0.50) or cancer-specific mortality (p=0.81). Older patient age, increased pathologic Gleason score, advanced tumor stage, and rapid PSA doubling time (DT) predicted systemic progression and death from PCa. Limitations included retrospective design, varied utilization of salvage therapies, and the inclusion of few patients with positive lymph nodes. CONCLUSIONS Only a minority of men experience systemic progression and death from PCa following BCR. The decision to institute secondary therapies must balance the risk of disease progression with the cost and morbidity of treatment, independent of time from RRP to BCR.

Changing Incidence of Glomerular Disease in Olmsted County, Minnesota: A 30-Year Renal Biopsy Study

Membranous nephropathy (MN) is considered the most common cause of nephrotic syndrome in white adults, but recent studies have shown an increasing incidence of focal segmental glomerulosclerosis (FSGS). These studies are difficult to interpret because the majority of cases came from urban tertiary referral centers. For validating these findings in the general population, trends in the incidence of various forms of glomerular disease (glomerulonephritis [GN]) among the residents of Olmsted County, MN were studied. Biopsy data of local patients who had a diagnosis of a nondiabetic glomerular disease from 1974 through 2003 were reviewed. Biopsies were categorized as (1) FSGS, (2) MN, (3) minimal change, (4) lupus nephritis, (5) membranoproliferative GN (MPGN), (6) IgA nephropathy (IgAN), (7) crescentic/necrotizing GN, and (8) other. Time trends in the annual age- and gender-adjusted (2000 US population) incidence rate per 100,000 Olmsted County population were estimated. A total of 195 biopsies were analyzed. Overall, IgAN was present in 22%, FSGS was present in 17%, and MN was present in 10%. Between 1974 to 1983 and 1994 to 2003, the incidence of any type of GN among Olmsted County residents increased more than two-fold (P < 0.001), FSGS by 13-fold (P < 0.001), and IgAN by three-fold (P = 0.002). Increases in MN were nonsignificant (2.5-fold; P = 0.13). Currently (1994 to 2003), the most frequent type of GN is IgAN (25%), followed by FSGS (20%) and MN (11%), with annual incidence rates of 2.1, 1.8, and 1.0 per 100,000/yr, respectively. This study confirms that the incidence of GN is growing overall, particularly for FSGS, which is the leading cause of nephrotic syndrome in white adults.