Publications by authors named "Ryan P Smith"

95 Publications

Impact of environmental toxin exposure on male fertility potential.

Transl Androl Urol 2020 Dec;9(6):2797-2813

Department of Urology, University of Virginia, Charlottesville, VA, USA.

Idiopathic infertility is the most common individual diagnosis in male infertility, representing nearly 44% of cases. Research studies dating over the last half-century consistently demonstrate a decline in male fertility that is incompletely explained by obesity, known genetic causes, or diet and lifestyle changes alone. Human exposures have changed dramatically over the same time course as this fertility decline. Synthetic chemicals surround us. Some are benevolent; however, many are known to cause disruption of the hypothalamic-pituitary-gonadal axis and impair spermatogenesis. More than 80,000 chemicals are registered with the United States National Toxicology Program and nearly 2,000 new chemicals are introduced each year. Many of these are known toxins, such as phthalates, polycyclic aromatic hydrocarbons, aromatic amines, and organophosphate esters, and have been banned or significantly restricted by other countries as they carry known carcinogenic effects and are reproductively toxic. In the United States, many of these chemicals are still permissible in exposure levels known to cause reproductive harm. This contrasts to other chemical regulatory legislature, such as the European Union's REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) regulations which are more comprehensive and restrictive. Quantification of these diverse exposures on an individual level has proven challenging, although forthcoming technologies may soon make this data available to consumers. Establishing causality and the proportion of idiopathic infertility attributable to environmental toxin exposures remains elusive, however, continued investigation, avoidance of exposure, and mitigation of risk is essential to our reproductive health. The aim of this review is to examine the literature linking changes in male fertility to some of the most common environmental exposures. Specifically, pesticides and herbicides such as dichlorodiphenyltrichloroethane (DDT), dibromochloropropane (DBCP), organophosphates and atrazine, endocrine disrupting compounds including plastic compounds phthalates and bisphenol A (BPA), heavy metals, natural gas/oil, non-ionizing radiation, air and noise pollution, lifestyle factors including diet, obesity, caffeine use, smoking, alcohol and drug use, as well as commonly prescribed medications will be discussed.
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http://dx.doi.org/10.21037/tau-20-685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807371PMC
December 2020

Hypofractionated Prostate Radiation Therapy: Adoption and Dosimetric Adherence Through Clinical Pathways in an Integrated Oncology Network.

JCO Oncol Pract 2020 Oct 23:OP2000508. Epub 2020 Oct 23.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Purpose: Updates to consensus guidelines in October 2018 recommending moderately hypofractionated external beam radiotherapy (mHF-EBRT) in prostate cancer lagged several years after publication of evidence supporting its efficacy. In January 2018, we amended our prostate cancer clinical pathway (CP) to facilitate adoption of mHF-EBRT. Herein, we analyze patterns of care and changes in mHF-EBRT use after the CP modification.

Methods: Our prostate CP was amended in January 2018 to make mHF-EBRT the recommended treatment for patients with low- and intermediate-risk prostate cancer pursuing curative EBRT monotherapy. Normal-tissue dose constraints accompanied the CP modification to guide planning. Use of mHF-EBRT from 2015 to 2017 was compared with use in 2018 after the CP modification, using the Cochran-Armitage test for trend. Predictors of mHF-EBRT use and adherence to dose constraints were analyzed with binary logistic regression.

Results: In 560 patients treated with EBRT monotherapy, mHF-EBRT use increased from 3.7% in 2015-2017 to 85.6% in 2018 ( < .001), whereas conventionally fractionated EBRT (CF-EBRT) use decreased from 96.3% to 14.4% ( < .001). Consultation year of 2018 (odds ratio [OR], 214.6; 95% CI, 94.5 to 484.6; < .001), treatment at an academic facility (OR, 4.5; 95% CI, 1.8 to 11.3; = 0.001), and having a smaller prostate (OR, 0.99; 95% CI, 0.97 to 1.00; = .028) predicted for mHF-EBRT use. At least five of six recommended bladder and rectal dose constraints were met in 89.4% of patients.

Conclusion: Modification of our prostate cancer CP, in concert with institutional policies to monitor and audit CP compliance, facilitated rapid adoption of mHF-EBRT in our large, integrated cancer center with good adherence to dosimetric constraints.
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http://dx.doi.org/10.1200/OP.20.00508DOI Listing
October 2020

Acute patient-reported bowel quality of life and rectal bleeding with the combination of prostate external beam radiation, low-dose-rate brachytherapy boost, and SpaceOAR.

Brachytherapy 2020 Jul - Aug;19(4):477-483. Epub 2020 Apr 21.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Purpose: This study evaluates acute patient-reported bowel quality of life (QOL) and rectal bleeding in prostate cancer patients treated with combination external beam radiation (EBRT), low-dose-rate brachytherapy (LDR-BT), and SpaceOAR.

Materials And Methods: A retrospective review of prostate cancer patients treated with EBRT (45 Gy), cesium-131 LDR-BT (85 Gy), and SpaceOAR was conducted. Patient-reported acute (≤3 months after LDR-BT) bowel QOL and rectal bleeding was analyzed from Expanded Prostate Cancer Index Composite (EPIC) questionnaires. Five-point changes in mean bowel QOL scores were considered clinically significant. Clinically significant rectal bleeding was bleeding occurring more than "rarely" ("about half the time," "usually," or "always"), and clinically significant bleeding bother was considering bleeding a "small, moderate, or big problem." Outcomes were analyzed using descriptive statistics and paired t-tests.

Results: 69 patients were identified. Bowel summary, function, and bother scores clinically and significantly decreased 2 weeks after LDR-BT (79.9 ± 15.6, 80.5 ± 15.4, and 79.4 ± 18.1, respectively) compared with pre-EBRT scores (92.3 ± 9.1, 93.3 ± 9.0, and 92.6 ± 11.9, respectively) and pre-LDR-BT scores (91.1 ± 11.0, 91.6 ± 9.8, and 90.6 ± 13.3, respectively), but returned to clinical and statistical baseline pre-EBRT values at 3 months (88.7 ± 12.4, 88.8 ± 11.1, and 88.7 ± 14.5, respectively). The 3-month cumulative incidence of clinically significant rectal bleeding and bleeding bother was 4.35% and 2.90%, respectively.

Conclusions: With combination EBRT, LDR-BT, and SpaceOAR, bowel QOL returned to the baseline 3 months after LDR-BT. Clinically significant rectal bleeding was <5%. Further followup will confirm if low acute rectal toxicity translates to reduced late toxicity.
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http://dx.doi.org/10.1016/j.brachy.2020.03.006DOI Listing
April 2020

Future diagnostics in male infertility: genomics, epigenetics, metabolomics and proteomics.

Transl Androl Urol 2020 Mar;9(Suppl 2):S195-S205

Men's Health Center, Indianapolis, IN, USA.

A male factor is involved in 50% of couples with infertility. Unfortunately, the etiology of male factor infertility remains classified as idiopathic in nearly 50% of cases. The semen analysis (SA) continues to be first line for the workup of male infertility, but it is an imperfect test with high variability between samples. This lack of diagnostic capability has led to the desire to develop minimally invasive tests to aid with understanding the etiology of male factor infertility. Genetic factors are known to play a role in male infertility, and much work has been done to identify the many genes involved. The study of the genes involved, the impact of epigenetic modifications, proteins and metabolites produced are attractive targets for development of biomarkers which may be used to diagnose the etiology of male infertility. This review aims to explore recent advances in these fields as they pertain to the diagnosis of male infertility.
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http://dx.doi.org/10.21037/tau.2019.10.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108983PMC
March 2020

Non-testosterone management of male hypogonadism: an examination of the existing literature.

Transl Androl Urol 2020 Mar;9(Suppl 2):S160-S170

Department of Urology, University of Virginia, Charlottesville, VA, USA.

Testosterone deficiency is defined as a total testosterone level <300 ng/dL confirmed on two early morning lab draws. Testosterone therapy has historically been offered to men with symptomatic testosterone deficiency in the form of injections, gels, or pellets. However, these treatments are invasive or have undesirable effects including the risk of drug transference. Additionally, testosterone therapy has been associated with increases in hematocrit and controversy remains regarding the risk of cardiovascular and thromboembolic events while on testosterone therapy. As such, much interest has recently been focused on alternative treatment options for testosterone deficiency in the form of orally-administered medications with more favorable side effect profiles. Lifestyle modifications and varicocelectomy have been shown to raise endogenous testosterone production. Similarly, SERMs and aromatase inhibitors (AIs) have been shown to raise testosterone levels safely and effectively. Human chorionic gonadotropin (hCG) remains the only FDA-approved non-testosterone treatment option for testosterone deficiency in men. However, this medication is expensive and requires patient-administered injections. Over the counter herbal supplements and designer steroids remain available though they are poorly studied and are associated with the potential for abuse as well as increased hepatic and cardiovascular risks. This review aims to discuss the existing treatment alternatives to traditional testosterone therapy, including efficacy, safety, and side effects of these options. The authors suggest that the SERM clomiphene citrate (CC) holds the greatest promise as a non-testosterone treatment option for testosterone deficiency.
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http://dx.doi.org/10.21037/tau.2019.11.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108991PMC
March 2020

Cesium-131 prostate brachytherapy: A single institutional long-term experience.

Brachytherapy 2020 May - Jun;19(3):298-304. Epub 2020 Apr 2.

Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Aims: To report on the PSA outcomes in men undergoing prostate seed implant (PSI) with Cesium-131 at a single institution.

Materials And Methods: All patients who underwent prostate brachytherapy with Cesium-131 (Cs) at our institution and had the potential for at least 24 months of follow up were included in this study. Results are reported for the by NCCN risk group (low, low/high-intermediate, and high), as well as by treatment received (monotherapy, combination external beam radiation + PSI, or trimodal therapy with androgen deprivation). The Phoenix definition (absolute nadir plus 2 ng/mL) was used to define biochemical freedom from disease (BFD).

Results: Eight hundred and six men have undergone prostate brachytherapy with Cesium-131 at our institution, and 669 men were included in analysis. Median follow up was 60.0 months (range: 0-144 months). According to NCCN risk categories, 29.9% were low-, 55.6% intermediate-, and 14.5% high-risk. Using the Phoenix criteria, 5/10-year BFD was 97.1/95.3% for patients in the low-risk category, 94.0/90.1% for patients in the intermediate-risk category, and 86.2/56.6% for patients in the high-risk category. PSA ≤0.2 ng/dL at 4 years was predictive of 10 year biochemical control: 96.3% vs 70.4%, p < 0.001.

Conclusions: The present study demonstrates that prostate brachytherapy with Cs achieves excellent long-term biochemical control.
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http://dx.doi.org/10.1016/j.brachy.2020.02.006DOI Listing
January 2021

Editorial Comment.

Authors:
Ryan P Smith

J Urol 2020 04 9;203(4):772. Epub 2020 Jan 9.

Reproductive Medicine and Surgery, Department of Urology, University of Virginia, Charlottesville, Virginia.

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http://dx.doi.org/10.1097/JU.0000000000000658.02DOI Listing
April 2020

EDITORIAL COMMENT.

Urology 2019 10;132:116

University of Virginia, Department of Urology, Charlottesville, VA.

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http://dx.doi.org/10.1016/j.urology.2019.06.039DOI Listing
October 2019

Phosphatidylserine on viable sperm and phagocytic machinery in oocytes regulate mammalian fertilization.

Nat Commun 2019 10 1;10(1):4456. Epub 2019 Oct 1.

The Center for Cell Clearance, School of Medicine, University of Virginia, 1340 Jefferson Park Avenue, Pinn Hall, Charlottesville, VA, 22903, USA.

Fertilization is essential for species survival. Although Izumo1 and Juno are critical for initial interaction between gametes, additional molecules necessary for sperm:egg fusion on both the sperm and the oocyte remain to be defined. Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts. Collectively, these data identify phosphatidylserine on viable sperm and PtdSer recognition receptors on oocytes as key players in sperm:egg fusion.
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http://dx.doi.org/10.1038/s41467-019-12406-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773685PMC
October 2019

Coherent two-dimensional Fourier transform spectroscopy using a 25 Tesla resistive magnet.

Rev Sci Instrum 2019 Jun;90(6):063901

Department of Physics, University of South Florida, Tampa, Florida 33620, USA.

We performed nonlinear optical two-dimensional Fourier transform spectroscopy measurements using an optical resistive high-field magnet on GaAs quantum wells. Magnetic fields up to 25 T can be achieved using the split helix resistive magnet. Two-dimensional spectroscopy measurements based on the coherent four-wave mixing signal require phase stability. Therefore, these measurements are difficult to perform in environments prone to mechanical vibrations. Large resistive magnets use extensive quantities of cooling water, which causes mechanical vibrations, making two-dimensional Fourier transform spectroscopy very challenging. Here, we report on the strategies we used to overcome these challenges and maintain the required phase-stability throughout the measurement. A self-contained portable platform was used to set up the experiments within the time frame provided by a user facility. Furthermore, this platform was floated above the optical table in order to isolate it from vibrations originating from the resistive magnet. Finally, we present two-dimensional Fourier transform spectra obtained from GaAs quantum wells at magnetic fields up to 25 T and demonstrate the utility of this technique in providing important details, which are obscured in one dimensional spectroscopy.
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http://dx.doi.org/10.1063/1.5055891DOI Listing
June 2019

Long-Term Safety and Efficacy of Clomiphene Citrate for the Treatment of Hypogonadism.

J Urol 2019 11 9;202(5):1029-1035. Epub 2019 Oct 9.

Austin Fertility and Reproductive Medicine/Westlake IVF, Austin, Texas.

Purpose: Clomiphene citrate may be used as an off label treatment of hypogonadism. There are few long-term data on clomiphene citrate efficacy and safety when administered for more than 3 years. We assessed improvements in testosterone and hypogonadal symptoms while on clomiphene citrate for extended periods.

Materials And Methods: We performed a retrospective review to identify patients treated with clomiphene citrate for hypogonadism (baseline testosterone less than 300 ng/dl) at a total of 2 institutions from 2010 to 2018. We assessed the duration of clomiphene citrate therapy, serum testosterone levels, symptom improvement and clomiphene citrate side effects.

Results: A total of 400 patients underwent clomiphene citrate treatment for a mean ± SD of 25.5 ± 20.48 months (range 0 to 84). Of the patients 280 received clomiphene citrate for 3 years or less (mean 12.75 ± 9.52 months) and 120 received it for more than 3 years (mean 51.93 ± 10.52 months). Of men on clomiphene citrate for more than 3 years 88% achieved eugonadism, 77% reported improved symptoms and 8% reported side effects. Estradiol was significantly increased following clomiphene citrate treatment. Results did not significantly differ between patients treated for more than 3, or 3 or fewer years. The most common side effects reported by patients treated more than 3 years included changes in mood in 5, blurred vision in 3 and breast tenderness in 2. There was no significant adverse event in any patient treated with clomiphene citrate.

Conclusions: Clomiphene citrate is not typically offered as primary treatment of hypogonadism in men who do not desire fertility preservation. These data demonstrate that clomiphene citrate is safe and effective with few side effects when used as long-term treatment of hypogonadism.
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http://dx.doi.org/10.1097/JU.0000000000000396DOI Listing
November 2019

Physician Burnout and Physician Health: Three Simple Suggestions for a Complex Problem.

Pract Radiat Oncol 2019 Sep - Oct;9(5):297-299. Epub 2019 May 8.

Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

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http://dx.doi.org/10.1016/j.prro.2019.04.011DOI Listing
April 2020

Editorial Comment.

J Urol 2019 04;201(4):791

Department of Urology, University of Virginia , Charlottesville , Virginia.

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http://dx.doi.org/10.1097/01.JU.0000554778.62163.51DOI Listing
April 2019

Long-Term Patient-Reported Rectal Bleeding and Bowel-Related Quality of Life After Cs-131 Prostate Brachytherapy.

Int J Radiat Oncol Biol Phys 2019 07 8;104(3):622-630. Epub 2019 Mar 8.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Purpose: There is limited long-term data on outcome and side effects of Cs-131 prostate brachytherapy and minimal patient-reported data on rectal bleeding with any isotope. We aimed to describe the incidence, prevalence, and predictors of late patient-reported rectal bleeding after Cs-131 brachytherapy.

Methods And Materials: We reviewed a prospectively collected database of 620 men treated with Cs-131 prostate brachytherapy. Of 620 patients, 390 (62.9%) received brachytherapy as monotherapy; the remainder received combination therapy with external beam radiation therapy (EBRT). Patients were administered Expanded Prostate Cancer Index Composite questionnaires preoperatively and postoperatively at each follow-up visit. The primary outcome was late rectal bleeding, defined as rectal bleeding reported at the 6-month follow-up or later. Clinically significant rectal bleeding was defined as occurring more than "rarely," and clinically significant bother from rectal bleeding was defined as considering bleeding more than a "very small problem." Univariate and multivariate Cox regression were performed to identify factors predictive for rectal bleeding.

Results: With a median follow-up time of 48 months, the cumulative incidence of clinically significant late rectal bleeding was 12.4%, with 15.2% reporting clinically significant bother from bleeding. At the time of last follow-up, the prevalence of clinically significant rectal bleeding and bother were 4.0% and 4.7%, respectively. On univariate analysis, acute clinically significant rectal bleeding, defined as occurring within the first 6 months (P = .001) and combination therapy with EBRT (P = .001) predicted for clinically significant late rectal bleeding. On multivariate analysis, both EBRT (P = .001; hazard ratio, 2.50; 95% confidence interval, 1.58-3.94) and acute rectal bleeding (P < .001; hazard ratio, 3.11; 95% confidence interval, 1.75-5.53) remained significant predictors for late rectal bleeding.

Conclusions: Prostate brachytherapy with Cs-131 is well tolerated in the long term. Although the incidence of clinically significant patient-reported late rectal bleeding was 12.4%, the prevalence at last follow-up was only 4.0%, suggesting that this problem tends to resolve.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.056DOI Listing
July 2019

Recent advances in the understanding and management of erectile dysfunction.

F1000Res 2019 25;8. Epub 2019 Jan 25.

Men's Health Center, Indianapolis, Indiana, USA.

Erectile dysfunction (ED) is important to a man's well-being and health, since it not only affects the individual but also causes strain on a couple's lifestyle and relationship. There are multiple non-invasive treatments that exist for ED including lifestyle changes, oral medications (phosphodiesterase type 5 inhibitors), vacuum-assisted erectile devices, and intraurethral suppositories. While lifestyle changes and oral medications are typically first-line treatments for ED, more-invasive treatments including intracavernosal injections and surgically implanted prosthetic devices may be required for the management of complex cases. Additionally, novel therapies are currently being developed, and future treatment options may include shock-wave therapy, external prosthetic devices, and injection of stem cells or platelet-rich plasma. The current manuscript seeks to highlight advances in management and may eventually alter the treatment paradigm to allow more-inclusive care pathways.
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http://dx.doi.org/10.12688/f1000research.16576.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348436PMC
June 2020

Clomiphene Citrate for the Treatment of Hypogonadism.

Sex Med Rev 2019 04 3;7(2):272-276. Epub 2018 Dec 3.

Department of Urology, University of Virginia, Charlottesville, VA, USA.

Introduction: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamic-pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility.

Aim: To review the literature regarding the use of CC in the setting of hypogonadism.

Methods: A review of the relevant literature through September 2018 was performed via PubMed.

Main Outcome Measure: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized.

Results: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated.

Conclusion: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2019;7:272-276.
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http://dx.doi.org/10.1016/j.sxmr.2018.10.001DOI Listing
April 2019

Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420.

Int J Radiat Oncol Biol Phys 2019 03 27;103(4):878-886. Epub 2018 Nov 27.

University of Maryland Medical Systems, Baltimore, Maryland.

Purpose: To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM).

Methods And Materials: Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles.

Results: A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100 mg/m on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9 months compared with 13.7 months of the historical control (P = .03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients).

Conclusions: Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with historical control data at the time the study was conducted, the historical control median survival time of 13.7 months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared with the current standard.
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http://dx.doi.org/10.1016/j.ijrobp.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034757PMC
March 2019

Declining brachytherapy utilization for high-risk prostate cancer-Can clinical pathways reverse the trend?

Brachytherapy 2018 Nov - Dec;17(6):895-898. Epub 2018 Sep 11.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Purpose: Although external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) offers a 20% improvement in biochemical progression-free survival compared with dose-escalated EBRT alone for men with intermediate and high-risk prostate cancer, population studies show a concerning decline in BB utilization.

Methods: We modified our clinical pathway (CP) in January 2016 to indicate EBRT with BB as first-choice modality for high-risk prostate cancer, based on preliminary findings of Androgen Suppression Combined with Elective Nodal and Dose-Escalated Radiation Therapy. A retrospective review was performed on 659 patients with high-risk prostate cancer treated with definitive intent EBRT ± BB within a network of 19 sites between December 2011 and July 2017. χ test was used to determine changes in practice pattern before vs. after CP modification.

Results: Before CP modification, 25.2% of patients were planned for BB, compared with 45.4% afterward (p < 0.001). Among 23 nonbrachytherapist physicians, utilization of BB increased from 3.4% to 14.8% (p < 0.001) after CP modification. Among nine brachytherapists, utilization increased from 46.4% to 55.6% (p = 0.120). Among patients treated by a nonbrachytherapist who did not receive BB, the reason was physician preference in 59.7%, patient preference in 19.9%, and other in 20.4%.

Conclusion: Based on recent evidence suggesting improved biochemical progression-free survival with use of BB for high-risk prostate cancer, we modified our CP, after which we observed increased use of a BB across a network, especially among physicians who do not perform brachytherapy. However, physician preference remains the most significant factor in the nonutilization of BB. New mechanisms are needed to overcome this barrier.
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http://dx.doi.org/10.1016/j.brachy.2018.08.004DOI Listing
April 2019

Declining brachytherapy utilization for high-risk prostate cancer-Can clinical pathways reverse the trend?

Brachytherapy 2018 Nov - Dec;17(6):895-898. Epub 2018 Sep 11.

Department of Radiation Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address:

Purpose: Although external beam radiation therapy (EBRT) plus a brachytherapy boost (BB) offers a 20% improvement in biochemical progression-free survival compared with dose-escalated EBRT alone for men with intermediate and high-risk prostate cancer, population studies show a concerning decline in BB utilization.

Methods: We modified our clinical pathway (CP) in January 2016 to indicate EBRT with BB as first-choice modality for high-risk prostate cancer, based on preliminary findings of Androgen Suppression Combined with Elective Nodal and Dose-Escalated Radiation Therapy. A retrospective review was performed on 659 patients with high-risk prostate cancer treated with definitive intent EBRT ± BB within a network of 19 sites between December 2011 and July 2017. χ test was used to determine changes in practice pattern before vs. after CP modification.

Results: Before CP modification, 25.2% of patients were planned for BB, compared with 45.4% afterward (p < 0.001). Among 23 nonbrachytherapist physicians, utilization of BB increased from 3.4% to 14.8% (p < 0.001) after CP modification. Among nine brachytherapists, utilization increased from 46.4% to 55.6% (p = 0.120). Among patients treated by a nonbrachytherapist who did not receive BB, the reason was physician preference in 59.7%, patient preference in 19.9%, and other in 20.4%.

Conclusion: Based on recent evidence suggesting improved biochemical progression-free survival with use of BB for high-risk prostate cancer, we modified our CP, after which we observed increased use of a BB across a network, especially among physicians who do not perform brachytherapy. However, physician preference remains the most significant factor in the nonutilization of BB. New mechanisms are needed to overcome this barrier.
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http://dx.doi.org/10.1016/j.brachy.2018.08.004DOI Listing
April 2019

Effect of body mass index on recurrence following urethroplasty.

Transl Androl Urol 2018 Aug;7(4):673-677

Department of Urology, University of Virginia, Charlottesville, VA, USA.

Background: Limited investigation exists to understand whether obesity affects outcomes of urethral reconstruction. We sought to assess whether body mass index (BMI) is an independent predictor for stricture recurrence following urethroplasty.

Methods: We performed a retrospective review of patients undergoing urethroplasty between 2007-2014, identifying 137 patients for study inclusion. Data collected included BMI and patient demographic and surgical characteristics, including age, stricture length and location, etiology, and urethroplasty technique. Stricture-free survival analysis was performed using Kaplan-Meier method. Logistic regression was performed to assess predictors for stricture recurrence using both univariate and multivariate models.

Results: Mean patient age and follow-up was 46.7 (±16.4) years and 91.8 (±30.5) months, respectively. A recurrence rate of 17% was identified, with a mean time to recurrence of 29 months. There was no difference when comparing the mean BMI in patients with and without recurrence (28.9 . 30.4 kg/m, respectively) (P=0.4). A higher rate of stricture recurrence was seen when comparing the cohort with a BMI <25 kg/m versus remaining cohorts (BMI: 25-30 kg/m; BMI >30 kg/m). However, in univariate and multivariate analysis, BMI failed to demonstrate statistical significance as a predictor for urethroplasty outcome. On multivariate analysis, fasciocutaneous repair type was predictive of stricture recurrence. No additional potential predictors assessed were found to be significant.

Conclusions: In the present study, BMI did not independently predict for stricture recurrence following urethroplasty.
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http://dx.doi.org/10.21037/tau.2018.06.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127538PMC
August 2018

Frontiers in hormone therapy for male infertility.

Transl Androl Urol 2018 Jul;7(Suppl 3):S353-S366

Department of Urology, University of Virginia Health System, Charlottesville, VA, USA.

For a significant number of couples worldwide, infertility is a harsh reality. As specialists in male infertility, much of our armamentarium lacks definitive, evidence-based therapies. For years, we have relied on manipulation of the male hormonal axis to treat those men who help carry the burden of infertility in their partnerships. Indeed, male factor infertility is the sole component of infertility in at least 20% of couples. Further compounding this dilemma is that 25% to 50% of males with infertility have no identifiable etiology and thus present a true management conundrum. This manuscript is an attempt to clarify what therapies exist for the treatment of male factor infertility. We have reviewed the relevant infertility literature honing, our focus on hormonal anomalies and their subsequent impact on fertility. Many of the therapies discussed have been utilized in practice for generations. Thus, this article attempts to provide the evidence-based literature to support the continued use of the current treatment paradigm. Furthermore, we recognize that any review beckons a discussion of what challenges and therapies await on the horizon. For instance, there has been significant interest in restoring spermatogenesis after testosterone replacement therapy (TRT). We explore the adverse long-term spermatogenic outcomes associated with TRT, which with the widespread use of TRT, will inevitably present a great challenge for male infertility specialists. Moreover, we discuss the role of varicocelectomy in the treatment of hypogonadism and infertility, review the association between growth hormone (GH) and male fertility and address the challenges presented by the rising prevalence of obesity.
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http://dx.doi.org/10.21037/tau.2018.04.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087845PMC
July 2018

S-nitrosylation of endothelial nitric oxide synthase impacts erectile function.

Int J Impot Res 2019 Jan 20;31(1):31-38. Epub 2018 Aug 20.

Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.

Neuronal and endothelial nitric oxide synthases (nNOS and eNOS respectively) play major roles in generating the nitric oxide bioactivity necessary for erectile function. S-nitrosylation has been shown to regulate NOS activity. The presence of S-nitrosylated NOS in the penis and the impact of NOS S-nitrosylation/denitrosylation on erectile function were examined. S-nitrosylated forms of NOS were identified by biotin-switch assay followed by western blot analysis. Erectile function in S-nitrosoglutathione reductase deficient (GSNO) and null (GSNO) mice were assessed by continuous cavernous nerve electrical stimulation (CCNES). Glutathione ethyl ester (GSHee) was used to manipulate S-nitrosylated NOS levels. Immunohistological and immunofluorescence analyses were used to identify the location of eNOS and GSNO-R in corporal tissue. eNOS and nNOS were S-nitrosylated in unstimulated penises of the mice. CCNES resulted in a time-dependent increase in eNOS S-nitrosylation with peak eNOS S-nitrosylation observed during detumescence. S-nitrosylated nNOS levels were unchanged. Intracorporal injection of GSHee reduced S-nitrosylated eNOS levels, enhancing time to maximum intracorporal pressure (ICP). eNOS and GSNO-R co-localize to the endothelium of the corpus cavernosum in the mouse and the human. ICP measurements obtained during CCNES demonstrate GSNO-R and GSNO-R animals cannot maintain an elevated ICP. Results suggest eNOS S-nitrosylation/denitrosylation is an important mechanism regulating eNOS activity during erectile function. GSNO-R is a key enzyme involved in the eNOS denitrosylation. The increase in eNOS S-nitrosylation (inactivation) observed with tumescence may begin a cycle leading to detumescence. Clinically this may indicate that alterations in the balance of S-nitrosylation/denitrosylation either directly or indirectly contribute to erectile dysfunction.
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http://dx.doi.org/10.1038/s41443-018-0056-0DOI Listing
January 2019

Troubleshooting intraoperative complications of penile prosthesis placement.

Transl Androl Urol 2017 Nov;6(Suppl 5):S892-S897

Department of Urology, University of Virginia Health System, Charlottesville, VA 22908, USA.

Placement of a penile prosthesis is an excellent option for well-selected patients, offering high patient satisfaction and a low rate of complications. Most urologists who perform the procedure are not high volume implanters and may have limited experience with troubleshooting intraoperative issues. In this review, the authors use current literature to provide recommendations for the management of various intraoperative issues such as difficultly with dilation, incongruent measurement, perforation, urethral injury, crossover, complications of reservoir placement, penile curvature, glans mobility, and hemostasis are all discussed. Preparedness for the management of intraoperative issues can help improve patient outcomes and limit morbidity.
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http://dx.doi.org/10.21037/tau.2017.07.13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715183PMC
November 2017

Assessing Changes in the Activity Levels of Breast Cancer Patients During Radiation Therapy.

Clin Breast Cancer 2018 02 24;18(1):e1-e6. Epub 2017 Aug 24.

Department of Radiation Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.

Background: Radiation therapy (RT) is often delivered after lumpectomy for women with breast cancer. A common perceived side effect of RT is fatigue, yet its exact effect on activity levels and sleep is unknown. In this study we analyzed the change in activity levels and sleep using an activity tracking device before, during, and after RT for women with early stage breast cancer and ductal carcinoma in situ who underwent adjuvant RT.

Patients And Methods: After institutional review board approval, activity levels were quantified before, during, and after RT with measurements of steps, miles walked, calories burned, and sleep metrics in 10 women fitted with activity trackers. All data were uploaded and tabulated on a secure database. Multivariable linear regressions were used to evaluate changes in these variables over time during the RT course.

Results: Median step count was 5047 per day (range, 2741-15,508) and distance traveled was 1.6 miles per day (range, 0.9-5.3). Step count, distance, and calories decreased by an average of 54 steps per day, 0.02 miles per day, and 3 calories per day (median calories 1822; range, 1461-2712) during RT, respectively. These changes were statistically significant (P < .001), but not clinically relevant. There was no significant change in sleep (average 6.8 hours per night; range, 5.5-8.3).

Conclusion: RT has a minimal effect on activity or sleep in women undergoing treatment for breast cancer. Activity levels varied greatly between patients in a population of women undergoing hypofractionated RT. Because increased activity levels correlate with improved outcomes, further studies evaluating attempts to increase physical activity during as well as after treatment with radiation are warranted.
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http://dx.doi.org/10.1016/j.clbc.2017.08.009DOI Listing
February 2018

Vasectomy reversal for post-vasectomy pain syndrome.

Transl Androl Urol 2017 May;6(Suppl 1):S10-S13

Department of Urology, University of Virginia Health System, Charlottesville, VA 22908, USA.

Post-vasectomy pain syndrome (PVPS) is a rare, but devastating outcome following vasectomy. Given the widespread utilization of vasectomy for permanent contraception, with more than 500,000 procedures performed annually in the United States, it can be a significant challenge for both patients and providers. Vasectomy reversal is a surgical option for men who fail conservative or medical management. Despite improvements in technique, vasectomy carries some inherent risks making pre-procedure counseling regarding the risks of PVPS paramount. Chronic post-operative pain, or PVPS, occurs in 1-2% of men undergoing the procedure. This review will examine the utility of vasectomy reversal as a means of addressing PVPS.
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http://dx.doi.org/10.21037/tau.2017.04.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503916PMC
May 2017

Chronic orchialgia.

Transl Androl Urol 2017 May;6(Suppl 1):S1

Department of Urology, University of Virginia, Charlottesville, USA.

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http://dx.doi.org/10.21037/tau.2017.05.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503919PMC
May 2017

Long-Term Quality of Life in Prostate Cancer Patients Treated With Cesium-131.

Int J Radiat Oncol Biol Phys 2017 08 31;98(5):1053-1058. Epub 2017 Mar 31.

Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Electronic address:

Purpose: To evaluate long-term patient-reported quality of life (QOL) scores in men with prostate cancer treated at our institution with Cs prostate brachytherapy.

Methods And Materials: Patients treated more than 4 years ago with Cs (n=290) were asked to fill out an Expanded Prostate Cancer Index Composite (EPIC) QOL questionnaire and American Urological Association Symptom Score (AUASS) survey, before treatment and at each follow-up appointment. We compared patients' EPIC and AUA scores at baseline with scores at a last follow-up of at least 4 years after treatment using the Wilcoxon signed-rank test.

Results: At a median last follow-up of 5.5 years after treatment with Cs prostate brachytherapy there were no clinically significant changes in the EPIC or AUA scores from baseline. There was statistical worsening in the EPIC urinary incontinence subscore. Subset analyses revealed improved QOL outcomes in patients who received external beam radiation therapy or α-blocker therapy, whereas androgen deprivation therapy was not associated with differences in QOL change.

Conclusions: Our results demonstrate minimal long-term changes in urinary or bowel patient-reported QOL with Cs prostate brachytherapy. These findings suggest that patients treated with this isotope are able to recover and then maintain their baseline QOL in the long term.
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http://dx.doi.org/10.1016/j.ijrobp.2017.03.046DOI Listing
August 2017

What is the Role of the Oncology Nurse in Fertility Preservation Counseling and Education for Young Patients?

J Cancer Educ 2018 12;33(6):1301-1305

University of Virginia Emily Couric Cancer Center, Charlottesville, VA, USA.

Oncology nurses are uniquely positioned to offer fertility preservation counseling and education for cancer patients of reproductive age, yet there is a dearth of research that focuses on current practice and perceptions of nursing role. In 2013, the American Society of Clinical Oncology extended the duties of fertility preservation counseling among patients of reproductive age undergoing cancer treatment to include registered nurses and other allied health professionals as active partners in the counseling and education process. This study used a cross-sectional descriptive survey to assess current practices, role perceptions, and barriers to fertility preservation counseling among registered nurses working in an academic care setting with outpatient and inpatient services. There were significant gaps in current practices and perceptions of roles regarding fertility preservation counseling. Many nurses expressed the perception that fertility preservation counseling was important, but it was outside the scope of their practice to perform this education. This preliminary work defined need for an interdisciplinary fertility preservation team, communication surrounding educational practice norms, and designated oncofertility navigator.
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http://dx.doi.org/10.1007/s13187-017-1247-yDOI Listing
December 2018

Drugs in preclinical to phase II clinical development for the treatment of erectile dysfunction.

Expert Opin Investig Drugs 2017 Jun 5;26(6):669-675. Epub 2017 May 5.

b Men's Health Center , Urology of Indiana , Indianapolis , IN , USA.

Introduction: Erectile function is an important aspect in the quality of life of many men. For men with erectile dysfunction (ED), a spectrum of treatment options exists. Novel therapies for ED are currently being developed in order to delay surgical placement of a penile prosthesis - the final step in the management of treatment-refractory ED. Areas covered: This review examines innovative treatments such as alternative vasoactive agents, trophic factors and bio-compounds as well as gene and stem cell therapy. All therapies are currently in some phase of development for the management of ED. Using the MedLine and FDA Clinical Trials Registry, recent developments in treatment of ED were queried. Expert opinion: Recent studies have demonstrated the potential for multiple, novel therapies in the treatment of ED. Much of the work requires further experimentation in large-scale, blinded, placebo-controlled studies. This will require a concerted effort to bring these products to market.
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http://dx.doi.org/10.1080/13543784.2017.1324570DOI Listing
June 2017

Prognostic implications of immediate PSA response to early salvage radiotherapy.

Can J Urol 2016 Dec;23(6):8568-8575

Department of Urology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.

Introduction: Up to 25% of men with prostate cancer who undergo radical prostatectomy will recur. In this setting, salvage radiotherapy may cure patients with local recurrence, but is unable to cure those with occult metastatic disease. The objective of this study is to examine how prostate-specific antigen (PSA) response to radiotherapy predicts subsequent disease progression and survival.

Materials And Methods: Using a prospectively populated database of 3089 men who underwent open radical prostatectomy, 212 patients (7%) were identified who received early salvage radiotherapy for biochemical recurrence. The main outcome was time to disease progression after salvage radiotherapy. Patients were stratified by PSA response after radiotherapy: 1) PSA < 0.1 ng/mL, 2) persistently detectable PSA, and 3) rising PSA.

Results: Patients received salvage radiotherapy at a median PSA of 0.20 ng/mL (IQR 0.10-0.30 ng/mL). At a median follow up of 47.3 months, a total of 52 (25%) patients experienced disease progression. On multivariable analysis, both persistent PSA (HR 5.12; 95% CI 1.98-13.23) and rising PSA (HR 16.55; 95% CI 6.61-41.48) were associated with increased risk of disease progression compared to those with PSA < 0.1 ng/mL after adjusting for pre-radiotherapy PSA, Gleason score, margin status, stage, and time to radiotherapy. Only rising PSA was associated with an increased risk of cancer-specific and all-cause mortality.

Conclusions: PSA response is associated with the risk of disease progression following salvage radiotherapy. This information can be used to counsel patients on the potential need for additional therapy and identify those at greatest risk for progression and cancer-related mortality.
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December 2016