Seasonal increase in syphilis screening reactivity rates in whole blood donors, United States, 2011-2023.

BACKGROUND: In December 2021, the U.S. Food and Drug Administration published a letter to clinical laboratory staff and healthcare providers detailing a risk of false Rapid Plasma Reagin (RPR) when using the Bio-Rad Laboratories BioPlex 2200 Syphilis Total & RPR kit in people who had received COVID-19 vaccination; Treponema pallidum particle agglutination assays did not appear to be impacted by this issue. We evaluated reactivity rates of syphilis screening with negative confirmatory testing at our institution by year and seasonality. METHODS: We performed a retrospective study of routine syphilis testing of whole blood (WB) collections at an academic hospital-based donor center in the eastern United States. All WB donations from 2011 to 2023 which demonstrated reactive syphilis screening (Beckman Coulter PK TP Microhemagglutination) with negative confirmatory testing (CAPTIA Syphilis (T. pallidum)-G) were evaluated. Reactivity rates by year and season of donation were compared using unpaired t-tests. RESULTS: A total of 109 WB donations from 86 unique donors who donated from 2011 to 2023 screened reactive for syphilis with negative confirmatory testing. The unconfirmed syphilis reactivity rate increased from 2018 to 2023 (mean: 0.360%) compared to 2011-2017 (mean: 0.071%, p < .05). An autumnal peak in unconfirmed reactives was observed. CONCLUSION: The unconfirmed syphilis reactivity rate among WB donors at our institution increased markedly since 2017 compared to the 7 years prior and doubled from 2020 to 2021. No testing assay changes explain these results. The autumnal peak in unconfirmed reactives suggests a possible environmental trigger such as viral infection or vaccination.

CD34+ cell yield among healthy donors: Large-scale model development and validation.

BACKGROUND: Successful engraftment in hematopoietic stem cell transplantation necessitates the collection of an adequate dose of CD34+ cells. Thus, the precise estimation of CD34+ cells harvested via apheresis is critical. Current CD34+ cell yield prediction models have limited reproducibility. This study aims to develop a more reliable and universally applicable model by utilizing a large dataset, enhancing yield predictions, optimizing the collection process, and improving clinical outcomes. MATERIALS AND METHODS: A secondary analysis was conducted using the Center for International Blood and Marrow Transplant Research database, involving data from over 17 000 healthy donors who underwent filgrastim-mobilized hematopoietic progenitor cell apheresis. Linear regression, gradient boosting regressor, and logistic regression classification models were employed to predict CD34+ cell yield. RESULTS: Key predictors identified include pre-apheresis CD34+ cell count, weight, age, sex, and blood volume processed. The linear regression model achieved a coefficient of determination (R2) value of 0.66 and a correlation coefficient (r) of 0.81. The gradient boosting regressor model demonstrated marginally improved results with an R2 value of 0.67 and an r value of 0.82. The logistic regression classification model achieved a predictive accuracy of 96% at the 200 × 106 CD34+ cell count threshold. At thresholds of 400, 600, 800, and 1000 × 106 CD34+ cell count, the accuracies were 88%, 83%, 83%, and 88%, respectively. The model demonstrated a high area under the receiver operator curve scores ranging from 0.90 to 0.93. CONCLUSION: This study introduces advanced predictive models for estimating CD34+ cell yield, with the logistic regression classification model demonstrating remarkable accuracy and practical utility.

Increased serum pro-B-type natriuretic peptide in hematopoietic progenitor cell donors stimulated with G-CSF.

Hematopoietic stem cells (HPCs) donors mobilized by granulocyte-colony-stimulating factor (G-CSF) can develop various signs and symptoms. proBNP (pro-B-type natriuretic peptide) is a serum marker of heart failure. A donor who developed severe adverse reactions after G-CSF mobilization was found to have high serum proBNP levels. We followed additional donors who received identical mobilization regimen to investigate the prevalence of this phenomenon. Eighteen healthy donors underwent a mobilization regimen of 10 µg/Kg G-CSF daily for 5 days prior to allogeneic HPC collection using Spectra Optia between January 2016 and February 2017 were included in this study. Serum proBNP levels were measured before and after G-CSF stimulation and immediately after apheresis. Apheresis collection parameters and other laboratory results were also reviewed. The majority of donors (86.7%) had post-G-CSF elevation of serum proBNP. Seven of those had elevated proBNP above upper normal range (124 pg/ml). The subgroup of donors with normal proBNP is younger (median age of 37 vs 42 years), with majority being male (90.9% vs 28.6%) and with smaller processed blood volume (2.2 vs 3 × total blood volume). This case series demonstrates an increase of serum proBNP can be common in HPC donors stimulated with 5 days of 10 mcg/kg G-CSF. This is an adverse reaction that has not been described before. The temporary elevation of proBNP in these donors is not associated with ventricular dysfunction of the heart. The risk factors for marked elevation of proBNP post-G-CSF should be further investigated.

Naturally Acquired SARS-CoV-2 Immunity Persists for Up to 11 Months Following Infection.

BACKGROUND: Characterizing the kinetics of the antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of critical importance to developing strategies that may mitigate the public health burden of coronavirus disease 2019 (COVID-19). We conducted a prospective, longitudinal analysis of COVID-19 convalescent plasma donors at multiple time points over an 11-month period to determine how circulating antibody levels change over time following natural infection. METHODS: From April 2020 to February 2021, we enrolled 228 donors. At each study visit, subjects either donated plasma or had study samples drawn only. Anti-SARS-CoV-2 donor testing was performed using the VITROS Anti-SARS-CoV-2 Total and IgG assays and an in-house fluorescence reduction neutralization assay. RESULTS: Anti-SARS-CoV-2 antibodies were identified in 97% of COVID-19 convalescent donors at initial presentation. In follow-up analyses, of 116 donors presenting at repeat time points, 91.4% had detectable IgG levels up to 11 months after symptom recovery, while 63% had detectable neutralizing titers; however, 25% of donors had neutralizing levels that dropped to an undetectable titer over time. CONCLUSIONS: Our data suggest that immunological memory is acquired in most individuals infected with SARS-CoV-2 and is sustained in a majority of patients for up to 11 months after recovery. Clinical Trials Registration. NCT04360278.

How do I structure logistic processes in preparation for outsourcing of cellular therapy manufacturing?

As cell and gene therapies (CGT) assume center stage in early-phase clinical trials for several acute and chronic diseases, there is heightened interest in the standardization and automation of manufacturing processes in preparation for commercialization. Toward this goal, a hybrid and oftentimes geographically separated model comprising regional cell procurement and infusion facilities and a centralized cell manufacturing unit is gaining traction in the field. Although CGT processing facilities in academic institutions are not involved directly in the manufacturing of these therapies, they must be prepared to collaborate with commercial or contract manufacturing organizations (CMOs) and be ready to address several supply-chain challenges that have emerged for autologous and allogeneic CGT. Academic center cell-processing facilities must handle many events up- and downstream of manufacturing such as donor screening, cell collection, product labeling, cryopreservation, transportation, and thaw infusion. These events merit closer evaluation in the context of multifacility manufacturing since standard procedures have yet to be established. Based on our institutional experience, we summarize logistical challenges encountered in the handling and distribution of CGT products in early phase studies, specifically those involving CMO (outsourced) manufacturing. We also make recommendations to standardize processes unique to the CGT supply chain, emphasizing the need to maintain needle-to-needle traceability from product collection to infusion. These guidelines will inform the development of more complex supply-chain models for larger-scale cell and gene therapeutics.

Serological weak D phenotypes: a review and guidance for interpreting the RhD blood type using the RHD genotype.

Approximately 0·2-1% of routine RhD blood typings result in a "serological weak D phenotype." For more than 50 years, serological weak D phenotypes have been managed by policies to protect RhD-negative women of child-bearing potential from exposure to weak D antigens. Typically, blood donors with a serological weak D phenotype have been managed as RhD-positive, in contrast to transfusion recipients and pregnant women, who have been managed as RhD-negative. Most serological weak D phenotypes in Caucasians express molecularly defined weak D types 1, 2 or 3 and can be managed safely as RhD-positive, eliminating unnecessary injections of Rh immune globulin and conserving limited supplies of RhD-negative RBCs. If laboratories in the UK, Ireland and other European countries validated the use of potent anti-D reagents to result in weak D types 1, 2 and 3 typing initially as RhD-positive, such laboratory results would not require further testing. When serological weak D phenotypes are detected, laboratories should complete RhD testing by determining RHD genotypes (internally or by referral). Individuals with a serological weak D phenotype should be managed as RhD-positive or RhD-negative, according to their RHD genotype.

Late urinary toxicity modeling after stereotactic body radiotherapy (SBRT) in the definitive treatment of localized prostate cancer.

BACKGROUND: Late urinary symptom flare has been shown to occur in a small subset of men treated with ultra- hypofractionated stereotactic body radiotherapy (SBRT) for prostate cancer. The purpose of this study was to use normal tissue complication probability modeling in an effort to derive SBRT specific dosimetric predictor's of late urinary flare. MATERIAL AND METHODS: Two hundred and sixteen men were treated for localized prostate cancer using ultra- hypofractionated SBRT. A dose of 35-36.25 Gy in 5 fractions was delivered to the prostate and proximal seminal vesicles. Functional surveys were conducted before and after treatment to assess late toxicity. Phenomenologic NTCP models were fit to bladder DVHs and late urinary flare outcomes using maximum likelihood estimation. RESULTS: Twenty-nine patients experienced late urinary flare within two years of completion of treatment. Fitting of bladder DVH data to a Lyman NTCP model resulted in parameter estimates of m, TD50, and n of 0.19 (0-0.47), 38.7 Gy (31.1-46.4), and 0.13 (-0.14-0.41), respectively. Subsequent fit to a hottest volume probit model revealed a significant association of late urinary flare with dose to the hottest 12.7% of bladder volume. Multivariate analysis resulted in a final model that included patient age and hottest volume probit model predictions. Kaplan-Meier analysis demonstrated a two-year urinary flare free survival of 95.7% in patients 65 years or older with a bladder D12.7% of 33.5 Gy or less, compared to 74.5% in patients meeting none of these criteria. CONCLUSION: NTCP modeling of late urinary flare after ultra-hypofractionated prostate SBRT demonstrates a relatively small volume effect for dose to the bladder, suggesting that reduction of volume receiving elevated dose will result in decreased incidence of late urinary toxicity. Future studies will be needed to examine the impact of dose to other potential sources of late genitourinary toxicity.

Prostate specific antigen kinetics following robotic stereotactic body radiotherapy for localized prostate cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged as an effective treatment for localized prostate cancer. However, prostate specific antigen (PSA) kinetics after prostate SBRT have not been well characterized. The purpose of this study was to analyze the trend in PSA decline following robotic SBRT from a prospective cohort of patients. MATERIAL AND METHODS: In total 175 patients were treated definitively for localized prostate cancer to a dose of 35-36.25 Gy in 5 fractions using robotic SBRT in the absence of androgen deprivation therapy (ADT). PSA and testosterone were collected at regular intervals following treatment and patients were assessed for biochemical failure and benign PSA bounce. A PSA nadir threshold of 0.5 ng/ml was used as a predictor of long-term disease-free survival. Multivariate logistic regression was used to assess the effect of disease specific covariates on the likelihood of achieving a PSA nadir less than threshold. PSA kinetics were analyzed a multi-component exponential model accounting for benign and malignant sources of PSA. RESULTS AND CONCLUSION: At a median follow-up of 3 years, 70% of patients achieved a PSA nadir below 0.5 ng/ml with a median PSA nadir of 0.3 ng/ml at a median time to nadir of 30 months. In our cohort, 36.2% experienced a benign PSA bounce. Absence of PSA bounce, initial PSA, and testosterone at the time of nadir proved to be significant predictors of achieving a PSA nadir below threshold. PSA kinetics after prostate SBRT were well described with a functional volume model with fitted half-lives of 4.4 and 14.8 months for malignant and benign sources of PSA, respectively. Patients treated with prostate SBRT experience an initial period of rapid PSA decline followed by a slow decline which will likely result in lower PSA nadirs after longer follow-up. The long-term disease specific impacts of these results remain to be determined.

Correlation of HOXD3 promoter hypermethylation with clinical and pathologic features in screening prostate biopsies.

BACKGROUND: Molecular markers that can discriminate indolent cancers from aggressive ones may improve the management of prostate cancer and minimize unnecessary treatment.Aberrant DNA methylation is a common epigenetic event in cancers and HOXD3 promoter hypermethylation (H3PH) has been found in prostate cancer. Our objective was to evaluate the relationship between H3PH and clinicopathologic features in screening prostate biopsies. METHODS: Ninety-two patients who underwent a prostate biopsy at our institution between October 2011 and May 2012 were included in this study. The core with the greatest percentage of the highest grade disease was analyzed for H3PH by methylation-specific PCR. Correlational analysis was used to analyze the relationship between H3PH and various clinical parameters. Chi-square analysis was used to compare H3PH status between benign and malignant disease. RESULTS: Of the 80 biopsies with HOXD3 methylation status assessable, 66 sets were confirmed to have cancer. In the 14 biopsies with benign disease there was minimal H3PH with the mean percentage of methylation reference (PMR) of 0.7%. In contrast, the HOXD3 promoter was hypermethylated in 16.7% of all cancers and in 50% of high risk tumors with an average PMR of 4.3% (P=0.008). H3PH was significantly correlated with age (P=0.013), Gleason score (P=0.031) and the maximum involvement of the biopsy core (P=0.035). CONCLUSIONS: H3PH is associated with clinicopathologic features. The data indicate that H3PH is more common in older higher risk patients. More research is needed to determine the role of this marker in optimizing management strategies in men with newly diagnosed prostate cancer.

mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants.

Several variants of SARS-CoV-2 have emerged. Those with mutations in the angiotensin-converting enzyme (ACE2) receptor binding domain (RBD) are associated with increased transmission and severity. In this study, we developed both antibody quantification and functional neutralization assays. Analyses of both COVID-19 convalescent and diagnostic cohorts strongly support the use of RBD antibody levels as an excellent surrogate to biochemical neutralization activities. Data further revealed that the samples from mRNA vaccinated individuals had a median of 17 times higher RBD antibody levels and a similar degree of increased neutralization activities against RBD-ACE2 binding than those from natural infections. Our data showed that N501Y RBD had fivefold higher ACE2 binding than the original variant. While some antisera from naturally infected subjects had substantially reduced neutralization ability against N501Y RBD, all blood samples from vaccinated individuals were highly effective in neutralizing it. Thus, our data indicates that mRNA vaccination may generate more neutralizing RBD antibodies than natural immunity. It further suggests a potential need to maintain high RBD antibody levels to control the more infectious SARS-CoV-2 variants.

Extramedullary Hematopoiesis Presenting as Bilateral Glomus Tympanicum-First Case Report in a Pediatric Patient and With Bilateral Presentation.

To the best of our knowledge, this is the first case report of middle ear extramedullary hematopoiesis (EMH) in a pediatric patient as well as the first bilateral presentation reported in both children and adults. We report a 13-year-old African-American female with sickle cell disease who developed bilateral hearing loss, with magnetic resonance imaging findings consistent with bilateral glomus tympanicum (GT). Upon excisional biopsy, however, EMH was diagnosed histologically. Besides its novelty, this case highlights the importance of considering EMH in the differential diagnosis of GT including cases with bilateral presentation that may be otherwise highly suggestive of the familial form of GT.

Proctitis 1 Week after Stereotactic Body Radiation Therapy for Prostate Cancer: Implications for Clinical Trial Design.

BACKGROUND: Proctitis following prostate cancer radiation therapy is a primary determinant of quality of life (QOL). While previous studies have assessed acute rectal morbidity at 1 month after stereotactic body radiotherapy (SBRT), little data exist on the prevalence and severity of rectal morbidity within the first week following treatment. This study reports the acute bowel morbidity 1 week following prostate SBRT. MATERIALS AND METHODS: Between May 2013 and August 2014, 103 patients with clinically localized prostate cancer were treated with 35-36.25 Gy in five fractions using robotic SBRT delivered on a prospective clinical trial. Bowel toxicity was graded using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv.4). Bowel QOL was assessed using the EPIC-26 questionnaire bowel domain at baseline, 1 week, 1 month, and 3 months. Time-dependent changes in bowel symptoms were statistically compared using the Wilcoxon signed-rank test. Clinically significant change was assessed by the minimally important difference (MID) in EPIC score. This was defined as a change of 1/2 standard deviation (SD) from the baseline score. RESULTS: One-hundred and three patients with a minimum of 3 months of follow-up were analyzed. The cumulative incidence of acute grade 2 gastrointestinal (GI) toxicity was 23%. There were no acute ≥ grade 3 bowel toxicities. EPIC bowel summary scores maximally declined at 1 week after SBRT (-13.9, p < 0.0001) before returning to baseline at 3 months after SBRT (+0.03, p = 0.94). Prior to treatment, 4.9% of men reported that their bowel bother was a moderate to big problem. This increased to 28.4% (p < 0.0001) 1 week after SBRT and returned to baseline at 3 months after SBRT (0.0%, p = 0.66). Only the bowel summary and bowel bother score declines at 1 week met the MID threshold for clinically significant change. CONCLUSION: The rate and severity of acute proctitis following prostate SBRT peaked at 1 week after treatment and returned to baseline by 3 months. Toxicity assessment at 1 week can therefore minimize recall bias and should aid in the design of future clinical trials focused on accurately capturing and minimizing acute morbidity following SBRT.

Acute Urinary Morbidity Following Stereotactic Body Radiation Therapy for Prostate Cancer with Prophylactic Alpha-Adrenergic Antagonist and Urethral Dose Reduction.

BACKGROUND: Stereotactic body radiation therapy (SBRT) delivers high doses of radiation to the prostate while minimizing radiation to the adjacent critical organs. Large fraction sizes may increase urinary morbidity due to unavoidable treatment of the prostatic urethra. This study reports rates of acute urinary morbidity following SBRT for localized prostate cancer with prophylactic alpha-adrenergic antagonist utilization and urethral dose reduction (UDR). METHODS: From April 2013 to September 2014, 102 patients with clinically localized prostate cancer were treated with robotic SBRT to a total dose of 35-36.25 Gy in five fractions. UDR was employed to limit the maximum point dose of the prostatic urethra to 40 Gy. Prophylactic alpha-adrenergic antagonists were initiated 5 days prior to SBRT and continued until resolution of urinary symptoms. Quality of life (QoL) was assessed before and after treatment using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite-26 (EPIC-26). Clinical significance was assessed using a minimally important difference (MID) of one half SD change from baseline. RESULTS: One hundred two patients underwent definitive prostate SBRT with UDR and were followed for 3 months. No patient experienced acute urinary retention requiring catheterization. A mean baseline AUA symptom score of 9.06 significantly increased to 11.83 1-week post-SBRT (p = 0.0024) and 11.84 1-month post-SBRT (p = 0.0023) but returned to baseline by 3 months. A mean baseline EPIC-26 irritative/obstructive score of 87.7 decreased to 74.1 1-week post-SBRT (p < 0.0001) and 77.8 1-month post-SBRT (p < 0.0001) but returned to baseline at 3 months. EPIC-26 irritative/obstructive score changes were clinically significant, exceeding the MID of 6.0. At baseline, 8.9% of men described their urinary function as a moderate to big problem, and that proportion increased to 37.6% 1 week following completion of SBRT before returning to baseline by 3 months. CONCLUSION: Stereotactic body radiation therapy for localized prostate cancer with utilization of prophylactic alpha-adrenergic antagonist and UDR was well tolerated as determined by acute urinary function and bother, and symptoms were comparable to those observed following conventionally fractionated external beam radiation therapy (EBRT). Longer follow-up is required to assess long-term toxicity and efficacy following SBRT with UDR.

Intensity-Modulated Radiation Therapy with Stereotactic Body Radiation Therapy Boost for Unfavorable Prostate Cancer: The Georgetown University Experience.

PURPOSE/OBJECTIVES: Stereotactic body radiation therapy (SBRT) is emerging as a minimally invasive alternative to brachytherapy to deliver highly conformal, dose--escalated radiation therapy (RT) to the prostate. SBRT alone may not adequately cover the tumor extensions outside the prostate commonly seen in unfavorable prostate cancer. External beam radiation therapy (EBRT) with high dose rate brachytherapy boost is a proven effective therapy for unfavorable prostate cancer. This study reports on early prostate-specific antigen and prostate cancer-specific quality of life (QOL) outcomes in a cohort of unfavorable patients treated with intensity-modulated radiation therapy (IMRT) and SBRT boost. MATERIALS/METHODS: Prostate cancer patients treated with SBRT (19.5 Gy in three fractions) followed by fiducial-guided IMRT (45-50.4 Gy) from March 2008 to September 2012 were included in this retrospective review of prospectively collected data. Biochemical failure was assessed using the Phoenix definition. Patients completed the expanded prostate cancer index composite (EPIC)-26 at baseline, 1 month after the completion of RT, every 3 months for the first year, then every 6 months for a minimum of 2 years. RESULTS: One hundred eight patients (4 low-, 45 intermediate-, and 59 high-risk) with median age of 74 years completed treatment, with median follow-up of 4.4 years. Sixty-four percent of the patients received androgen deprivation therapy prior to the initiation of RT. The 3-year actuarial biochemical control rates were 100 and 89.8% for intermediate- and high-risk patients, respectively. At the initiation of RT, 9 and 5% of men felt their urinary and bowel function was a moderate to big problem, respectively. Mean EPIC urinary and bowel function and bother scores exhibited transient declines, with subsequent return to near baseline. At 2 years posttreatment, 13.7 and 5% of men felt their urinary and bowel function was a moderate to big problem, respectively. CONCLUSION: At 3-year follow-up, biochemical control was favorable. Acute urinary and bowel symptoms were comparable to conventionally fractionated IMRT and brachytherapy. Patients recovered to near their baseline urinary and bowel function by 2 years posttreatment. A combination of IMRT with SBRT boost is well tolerated with minimal impact on prostate cancer-specific QOL.

Dysuria Following Stereotactic Body Radiation Therapy for Prostate Cancer.

BACKGROUND: Dysuria following prostate radiation therapy is a common toxicity that adversely affects patients' quality of life and may be difficult to manage. METHODS: Two hundred four patients treated with stereotactic body radiation therapy (SBRT) from 2007 to 2010 for localized prostate carcinoma with a minimum follow-up of 3 years were included in this retrospective review of prospectively collected data. All patients were treated to 35-36.25 Gy in five fractions delivered with robotic SBRT with real time fiducial tracking. Dysuria and other lower urinary tract symptoms were assessed via Question 4b (Pain or burning on urination) of the expanded prostate index composite-26 and the American Urological Association (AUA) Symptom Score at baseline and at routine follow-up. RESULTS: Two hundred four patients (82 low-, 105 intermediate-, and 17 high-risk according to the D'Amico classification) at a median age of 69 years (range 48-91) received SBRT for their localized prostate cancer with a median follow-up of 47 months. Bother associated with dysuria significantly increased from a baseline of 12% to a maximum of 43% at 1 month (p < 0.0001). There were two distinct peaks of moderate to severe dysuria bother at 1 month and at 6-12 months, with 9% of patients experiencing a late transient dysuria flare. While a low level of dysuria was seen through the first 2 years of follow-up, it returned to below baseline by 2 years (p = 0.91). The median baseline AUA score of 7.5 significantly increased to 11 at 1 month (p < 0.0001) and returned to 7 at 3 months (p = 0.54). Patients with dysuria had a statistically higher AUA score at baseline and at all follow-ups up to 30 months. Dysuria significantly correlated with dose and AUA score on multivariate analysis. Frequency and strain significantly correlated with dysuria on stepwise multivariate analysis. CONCLUSION: The rate and severity of dysuria following SBRT is comparable to patients treated with other radiation modalities.

Hematuria following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer.

BACKGROUND: Hematuria following prostate radiotherapy is a known toxicity that may adversely affect a patient's quality of life. Given the higher dose of radiation per fraction using stereotactic body radiation therapy (SBRT) there is concern that post-SBRT hematuria would be more common than with alternative radiation therapy approaches. Herein, we describe the incidence and severity of hematuria following stereotactic body radiation therapy (SBRT) for prostate cancer at our institution. METHODS: Two hundred and eight consecutive patients with prostate cancer treated with SBRT monotherapy with at least three years of follow-up were included in this retrospective analysis. Treatment was delivered using the CyberKnife® (Accuray) to doses of 35-36.25 Gy in 5 fractions. Toxicities were scored using the CTCAE v.4. Hematuria was counted at the highest grade it occurred in the acute and late setting for each patient. Cystoscopy findings were retrospectively reviewed. Univariate and multivariate analyses were performed. Hematuria-associated bother was assessed via the Expanded Prostate Index Composite (EPIC)-26. RESULTS: The median age was 69 years with a median prostate volume of 39 cc. With a median follow-up of 48 months, 38 patients (18.3%) experienced at least one episode of hematuria. Median time to hematuria was 13.5 months. In the late period, there were three grade 3 events and five grade 2 events. There were no grade 4 or 5 events. The 3-year actuarial incidence of late hematuria ≥ grade 2 was 2.4%. On univariate analysis, prostate volume (p = 0.022) and history of prior procedure(s) for benign prostatic hypertrophy (BPH) (p = 0.002) were significantly associated with hematuria. On multivariate analysis, history of prior procedure(s) for BPH (p < 0.0001) and α1A antagonist use (p = 0.008) were significantly associated with the development of hematuria. CONCLUSIONS: SBRT for prostate cancer was well tolerated with hematuria rates comparable to other radiation modalities. Patients factors associated with BPH, such as larger prostate volume, alpha antagonist usage, and prior history of procedures for BPH are at increased risk for the development of hematuria.

Stereotactic Body Radiation Therapy for Prostate Cancer: What is the Appropriate Patient-Reported Outcome for Clinical Trial Design?

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. Consensus regarding the appropriate patient-reported outcome (PRO) endpoints for clinical trials evaluating radiation modalities for early stage prostate cancer is lacking. To aid in clinical trial design, this study presents PROs over a 36-month period following SBRT for clinically localized prostate cancer. METHODS: Between February 2008 and September 2010, 174 hormone-naïve patients with clinically localized prostate cancer were treated with 35-36.25 Gy SBRT (CyberKnife, Accuray) delivered in 5 fractions. Patients completed the validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire at baseline and all follow-ups. The proportion of patients developing a clinically significant decline in each EPIC domain score was determined. The minimally important difference (MID) was defined as a change of one-half the standard deviation from the baseline. Per Radiation Therapy Oncology Group (RTOG) 0938, we also examined the patients who experienced a decline in EPIC urinary domain summary score of >2 points (unacceptable toxicity defined as ≥60% of all patients reporting this degree of decline) and EPIC bowel domain summary score of >5 points (unacceptable toxicity defined as >55% of all patients reporting this degree of decline) from baseline to 1 year. RESULTS: A total of 174 patients at a median age of 69 years received SBRT with a minimum follow-up of 36 months. The proportion of patients reporting a clinically significant decline (MID for urinary/bowel are 5.5/4.4) in EPIC urinary/bowel domain scores was 34%/30% at 6 months, 40%/32.2% at 12 months, and 32.8%/21.5% at 36 months. The patients reporting a decrease in the EPIC urinary domain summary score of >2 points was 43.2% (CI: 33.7%, 54.6%) at 6 months, 51.6% (CI: 43.4%, 59.7%) at 12 months, and 41.8% (CI: 33.3%, 50.6%) at 36 months. The patients reporting a decrease in the EPIC bowel domain summary score of >5 points was 29.6% (CI: 21.9%, 39.3%) at 6 months, 29% (CI: 22%, 36.8%) at 12 months, and 22.4% (CI: 15.7%, 30.4%) at 36 months. CONCLUSION: Following prostate SBRT, clinically significant urinary symptoms are more common than bowel symptoms. Our prostate SBRT treatment protocol meets the RTOG 0938 criteria for moving forward to a Phase III trial comparing it to conventionally fractionated radiation therapy. Notably, between 12 and 36 months, the proportion of patients reporting a significant decrease in both EPIC urinary and bowel domain scores declined, suggesting a late improvement in these symptom domains. Further investigation is needed to elucidate (1) which EPIC domains bear the greatest influence on post-treatment quality of life and (2) at what time point PRO endpoint(s) should be assessed.

Stereotactic body radiation therapy (SBRT) for prostate cancer in men with large prostates (≥50 cm(3)).

BACKGROUND: Patients with large prostate volumes have been shown to have higher rates of genitourinary and gastrointestinal toxicities after conventional radiation therapy for prostate cancer. The efficacy and toxicity of stereotactic body radiation therapy (SBRT), which delivers fewer high-dose fractions of radiation treatment, is unknown for large prostate volume prostate cancer patients. We report our early experience using SBRT for localized prostate cancer in patients with large prostate volumes. METHODS: 57 patients with prostate volumes ≥50 cm(3) prior to treatment with SBRT for localized prostate carcinoma and with a minimum follow up of two years were included in this retrospective review of prospectively collected data. Treatment was delivered using Cyberknife (Accuray) with doses of 35-36.25 Gy in 5 fractions. Biochemical control was assessed using the Phoenix definition. Toxicities were scored using the CTCAE v.4. Quality of life was assessed using the American Urological Association (AUA) Symptom Score and the Expanded Prostate Cancer Index Composite (EPIC)-26. RESULTS: 57 patients (23 low-, 25 intermediate- and 9 high-risk according to the D'Amico classification) at a median age of 69 years (range, 54-83 years) received SBRT with a median follow-up of 2.9 years. The median prostate size was 62.9 cm(3) (range 50-138.7 cm(3)). 33.3% of patients received ADT. The median pre-treatment prostate-specific antigen (PSA) was 6.5 ng/ml and decreased to a median PSA of 0.4 ng/ml by 2 years (p <0.0001). A mean baseline AUA symptom score of 7.5 significantly increased to 13 at 1 month (p = 0.001) and returned to baseline by 3 months (p = 0.21). 23% of patients experienced a late transient urinary symptom flare in the first two years following treatment. Mean baseline EPIC bowel scores of 95.8 decreased to 78.1 at 1 month (p <0.0001), but subsequently improved to 93.5 three months (p = 0.08). The 2-year actuarial incidence rates of GU and GI toxicity ≥ grade 2 were 49.1% and 1.8%, respectively. Two patients (3.5%) experienced grade 3 urinary toxicity, and no patient experienced grade 3 gastrointestinal toxicity. CONCLUSIONS: SBRT for clinically localized prostate cancer was well tolerated in men with large prostate volumes.