Treated Prostate Cancer Research Articles

Physician variation in management of low-risk prostate cancer: a population-based cohort study.

Up-front treatment of older men with low-risk prostate cancer can cause morbidity without clear survival benefit; however, most such patients receive treatment instead of observation. The impact of physicians on the management approach is uncertain. To determine the impact of physicians on the management of low-risk prostate cancer with up-front treatment vs observation. Retrospective cohort of men 66 years and older with low-risk prostate cancer diagnosed from 2006 through 2009. Patient and tumor characteristics were obtained from the Surveillance, Epidemiology, and End Results cancer registries. The diagnosing urologist, consulting radiation oncologist, cancer-directed therapy, and comorbid medical conditions were determined from linked Medicare claims. Physician characteristics were obtained from the American Medical Association Physician Masterfile. Mixed-effects models were used to evaluate management variation and factors associated with observation. No cancer-directed therapy within 12 months of diagnosis (observation). A total of 2145 urologists diagnosed low-risk prostate cancer in 12,068 men, of whom 80.1% received treatment and 19.9% were observed. The case-adjusted rate of observation varied widely across urologists, ranging from 4.5% to 64.2% of patients. The diagnosing urologist accounted for 16.1% of the variation in up-front treatment vs observation, whereas patient and tumor characteristics accounted for 7.9% of this variation. After adjustment for patient and tumor characteristics, urologists who treat non-low-risk prostate cancer (adjusted odds ratio [aOR], 0.71 [95% CI, 0.55-0.92]; P = .01) and graduated in earlier decades (P = .004) were less likely to manage low-risk disease with observation. Treated patients were more likely to undergo prostatectomy (aOR, 1.71 [95% CI, 1.45-2.01]; P < .001), cryotherapy (aOR, 28.2 [95% CI, 19.5-40.9]; P < .001), brachytherapy (aOR, 3.41 [95% CI, 2.96-3.93]; P < .001), or external-beam radiotherapy (aOR, 1.31 [95% CI, 1.08-1.58]; P = .005) if their urologist billed for that treatment. Case-adjusted rates of observation also varied across consulting radiation oncologists, ranging from 2.2% to 46.8% of patients. Rates of management of low-risk prostate cancer with observation varied widely across urologists and radiation oncologists. Patients whose diagnosis was made by urologists who treated prostate cancer were more likely to receive up-front treatment and, when treated, more likely to receive a treatment that their urologist performed. Public reporting of physicians' cancer management profiles would enable informed selection of physicians to diagnose and manage prostate cancer.

Testosterone and the Prostate

Late-onset hypogonadism, lower urinary tract symptoms (LUTS) due to benign prostatic enlargement (BPE), and prostate cancer commonly coexist in the aging male. Due to a better understanding of the physiology and impact of testosterone on benign and malignant diseases of the prostate, the view toward testosterone replacement therapy (TRT) in these individuals has changed dramatically over time. This communication evaluates the effects of testosterone on benign prostatic growth and prostate cancer and reviews the evidence for TRT for men with BPE and prostate cancer. A literature review was performed with regards to TRT in men with prostate cancer as well as the effect of testosterone on the growth of benign prostate tissue and prostate cancer carcinogenesis. To evaluate the evidence for an effect of testosterone on the growth of benign prostate tissue and the development of prostate cancer and TRT in men with prostate cancer. TRT does not exacerbate LUTS. Current evidence is lacking but suggests that TRT may not increase the risk of subsequent diagnosis of prostate cancer, and is unlikely to impact recurrence or progression for men with treated prostate cancer, but longer follow-up is needed. There is no evidence to suggest that TRT is contraindicated in men with BPE or effectively treated prostate cancer. Tan RBW, Silberstein JL, and Hellstrom WJG. Testosterone and the prostate. Sex Med Rev 2014;2:112-120.

SU‐E‐T‐11: A Dosimetric Comparison of Robotic Prostatic Radiosugery Using Multi‐ Leaf Collimation Vs Circular Collimators

Purpose:The study compared the dosimetry plans of Stereotatic Body Radiotherapy (SBRT) prostate cancer patients using the M6 Cyberknife with Multi‐leaf Collimation (MLC) compared with the plans using G4 Cyberknife with circular collimators.Methods:Eight previously treated prostate cancer patients' SBRT plans using circular collimators, designed with Multiplan v3.5.3, were used as a benchmark. The CT, contours and the optimization scripts were imported into Multiplan v5.0 system and replanned with MLC. The same planning objectives were used: more than 95% of PTV received 36.25Gy, 90% of prostate received 40Gy and maximum dose &lt;45Gy, in five fractions. For organs at risk, less than 1cc of rectum received 36Gy and less than 10cc of bladder received 37Gy. Plans were evaluated on parameters derived from dose volume. The beam number, MU and delivery time were recorded to compare the treatment efficiency.Results:The mean CTV volume was 41.3cc (27.5∼57.6cc) and mean PTV volume was 76.77cc (59.1∼99.7cc). The mean PTV coverage was comparable between MLC (98.87%) and cone (98.74%). MLC plans had a slightly more favorable homogeneity index (1.22) and conformity index (1.17), than the cone (1.24 and 1.15). The mean rectum volume of 36 Gy (0.52cc) of MLC plans was slightly larger than cone (0.38cc) and the mean bladder volume of 37 Gy was smaller in MLC (1.82cc) than in cone plans (3.09cc). The mean number of nodes and beams were 65.9 and 80.5 in MLC vs 65.9 and 203.6 in cone. The mean MUs were significantly less for MLC plans (24,228MUs) than cone (32,347MUs). The total delivery time (which included 5 minutes for setup) was less, 29.6min (26∼32min) for MLC vs 45min (35∼55min) for cone.Conclusion:While the differences in the dosimetry between the MLC and circular collimator plans were rather minor, the MLC plans were much more efficient and required significantly less treatment time.

Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer

Despite a multitude of p53 immunohistochemistry (IHC) studies, data on the combined effect of nuclear p53 protein accumulation and TP53 genomic inactivation are lacking for prostate cancer. A tissue microarray including 11,152 prostate cancer samples was analyzed by p53 IHC and fluorescence in situ hybridization. Nuclear p53 accumulation was found in 10.1% of patients including 1.4% with high-level and 8.7% with low-level immunostaining. TP53 sequencing revealed that 17 of 22 (77%) cases with high-level p53 immunostaining, but only 3% (1 of 31) low-level p53 cases carried putative dominant-negative mutations. TP53 deletions occurred in 14.8% of cancers. Both deletions and protein accumulation were linked to unfavorable tumor phenotype and prostate specific antigen (PSA) recurrence (p<0.0001 each). The combination of both methods revealed subgroups with remarkable differences in their clinical course. Tumors with either TP53 deletion (14%) or low-level p53 positivity (8.7%) had identical risks of PSA recurrence, which were markedly higher than in cancers without p53 alterations (p<0.0001). Tumors with both p53 deletion and low-level p53 positivity (1.5%) had a worse prognosis than patients with only one of these alterations (p<0.0001). Tumors with strong p53 immunostaining or homozygous inactivation through deletion of one allele and disrupting translocation involving the second allele had the worst outcome, independent from clinical and pathological parameters. These data demonstrate a differential clinical impact of various TP53 alterations in prostate cancer. Strong p53 immunostaining-most likely accompanying dominant negative or oncogenic p53 mutation-has independent prognostic relevance and may thus represent a clinical useful molecular feature of prostate cancer.

Imaging Evaluation of Recurrence in Treated Prostate Cancer

: Prostate cancer is the most common cancer in men and although most prostate cancers are slow growing but aggressive prostate cancers cases are seen too. Prevalence of prostate cancer vary widely across the world, it is more common in the developed countries. It is the second leading cause of cancer-related death in men in the United States and the sixth cause of cancer-related death globally in the world. Many cases of prostate cancer remain subclinical and never have symptoms until late progressive stages of the disease. About 85% of patients diagnosed with prostate cancer have localized disease and could be treated by definitive radiation therapy or radical prostatectomy. In 3050% of patients who had radical prostatectomy, PSA relapse happens at 5 years. Diagnosis and treatment of patients with PSA relapse are difficult. Detection of local recurrence of prostate cancer is important because it could be treated by local radiation therapy. Local treatment of local recurrence of prostate cancer have higher rate of complications in comparison to treatment of primary prostate cancer, hence, accurate detection of local recurrence and excluding distant metastasis is important. Distant metastasis is treated by hormone therapy. Imaging studies play an important role in detection of local recurrence of prostate cancer and its differentiation with distant metastasis. The main imaging studies that are used for evaluation of patients after radical prostatectomy are transrectal ultrasonography (TRUS) and magnetic resonance imaging (MRI). The patients with local recurrence of prostate cancer could be divided to three groups based on imaging studies. 1- Patients who have a mass lesion in surgical bed that is detectable by both MRI and TRUS. TRUS is useful for obtaining biopsy from these mass lesions. 2- Patients who have residual prostate tissue detectable by both MRI and TRUS. The residual tissue may be tumoral and responsible for local recurrence or may be non-tumoral. MRI functional studies including dynamic contrast study, diffusion weighted imaging (DWI) and MR spectroscopy (MRS) is able to confirm presence of tumoral tissue within the prostate glands remnant. Differentiation of tumoral and non-tumoral prostate remnant is not possible by means of TRUS but TRUS is useful for doing biopsy from the prostate remnant. 3- There is no mass lesion in surgical bed and anastomotic site and surrounding tissues have normal appearance in both TRUS and conventional MRI but local tumor recurrence is detected by functional MR studies like abnormal early phase enhancement in surgical bed structures, restrictive pattern in DWI or rise in choline to creatine ratio in MRS. There is no role for TRUS in detection and management of this third group of patients. CT scan is not useful for evaluation of prostate gland itself but is beneficial for evaluation of lungs and abdominal organs and can detect skeletal metastasis.

How to manage prostate cancer with lymph node metastases?

Few series have reported on the incidence of lymph node metastases, multimodal treatment, and long-term outcomes associated with extended pelvic lymph node dissection in large cohorts of patients with surgically treated prostate cancer. The first nomograms for predicting prognosis from such data have only recently been developed and internally validated.

Induction of Paclitaxel Resistance by ERα Mediated Prohibitin Mitochondrial-Nuclear Shuttling

Paclitaxel is a drug within one of the most promising classes of anticancer agents. Unfortunately, clinical success of this drug has been limited by the insurgence of cellular resistance. To address this, Paclitaxel resistance was modeled in an in vitro system using estrogen treated prostate cancer cells. This study demonstrates that emerging resistance to clinically relevant doses of Paclitaxel is associated with 17-β-estradiol (E2) treatment in PC-3 cells, but not in LNCaP cells. We found that small interfering RNA mediated knockdown of ERα lead to a decrease in E2 induced Paclitaxel resistance in androgen-independent cells. We also showed that ERα mediated the effects of estrogen, thereby suppressing androgen-independent cell proliferation and mediating Paclitaxel resistance. Furthermore, E2 promoted Prohibitin (PHB) mitochondrial-nucleus translocation via directly mediation of ERα, leading to an inhibition of cellular proliferation by PHB. Additionally, restoration of Paclitaxel sensitivity by ERα knockdown could be overcome by PHB overexpression and, conversely, PHB knockdown decreased E2 induced Paclitaxel resistance. These findings demonstrate that PHB lies downstream of ERα and mediates estrogen-dependent Paclitaxel resistance signaling cascades.

Multicriteria optimization informed VMAT planning

We developed a patient-specific volumetric-modulated arc therapy (VMAT) optimization procedure using dose-volume histogram (DVH) information from multicriteria optimization (MCO) of intensity-modulated radiotherapy (IMRT) plans. The study included 10 patients with prostate cancer undergoing standard fractionation treatment, 10 patients with prostate cancer undergoing hypofractionation treatment, and 5 patients with head/neck cancer. MCO-IMRT plans using 20 and 7 treatment fields were generated for each patient on the RayStation treatment planning system (clinical version 2.5, RaySearch Laboratories, Stockholm, Sweden). The resulting DVH of the 20-field MCO-IMRT plan for each patient was used as the reference DVH, and the extracted point values of the resulting DVH of the MCO-IMRT plan were used as objectives and constraints for VMAT optimization. Weights of objectives or constraints of VMAT optimization or both were further tuned to generate the best match with the reference DVH of the MCO-IMRT plan. The final optimal VMAT plan quality was evaluated by comparison with MCO-IMRT plans based on homogeneity index, conformity number of planning target volume, and organ at risk sparing. The influence of gantry spacing, arc number, and delivery time on VMAT plan quality for different tumor sites was also evaluated. The resulting VMAT plan quality essentially matched the 20-field MCO-IMRT plan but with a shorter delivery time and less monitor units. VMAT plan quality of head/neck cancer cases improved using dual arcs whereas prostate cases did not. VMAT plan quality was improved by fine gantry spacing of 2 for the head/neck cancer cases and the hypofractionation-treated prostate cancer cases but not for the standard fractionation–treated prostate cancer cases. MCO-informed VMAT optimization is a useful and valuable way to generate patient-specific optimal VMAT plans, though modification of the weights of objectives or constraints extracted from resulting DVH of MCO-IMRT or both is necessary.

Prostate-Specific Membrane Antigen Protein Expression in Tumor Tissue and Risk of Lethal Prostate Cancer

Overexpression of prostate-specific membrane antigen (PSMA) in tumor tissue and serum has been linked to increased risk of biochemical recurrence in surgically treated prostate cancer patients, but none of the studies have assessed its association with disease-specific mortality. We examined whether high PSMA protein expression in prostate tumor tissue was associated with lethal disease, and with tumor biomarkers of progression, among participants of two U.S.-based cohorts (n = 902, diagnosed 1983-2004). We used Cox proportional hazards regression to calculate multivariable HRs and 95% confidence intervals (CI) of lethal prostate cancer, defined as disease-specific death or development of distant metastases (n = 95). Partial Spearman rank correlation coefficients were used to correlate PSMA with tumor biomarkers. During an average 13 years of follow-up, higher PSMA expression at prostatectomy was significantly associated with lethal prostate cancer (age-adjusted HRQuartile(Q)4vs.Q1 = 2.42; Ptrend < 0.01). This association was attenuated and nonsignificant (multivariable-adjusted HRQ4vs.Q1 = 1.01; Ptrend = 0.52) after further adjusting for Gleason score and prostate-specific antigen (PSA) at diagnosis. High PSMA expression was significantly (P < 0.05) correlated with higher Gleason score and PSA at diagnosis, increased tumor angiogenesis, lower vitamin D receptor and androgen receptor expression, and absence of ets-related gene (ERG) expression. High tumor PSMA expression was not an independent predictor of lethal prostate cancer in the current study. PSMA expression likely captures, in part, malignant features of Gleason grade and tumor angiogenesis. PSMA is not a strong candidate biomarker for predicting prostate cancer-specific mortality in surgically treated patients.

Dysarthria as the Initial Manifestation of Esophageal Adenocarcinoma

Purpose: The majority of patients with esophageal cancer typically present with dysphagia, weight loss, and/or odynophagia at the time of diagnosis. Half of all newly diagnosed cases are unresectable or have distant metastasis with involvement of the lungs, liver, and/or adrenal glands. Brain metastases from esophageal carcinoma are very rare. In the available literature, the incidence of brain metastasis has been shown to be at 0-2% in clinical studies and 0-5.1% in autopsy studies. We report a case of a 65-year-old Caucasian man presenting with a 7-day history of progressive dysarthria. He denied any other complaint and had no other physical exam findings. The patient did admit to using chewing tobacco on and off for the past 20 years. His medical history was positive for being treated for prostate cancer 4 years prior with radiation. The initial head computed tomography (CT) demonstrated a left frontal lobe mass measuring 25 mm with metastatic characteristics (Figure 1). A wide search for a primary source of the cancer was undertaken and a dilated distal esophagus just proximal to the gastroesophageal junction with wall thickening was noted on CT scan. Endoscopy demonstrated a circumferential distal esophageal ulcerated mass extending 5 cm to the proximal part of the stomach. Biopsy of the mass proved to be positive for moderately differentiated invasive adenocarcinoma which was Gastric HER-2 NEU positive. Due to the rare occurrence of brain metastasis from esophageal cancer and given the history of previously treated prostate cancer the patient underwent a brain biopsy which also confirmed metastatic adenocarcinoma. The lesion was unable to be completely resected due to worsening dysarthria during the procedure. Despite the low incidence of brain metastasis from esophageal cancer, when other more common sources are excluded, one must keep esophageal carcinoma as a possible primary lesion.Figure

The Role of 11C-Choline PET Imaging in the Early Detection of Recurrence in Surgically Treated Prostate Cancer Patients With Very Low PSA Level &lt;0.5 ng/mL

This study aims to evaluate the role of (11)C-choline PET/CT in patients with biochemical relapse after radical prostatectomy (RP) showing prostate-specific antigen (PSA) values lower than 0.5 ng/mL. We performed (11)C-choline PET/CT in 71 consecutive patients previously treated with RP showing PSA values lower than 0.5 ng/mL. (11)C-Choline PET/CT was performed following standard procedure. (11)C-Choline PET/CT-positive findings were validated by transrectal ultrasonography + biopsy, repeated (11)C-choline PET/CT, other conventional imaging modality, and histology. (11)C-Choline PET/CT was true positive in 15/71 (21.1%). (11)C-Choline uptake was observed in pelvic lymph nodes (7/71; 9.9%), in the prostatic bed (7/71; 9.9%), and in bone (1/71; 1.4%). Mean PSA, PSA doubling time (PSAdt), and PSA velocity (PSAvel) values ± SD in (11)C-choline PET/CT-positive patients was 0.37 ± 0.1 ng/mL, 3.4 ± 2.1 months, and 0.05 ± 0.1 ng/mL/yr, respectively. (11)C-Choline PET/CT was false negative in 2 patients and false positive in 1 patient. Among all variables, only PSAdt and the ongoing hormonal treatment were statistically significant in the prediction of a positive (11)C-choline PET/CT at multivariate analysis. (11)C-Choline PET/CT could be used early after biochemical failure even if PSA values are very low, preferentially in hormonal resistant patients showing fast PSA kinetics. An early detection of the site of relapse could lead to a personalized and tailored treatment.

Androgen ablation for low-risk prostate cancer is common among male hip fracture patients

Objective. This study aimed to evaluate the prevalence of androgen deprivation therapy (ADT) among male hip fracture patients with prostate cancer and to analyse their indications for ADT with regard to prostate cancer risk classification. Material and methods. Tampere University Hospital records were screened for International Classification of Diseases, 10th revision (ICD-10) diagnoses S72.0–72.2 in 1998–2008 to identify hip fractures among males. Prostate cancer and fracture characteristics and concomitant medications were recorded. Fracture patients with prior prostate cancer diagnosis were compared to control patients from the Tampere University prostate cancer database and the risk factors for fracture were analysed by binary logistic regression analysis. Results. In total, 133 patients (11.0% of hip fractures) had a prostate cancer diagnosis prior to fracture; of these, 111 (84.1%) had osteoporotic, 14 (10.6%) pathological and seven (5.3%) high-energy fractures. Furthermore, 117 (88.0%) of fracture patients had received ADT for their prostate cancer. The mean interval between castration and fracture was 5.9 years (median 4.6 years). Of the fracture patients with prostate cancer, 24.8% had been primarily castrated for a low-risk disease. In multivariate analysis, ADT was a significant risk factor for fracture among low [odds ratio (OR) 3.02, 95% confidence interval (CI) 1.14–8.01, p = 0.027], intermediate (OR 4.52, 95% CI 1.32–15.40, p = 0.016) and high-risk prostate cancer patients (OR 5.85, 95% CI 1.30–26.30, p = 0.021). Conclusions. Hormonally treated prostate cancer is a major risk factor for osteoporotic hip fracture in males. Nearly a quarter of the prostate cancer patients suffering a hip fracture had been treated by primary castration despite having low-risk prostate cancer, emphasizing the importance of patient selection and timing for ADT.

Early biomarkers related to secondary primary cancer risk in radiotherapy treated prostate cancer patients: IMRT versus IMAT

PurposeTo investigate whether rotational techniques (Volumetric Modulated Arc Therapy – VMAT) are associated with a higher risk for secondary primary malignancies compared to step-and-shoot Intensity Modulated Radiation Therapy (ss-IMRT). To this end, radiation therapy (RT) induced DNA double-strand-breaks and the resulting chromosomal damage were assessed in peripheral blood T-lymphocytes of prostate cancer (PCa) patients applying γH2AX foci and G0 micronucleus (MN) assays. Methods and materialsThe study comprised 33PCa patients. A blood sample was taken before start of therapy and after the 1st and 3rd RT fraction to determine respectively the RT-induced γH2AX foci and MN. The equivalent total body dose (DETB) was calculated based on treatment planning data. ResultsA linear dose response was obtained for γH2AX foci yields versus DETB while MN showed a linear-quadratic dose response. Patients treated with large volume (LV) VMAT show a significantly higher level of induced γH2AX foci and MN compared to IMRT and small volume (SV) VMAT (p<0.01). Assuming a linear-quadratic relationship, a satisfactory correlation was found between both endpoints (R2 0.86). ConclusionsBiomarker responses were governed by dose and irradiated volume of normal tissues. No significant differences between IMRT and rotational therapy inherent to the technique itself were observed.

Bone turnover markers in patients with prostate carcinoma: influence of sex steroids levels

There are limited data about bone turnover markers (BTM) in androgen deprivation therapy (ADT)-treated prostate cancer (PCa) patients, and the relationship between sex steroids, bone mass, and BTM has not been explored. Our objective was to analyze the influence of sex steroids levels on BTM in patients with PCa treated with or without ADT. We performed a cross-sectional study including 83 subjects with PCa (54% with ADT). BTM, bone mineral density (BMD), and sex steroids were determined. BTM were inversely related to serum level of estrogens. Tartrate-specific acid phosphatase (TRAP-5b) showed a negative correlation with free estradiol (Free E) (r = -0.274, p = 0.014) and Bio E (r = -0.256, p = 0.022) that remained after adjustment for age: Free E (β = -0.241, p = 0.03) and Bio E (β = -0.213, p = 0.063). Bone-specific alkaline phosphatase (BSAP) concentrations were inversely related to Free E (r = -0.281, p = 0.011, age-adjusted β = -0.256, p = 0.024). There was a negative correlation between osteocalcin (OC) levels and Free E (r = -0.195, p = 0.082; age-adjusted β = -0.203, p = 0.076) and Bio E (r = -0.215, p = 0.054; age-adjusted β = -0.240, p = 0.039). BTM and androgens were inversely related to TRAP-5b: total testosterone (total T) (r = -0.238, p = 0.033), Free T (r = -0.309, p = 0.05), and Bio T (r = -0.310, p = 0.05), but these correlations disappeared after age-adjustment. We did not find any relationship between BMD at different locations and sex steroids. In conclusion, in patients with PCa, estrogen levels influence bone resorption and bone formation whereas androgens may exert actions only in bone resorption. These results suggest that estradiol is the main sex steroid that regulates bone metabolism in males with prostate carcinoma.

Imaging treated prostate cancer

In patients with a clinical suspicion of recurrence after treatment for prostate cancer, imaging can be used to distinguish between local recurrence and metastatic disease. Multiparametric magnetic resonance imaging (mpMRI) of the prostate may be a valuable imaging modality for the detection and localization of local recurrence in patients treated for prostate cancer. In mpMRI, morphological T2-weighted images are combined with functional MRI techniques including diffusion-weighted imaging, dynamic contrast-enhanced imaging, and magnetic resonance spectroscopic imaging to improve accuracy. In this paper, the current status of imaging techniques used to detect and to localize tumor recurrence in patients treated for prostate cancer will be reviewed, with emphasis on mpMRI for local prostate cancer recurrence.

Comparison of 18F-FACBC and 11C-choline PET/CT in patients with radically treated prostate cancer and biochemical relapse: preliminary results

We assessed the rate of detection rate of recurrent prostate cancer by PET/CT using anti-3-(18)F-FACBC, a new synthetic amino acid, in comparison to that using (11)C-choline as part of an ongoing prospective single-centre study. Included in the study were 15 patients with biochemical relapse after initial radical treatment of prostate cancer. All the patients underwent anti-3-(18)F-FACBC PET/CT and (11)C-choline PET/CT within a 7-day period. The detection rates using the two compounds were determined and the target-to-background ratios (TBR) of each lesion are reported. No adverse reactions to anti-3-(18)F-FACBC PET/CT were noted. On a patient basis, (11)C-choline PET/CT was positive in 3 patients and negative in 12 (detection rate 20%), and anti-3-(18)F-FACBC PET/CT was positive in 6 patients and negative in 9 (detection rate 40%). On a lesion basis, (11)C-choline detected 6 lesions (4 bone, 1 lymph node, 1 local relapse), and anti-3-(18)F-FACBC detected 11 lesions (5 bone, 5 lymph node, 1 local relapse). All (11)C-choline-positive lesions were also identified by anti-3-(18)F-FACBC PET/CT. The TBR of anti-3-(18)F-FACBC was greater than that of (11)C-choline in 8/11 lesions, as were image quality and contrast. Our preliminary results indicate that anti-3-(18)F-FACBC may be superior to (11)C-choline for the identification of disease recurrence in the setting of biochemical failure. Further studies are required to assess efficacy of anti-3-(18)F-FACBC in a larger series of prostate cancer patients.

Abstract 496: Inflammatory responses with infiltrating DC and functional cytotoxic T lymphocytes in the dermal vaccination sites of GVAX/ipilimumab treated prostate cancer patients.

Abstract We have been studying the safety and clinical efficacy of the Prostate GVAX vaccine (consisting of two allogeneic GM-CSF secreting tumor cell lines: LNCaP and PC3) and the CTLA-4 blocking antibody ipilimumab in prostate cancer patients in a phase I/II dose escalation/expansion trial. To assess immune reactivity against the GVAX vaccine, immune infiltrate analysis of the vaccination sites was performed. Punch biopsies of the vaccination site were taken 48 hours after the 1st, 5th, and 11th injections and analyzed by immunohistochemical staining. Injection of the GVAX vaccine evoked striking local reactions that were characterized by local erythema, induration and swelling in all patients. Analysis of the vaccination site biopsies revealed that the GVAX/ipilimumab combination resulted in an inflammatory response in the skin with intradermal infiltrates of CD1a+ dendritic cells (DC), DC-SIGN+/CD68+ immature DC/macrophages, CD14+ monocyte-like cells, eosinophils, and of CD4+, CD8+, and Granzyme-B+ T lymphocytes. Strikingly, CD56+ NK cells were completely absent. The inflammatory response significantly increased over the course of treatment and resulted in accelerated clearance of the vaccine in vivo. Moreover, analysis revealed that the PC3 vaccine was more immunogenic, and induced a more potent anti-vaccine T cell response. The latter was confirmed in an in vitro cytotoxicity assay. Upon multiple vaccinations T cell reactivity to PC3 was significantly enhanced in the PC3 but not in the LNCaP vaccination sites, whereas reactivity to LNCaP was not enhanced in either vaccination site. We conclude that the GVAX/ipilimumab combination elicits a local immune infiltrate that increases over time, consistent with an induced CD8+ effector T cell mediated cytolytic response, only in vaccination sites of the PC3 component of the vaccine. Citation Format: Saskia J. Santegoets, Leonieke JJ van Mens, Jeroen AM Beliën, Anita GM Stam, Sinead M. Lougheed, Rik J. Scheper, Shabnam Samiei, Helen Gall, Karin Jooss, Jean-Marie Cuillerot, Natalie Sacks, Kirsten Hege, Winald R. Gerritsen, Alfons JM van den Eertwegh, Tanja D. de Gruijl. Inflammatory responses with infiltrating DC and functional cytotoxic T lymphocytes in the dermal vaccination sites of GVAX/ipilimumab treated prostate cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 496. doi:10.1158/1538-7445.AM2013-496

Impact of Implantation Technique on Biochemical Disease-free Survival in I-125 Treated Prostate Cancer Patients

Impact of Implantation Technique on Biochemical Disease-free Survival in I-125 Treated Prostate Cancer Patients

Prognostic Impact of Subclassification of Radical Prostatectomy Positive Margins by Linear Extent and Gleason Grade

We evaluated the relationship of progression to positive surgical margin linear length and Gleason grade at a positive surgical margin. We studied 2,150 prostatectomies done for pT2 or pT3a disease to determine grade, stage and surgical margin status. In patients with positive surgical margins we recorded the location, number, positive margin linear length and highest Gleason grade at a positive margin. The Kaplan-Meier method and log rank test were used to determine differences in progression-free probability among positive margin features. The concordance index was used to discriminate the accuracy of grouping surgical margin status as negative/positive vs positive margin linear length/highest Gleason grade. A total of 207 cases (10%) showed positive surgical margins, including 93 (45%) that were pT2+ and 114 (55%) that were pT3a. Patients with pT3a and positive margins had greater prostate specific antigen and tumor volume, and Gleason score 7 or greater than those with pT2+. A total of 45 patients with positive margins progressed. We then subcategorized positive margins. Of the patients 164 (79%) had 1 positive margin. Positive margin linear length was 1 mm or less, 1.1 to 3 and greater than 3 in 104 (50%), 55 (27%) and 48 cases (23%), respectively. Two-year progression-free probability was 95%, 91%, 83% and 47% in patients with negative margins and the 3 positive margin linear length groups, respectively (p <0.001). Gleason grade at a positive margin was 3 and 4/5 in 154 (74%) and 53 patients (26%), respectively. The latter group was significantly more likely to progress (p <0.001). The overall margin status concordance index was 0.636. It was not considerably enhanced by categorizing by positive surgical margin linear length/highest Gleason grade at positive margins. The linear extent of and highest Gleason grade at a positive surgical margin are associated with progression. However, subcategorization does not importantly add to predictive models using margin status only. More robust markers are needed in patients with positive surgical margins to warrant routine reporting and identify those at risk for biochemical recurrence.

Diffuse Nodular Lymphoid Hyperplasia of Intestine in Selective IgG 2 Subclass Deficiency, Autoimunne Thyroiditis, and Autoimmune Hemolytic Anemia in 60 Year Old Male

Purpose: Diffuse Nodular Lymphoid Hyperplasia (DNLH) of the intestine is a rare lymphoproliferative disorder of uncertain etiology. We present a rare case of DNLH associated with IgG2 subclass deficiency, autoimmune thyroiditis and autoimmune hemolytic anemia. A 60 year old Turkish male presented to GI clinic with watery diarrhea and crampy abdominal pain for 1 month. He had a history of treated prostate cancer. He denied any family history, alcohol, tobacco, or illicit drugs. He denied any sick contacts, or recent travel. One week prior, he was seen in the ER for similar complaints where he was anemic (hemoglobin 7.4 g/dl, mean corpuscular volume 103). CT abdomen revealed extensive lymphadenopathy. He was discharged with a one week course of ciprofloxacin and metronidazole, and scheduled for follow up in the GI clinic. At follow up iron deficiency anemia was found. Assays for vitamin B12, folate, methylmalonic acid and homocysteine were within normal range. Lactate dehydrogenase and reticulocyte count was high, haptoglobin low, and direct coomb's test positive with warm antibody. Gastrointestinal bacterial and parasitic infections were ruled out. Tissue transglumatinase antibody IgA and anti-parietal cell antibody were negative. Thyroid stimulating hormone was 12.6, with elevated thyroglobulin and thyroid peroxidase antibody. EGD and colonoscopy showed nodular mucosa in duodenal bulb and rectosigmoid respectively. Small bowel series followed by capsule endoscopy was performed. Bone marrow and abdominal lymph node biopsy was negative for malignancy. Gallium scan was negative for any metastatic disease. An increased risk (2-10%) of malignancy, mainly gastrointestinal lymphoma has been reported in patients with DNLH and hypogammaglobulinemia. These lymphoid aggregates could be an independent response to antigenic stimuli in presence of deranged immunoglobulin function. However, the relationship is unclear. Because of the risk of malignant transformation prophylactic examinations and small bowel studies are recommended by some authors. Diffuse nodular lymphoid hyperplasia in itself is a rare benign condition of unknown etiology. In symptomatic patients, workup should be directed towards underlying hypogammaglulinemia, infections and possible malignancy. Eradication of infection could lead to resolution of symptoms. Patients should undergo prophylactic surveillance endoscopy to rule out complications and to establish extent of disease. However, there are no clear cut guidelines for surveillance.