Shaheen Alanee

Nomogram Predicting Prostate Cancer–specific Mortality for Men with Biochemical Recurrence After Radical Prostatectomy

BACKGROUND The natural history of prostate-specific antigen (PSA)-defined biochemical recurrence (BCR) of prostate cancer (PCa) after definitive local therapy is highly variable. Validated prediction models for PCa-specific mortality (PCSM) in this population are needed for treatment decision-making and clinical trial design. OBJECTIVE To develop and validate a nomogram to predict the probability of PCSM from the time of BCR among men with rising PSA levels after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS Between 1987 and 2011, 2254 men treated by radical prostatectomy at one of five high-volume hospitals experienced BCR, defined as three successive PSA rises (final value >0.2 ng/ml), single PSA >0.4 ng/ml, or use of secondary therapy administered for detectable PSA >0.1 ng/ml. Clinical information and follow-up data were modeled using competing-risk regression analysis to predict PCSM from the time of BCR. INTERVENTION Radical prostatectomy for localized prostate cancer and subsequent PCa BCR. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCSM. RESULTS AND LIMITATIONS The 10-yr PCSM and mortality from competing causes was 19% (95% confidence interval [CI] 16-21%) and 17% (95% CI 14-19%), respectively. A nomogram predicting PCSM for all patients had an internally validated concordance index of 0.774. Inclusion of PSA doubling time (PSADT) in a nomogram based on standard parameters modestly improved predictive accuracy (concordance index 0.763 vs 0.754). Significant parameters in the models were preoperative PSA, pathological Gleason score, extraprostatic extension, seminal vesicle invasion, time to PCa BCR, PSA level at PCa BCR, and PSADT (all p<0.05). CONCLUSIONS We constructed and validated a nomogram to predict the risk of PCSM at 10 yr among men with PCa BCR after radical prostatectomy. The nomogram may be used for patient counseling and the design of clinical trials for PCa. PATIENT SUMMARY For men with biochemical recurrence of prostate cancer after radical prostatectomy, we have developed a model to predict the long-term risk of death from prostate cancer.

Association of a HOXB13 variant with breast cancer

HOXB13 mutations were recently described in familial prostate cancer. In this study, the prevalence of a mutation in HOXB13 was seven times as high among families of patients with breast cancer as among controls. The affected women did not have BRCA1/2 mutations.

Suicide in men with testis cancer

Depression, anxiety and aggression are documented in testis cancer patients and can result in death from suicides; however, their risk of suicide is not defined. We report suicide rates among testis cancer patients in the USA and determine factors associated with higher rates. We used the Surveillance, Epidemiology, and End Results (SEER) database maintained by the National Cancer Institute to identify patients diagnosed with testis cancer between 1995 and 2008. Multivariate analysis was used to assess factors affecting suicide rate. Among 23,381 patients followed for 126,762 person-years, suicide rate was 26.0 per 100,000 person-years, with the average corresponding rate in the US population aged 25-44 years being 21.5 per 100,000 person-years; the calculated standardised mortality ratio for death by suicide was 1.2 [95% confidence interval (CI): 1.1-2.1]. The standardised mortality ratio for suicide was 1.5 (95% CI: 1.1-2.1) in ages less than 30 years, and 1.8 (95% CI: 1.3-2.4) in men of races other than White and Black. Other patient and disease characteristics were not predictive. In conclusion, patients with testis cancer have a 20% increase in the risk of suicide over that of the general population, and races other than White and Black and younger patients may commit suicide at higher rates.

Impact of County Rurality and Urologist Density on Urological Cancer Mortality in Illinois

PURPOSE The urology work force is contracting at a time when service demand is increasing due to demographic changes, especially in rural areas. We investigated the impact of rural status and urologist density on kidney and renal pelvis, bladder and prostate cancer mortality at the county level in Illinois. MATERIALS AND METHODS We stratified the 102 Illinois counties by 2003 RUCCs as urban (36, RUCCs 1 to 3) and rural (66, RUCCs 4 to 9). Area Health Resource Files were used for county demographic data and urologist density. County level age adjusted mortality rates from 1990 to 2010 were derived from National Center for Health Statistics data using SEER*Stat. We examined the associations of urological cancer mortality rates with rural status and urologist density. RESULTS Average urologist density significantly differed between rural and urban counties (1.9 vs 3.4/100,000 population, p < 0.01). The kidney and renal pelvis cancer mortality rate in rural counties was higher than in urban counties while that of prostate cancer was lower (4.9 vs 4.3 and 28.7 vs 32.2/100,000 population, respectively, each p < 0.01). Urologist density correlated with the mortality rate of kidney and renal pelvis cancer (Pearson coefficient -0.33, p < 0.01) but not with the bladder or prostate cancer mortality rate. Multiple regression analysis revealed that rurality and lower urologist density (p = 0.01 and < 0.05) were significantly associated with higher kidney and renal pelvis cancer mortality. CONCLUSIONS Rural residence and low urologist density were associated with increased kidney and renal pelvis cancer mortality on the county level in Illinois. Further expansion and testing of evidence-based telemedicine is warranted because remote technical consultation is now technologically feasible, effective, inexpensive and satisfactory to patients.

Delivering kidney cancer care in rural Central and Southern Illinois: a telemedicine approach

There is a growing body of experience and research suggesting that telemedicine (video conferencing, smart phones and online patient portals) could be the solution to addressing gaps in the provision of specialised healthcare in rural areas. The proposed role of telemedicine in providing needed services in hard to reach areas is not new. The United States Telecommunication Act of 1996 provided the initial traction for telemedicine by removing important economic and legal obstacles regarding the use of technology in healthcare delivery. This initial ruling has been supplemented by the availability of federal funding to support efforts aimed at developing telemedicine in underserved areas. In this paper, we explore one aspect of disease disparity pertinent to rural Illinois (kidney cancer incidence and mortality) and describe how we are planning to use an existing telemedicine program at Southern Illinois University School of Medicine (SIUSOM) to improve kidney cancer (Kca) care in rural Illinois. This represents an example of the possible role of telemedicine in addressing healthcare disparities in rural areas/communities and provides a description of general challenges and barriers to the implementation and maintenance of such systems.

Long-term mortality in patients with germ cell tumors: Effect of primary cancer site on cause of death

OBJECTIVES To examine the effect of extragonadal tumor site on the risk for cardiovascular, hematopoietic malignancies, and solid cancer-related causes of death. PATIENTS AND METHODS Male patients diagnosed with germ cell tumors (GCTs) between 1973 and 2008 were identified from the Surveillance, Epidemiology and End Results database, and stratified by the site of primary cancer (mediastinal and nonmediastinal extragonadal vs. gonadal). Using competing risk analysis restricted to events that happened at least 5 years after diagnosis, we examined the possible effect of primary tumor site on the risk for death related to hematopoietic malignancies, cardiovascular disorders, and solid cancers in the study cohort. RESULTS Of 37,283 patients included in our analysis, 17,715 were diagnosed with nonseminomas and 19,568 with seminomas. Eight hundred and twenty four patients (2%) were diagnosed with primary mediastinal GCTs and 1,469 (4%) with nonmediastinal extragonadal tumors. Patients with mediastinal GCTs had an increased risk for death related to hematopoietic malignancies (hazard ratio [HR] = 8.84; 95% confidence interval [CI]: 3.16-24; P<0.0001) and cardiovascular disorders (HR = 4.45; 95% CI: 2.52-8.0; P<0.0001), but no significant difference in risk of dying of solid cancers (HR = 1.46; 95% CI: 0.36-5.9; P = 0.59) compared to patients with gonadal GCTs. Patients with nonmediastinal extragonadal GCTs had a significantly increased risk for dying of cardiovascular disorders (HR = 2.75; 95% CI: 1.67-4.51; P<0.0001), but not a significantly different risk for dying of hematopoietic malignancies (HR = 0.93; 95% CI: 0.13-6.84; P = 0.94) or solid cancers (HR = 1.45; 95% CI: 0.68-5.0; P = 0.23) compared with patients with gonadal GCTs. CONCLUSIONS Patients with GCTs and extragonadal primary sites have an increased risk for death from cardiovascular disease and hematopoietic malignancies compared to those with gonadal GCTs, and could benefit from more intense preventive measures to decrease the risk of death related to these disorders.

Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

BACKGROUND Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.

Efficacy of Systemic Chemotherapy Plus Radical Nephroureterectomy for Metastatic Upper Tract Urothelial Carcinoma

Given the growing body of evidence supporting the benefit of primary tumor control for a wide range of metastatic malignancies, we hypothesized that chemotherapy plus radical nephroureterectomy (RNU) is associated with an overall survival (OS) benefit compared to chemotherapy alone for metastatic upper tract urothelial carcinoma (mUTUC). Within the National Cancer Data Base (2004-2012), we identified 398 (38.4%) and 637 (61.6%) patients who received chemotherapy plus RNU and chemotherapy alone, respectively. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves showed that 3-yr OS was 16.2% (95% confidence interval [CI] 12.1-20.3) for chemotherapy plus RNU and 6.4% (95%CI 4.1-8.7) for chemotherapy alone (p<0.001). In IPTW-adjusted Cox regression analysis, chemotherapy plus RNU was associated with a significant OS benefit (hazard ratio 0.70, 95% CI 0.61-0.80; p<0.001). Despite the usual biases related to the observational study design, our findings show a net OS benefit for fit patients who received chemotherapy plus RNU for mUTUC relative to their counterparts treated with chemotherapy alone. PATIENT SUMMARY We examined the role of radical nephroureterectomy in addition to systemic chemotherapy for metastatic upper tract urothelial carcinoma. We found that such treatment may be associated with an overall survival benefit compared to chemotherapy alone in fit patients.

Immune Characterization of the Programmed Death Receptor Pathway in High Risk Prostate Cancer

Micro‐Abstract The objective of this study was to determine the expression of programmed cell death‐1 (PD‐1) and programmed cell death ligand‐L1 (PD‐L1) in high‐grade prostate cancer tissues, and correlate the expression with disease and patient characteristics. Of the 25 samples, 2 (8%) scored high for PD‐1 expression, 2 (8%) scored high for PD‐L1 expression, and 18 (72%) scored high for CD3 expression. Background: Programmed cell death‐1 (PD‐1), a T‐cell inhibitory receptor, and its ligand, PD‐L1, have been reported to be expressed in many tumor types, and this expression has led to the development of many drugs targeting the PD‐1 pathway. The objective of this study was to determine the expression of PD‐1 and PD‐L1 in high‐grade prostate cancer tissues, and correlate the expression with disease and patient characteristics. Materials and Methods: Immunohistochemistry for PD‐1 (CD279), PD‐L1 (B7‐H1), and CD3 was performed and scored from 0 to 5 on prostatectomy/biopsy tissue samples taken from 25 men with high‐grade prostate cancer. Charts were then retrospectively reviewed for numerous patient and disease characteristics. Statistical analyses were done to investigate the association of these patient and disease characteristics with PD‐1, PD‐L1, and CD3 expression. Results: A score of 3 to 5 on the semiquantitative 0 to 5 score was deemed “high” expression whereas a score of 0 to 2 was deemed “low” expression. Of the 25 samples, 2 (8%) scored high for PD‐1 expression, 2 (8%) scored high for PD‐L1 expression, and 18 (72%) scored high for CD3 expression. There was no statistically significant difference between high and low expression groups of PD‐1, PD‐L1, or CD3 for any of the variables we collected. Conclusion: An overall low expression of PD‐1 and PD‐L1, and a concurrent high expression of CD3+ T cells was found in high‐risk prostate cancer tissue. No significant association was found between expression of PD‐1, PD‐L1, or CD3, and patient or disease characteristics. Because of this, one might be able to question the role of PD‐L1 in local immune suppression in prostate cancer.

A1 Adenosine Receptor-Mediated Inhibition of Parasympathetic Neuromuscular Transmission in Human and Murine Urinary Bladder

The potential role of A1 adenosine receptors in modulating neuromuscular transmission in the detrusor muscle of the urinary bladder has been tested in human and murine preparations with the intent to determine the viability of using adenosine receptor agonists as adjuncts to treat overactive bladder. In human detrusor muscle preparations, contractile responses to electrical field stimulation were inhibited by the selective A1 adenosine receptor agonists 2-chloro-N6-cyclopentyladenosine, N6-cyclopentyladenosine (CPA), and adenosine (rank order of potency: 2-chloro-N6-cyclopentyladenosine > CPA > adenosine). Pretreatment with 8-cyclopentyl-3-[3-[[4(fluorosulphonyl)benzoyl]oxy]propyl]-1-propylxanthine, an irreversible A1 antagonist, blocked the effects of CPA, thus confirming the role of A1 receptors in human detrusor preparations. In murine detrusor muscle preparations, contractions evoked by electrical field stimulation were reduced by CPA or adenosine. Amplitudes of the P2X purinoceptor–mediated excitatory junctional potentials (EJPs) recorded with intracellular microelectrodes were reduced in amplitude by CPA and adenosine with no effect on the spontaneous EJP amplitudes, confirming the prejunctional action of these agents. 8-Cyclopentyltheophylline, a selective A1 receptor antagonist, reversed the effects of CPA on EJP amplitudes with no effect of spontaneous EJPs, confirming the role of A1 receptors in mediating these effects.