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Details are provided on 17 previously unreported catches of blue whales, and 93 catches of North Pacific right whales, all taken illegally by the former USSR. The blue whale catches were made between mid-July and mid-September 1972 in the eastern North Pacific at distances of from 96 to 626 nautical miles from the US west coast (Oregon and Washington); they highlight the inadequacy of the International Observer Scheme, as implemented in 1972, to report or detect illegal whaling. These previously unknown blue whale catches bring the Soviet total to 1,638 for the period 1948–1972. The 93 right whale catches were made during the period 1951–62 around the Kuril Islands, which brings the known total of takes of this species from 1935–1971 to 775 (including 10 taken for scientific research and officially reported at the time).

AIMS: To evaluate the clinical significance of bronchiolocentric fibrosis in patients with a histopathologic pattern of usual interstitial pneumonia. METHODS AND RESULTS: Two hundred fifty-two patients with pathological usual interstitial pneumonia pattern were identified. Two hundred fifteen of these patients (215/252) had the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Prospectively defined clinical, radiologic and pathological features (including bronchiolocentric fibrosis) were recorded, and peripheral blood MUC5B genotype and telomere length were measured. Bronchiolocentric fibrosis was observed in 38% (96/252) of all patients and 33% (72/215) of idiopathic pulmonary fibrosis patients; its presence was associated with a non-IPF diagnosis on multivariate analysis (odds ratio 3.71, [95% confidence interval 1.68–8.19]). Bronchiolocentric fibrosis was not significantly associated with environmental exposures, gastroesophageal reflux, cigarette smoking, or radiologic patterns. There was no significant association of bronchiolocentric fibrosis with MUC5B genotype or telomere length. Bronchiolocentric fibrosis has no significant impact on survival time. CONCLUSIONS: Most patients with bronchiolocentric fibrosis and a histopathologic pattern of usual interstitial pneumonia have idiopathic pulmonary fibrosis. However, this combined fibrotic pattern is associated with a non-idiopathic pulmonary fibrosis multidisciplinary diagnosis with approximately one-quarter of these patients being diagnosed as chronic hypersensitivity pneumonia or unclassifiable interstitial fibrosis. The presence of bronchiolocentric fibrosis in these patients is not significantly associated with presumed clinical risk factors for bronchiolocentric involvement, radiologic findings, MUC5B genotype, telomere length, or survival time.

Author(s): Lee, Joyce S; La, Janet; Aziz, Sara; Dobrinskikh, Evgenia; Brownell, Robert; Jones, Kirk D; Achtar-Zadeh, Natalia; Green, Gary; Elicker, Brett M; Golden, Jeffrey A; Matthay, Michael A; Kukreja, Jasleen; Schwartz, David A; Wolters, Paul J | Abstract: AimsIdiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.Methods and resultsTo test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.ConclusionsMolecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

The AOAC Research Institute Performance Tested MethodsSM Program certified Sample6 DETECT/L™ in April 2014 (Certification No. 041401) for the detection of Listeria species (L. monocytogenes, L. innocua, L. ivanovii, L. seeligeri, L. marthii, L. welshimeri) on stainless steel environmental surfaces. A modification was approved in January 2016, increasing the concentration of sanitizer-neutralizing reagents in detection reagents, increasing the number of phage in the detection solution, and increasing the sample test volume. Moreover, changes to reduce the number of negative controls and add compatibility with polyurethane sponges were also approved. In this modification, to ensure that DETECT/L continues to meet performance expectations, Sample6 evaluated workflow changes to enhance sensitivity and the ease-of-use of the assay. Changes to the phage concentration and detection threshold, plus the inclusion of a confirmation step (DETECT Check), were validated to obtain better accuracy and optimize assay performance. Inclusivity, exclusivity, and robustness testing were conducted by Sample6 to evaluate the changes. A third-party laboratory compared the DETECT/L assay and the U.S. Department of Agriculture reference method in a stainless steel environmental surface matrix study. The data presented in this report demonstrate that the changes proposed to the DETECT/L assay meet or exceed the performance in the current configuration.

Background: Listeria spp. are an important foodborne human pathogen because of their ability to cause disease and high mortality in individuals, particularly pregnant women, neonates, the elderly, immunocompromised individuals, and children. The Sample6 DETECTTM HT/L Kit is a semi-automated qualitative pathogen detection system designed to detect Listeria spp. (L. monocytogenes, L. innocua, L. ivanovii, L. seeligeri, L. welshimeri, and L. marthii) in environmental samples using the Sample6 BioIlluminationTM technology. Objective: The study was done to evaluate the Sample6 DETECT HT/L Kit. The assay was evaluated for inclusivity, exclusivity, robustness, product consistency, and stability, and a matrix study of one environmental surface. Methods: The performance of the Sample6 DETECT HT/L was compared with U.S. Food and Drug Administration reference culture method for Listeria using an unpaired study design. Results: The Sample6 DETECT HT/L assay correctly identified all 50 inclusivity isolates and correctly excluded all 30 nontarget strains evaluated. The assay was not affected by minor variations in incubation temperature and time, or sample volume. Results across three production lots spanning the shelf life of the assay were consistent. In the matrix study, the Sample6 DETECT HT/L for Listeria correctly identified each test portion for the presence or absence of Listeria, and there were no statistically significant differences between candidate and reference method results. Conclusions: The data collected in this study demonstrate that the Sample6 DETECT HT/L assay is a reliable method for the detection of Listeria spp. on stainless-steel environmental surfaces after 22 h of enrichment.

TPS7571 Background: The majority of patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who relapse after HSCT, or who are not candidates for HSCT have poor outcomes and are in need of novel therapies. Brentuximab vedotin (BV) is a CD30-directed ADC and preclinical data provide a strong rationale for combining BV, lenalidomide, and rituximab in the treatment of R/R DLBCL. In addition, in a phase 1 trial in which 37 pts with R/R DLBCL were treated with BV + lenalidomide, the ORR was 56.7% (73.3% in CD30+ pts; manuscript in preparation). The median duration of remission was 13.2 months in pts with a CR or PR and 11.7 months in pts with CR, PR, or stable disease > 6 months. The PFS and median OS were 11.2 months and 14.3 months, respectively and results were similar in the CD30+ and CD30 < 1% groups. The clinical activity and manageable safety profiles of BV, lenalidomide, and rituximab as single agents, make the combination a viable option in multiply relapsed and heavily pretreated pts. Methods: This is a randomized, double-blind, placebo-controlled, active-comparator, multicenter phase 3 study designed to evaluate the efficacy of BV vs placebo, in combination with lenalidomide + rituximab, in subjects with R/R DLBCL (NCT04404283). Prior to randomization, there will be a safety and PK run-in period where 6 pts will receive BV, lenalidomide + rituximab, and safety and PK will be evaluated after the first cycle of treatment; 6/6 subjects have been enrolled. Key eligibility criteria include: pts aged ≥18 with R/R DLBCL with an eligible subtype; ≥2 prior lines of therapy and must be ineligible for, or have declined, stem cell transplant, and chimeric antigen receptor T-cell (CAR-T) therapy; ECOG 0 to 2; fluorodeoxyglucose-avid disease by PET and bidimensional measurable disease of at least 1.5 cm by CT. Patients (n = 400) will be randomized 1:1 to receive either BV or placebo in combination with lenalidomide + rituximab and will be stratified by CD30 expression (positive [ ≥1%] versus < 1%), prior allogeneic or autologous stem cell transplant therapy (received or not), prior CAR-T therapy (received or not), and cell of origin (GCB or non-GCB). The primary endpoints are PFS per BICR in the ITT and CD30+ populations. Key secondary endpoints are OS in the ITT and CD30+ populations, and ORR per BICR. Other secondary endpoints include CR rate, duration of response, and safety and tolerability of the combination. Disease response will be assessed by BICR and the investigator according to the Lugano Classification Revised Staging System. Radiographic disease evaluations, including contrast-enhanced CT scans and PET, will be assessed at baseline, then every 6 weeks from randomization until Week 48, then every 12 weeks. PET is not required after CR is achieved. The trial is currently enrolling and will be open in 16 countries. Clinical trial information: NCT04404283.

Bacteriophages have been used for diagnostic purposes in the past, but a lack of parallelizable engineering methods had limited their applicability to a narrow subset of diagnostic settings. More recently, however, advances in DNA sequencing and the introduction of more sensitive reporter systems have enabled novel engineering methods, which in turn have broadened the scope of modern phage diagnostics. Here we describe advanced methods to engineer the genomes of bacteriophages in a modular and rapid fashion.

Background: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive form of pulmonary fibrosis characterized pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (Non-IPF UIP) whose clinical course is similarly poor, suggesting common molecular drivers. Methods: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissue from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Results: Histopathologic changes in IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, noncaseating granulomas, airway centered inflammation or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs compared to age-similar, unused donor, controls. Telomere shortening was isolated to AECII cells when comparing telomere lengths between AECII and adjacent cells in individual patients. Molecular markers of senescence (p16, p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localized expression of these proteins to AECII cells. Conclusions: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the underlying clinical context.

Background Recent studies have suggested that non-definitive patterns on high-resolution CT (HRCT) scan provide sufficient diagnostic specificity to forgo surgical lung biopsy in the diagnosis of idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine test characteristics of non-definitive HRCT patterns for identifying histopathological usual interstitial pneumonia (UIP). Methods Patients with biopsy-proven interstitial lung disease (ILD) and non-definitive HRCT scans were identified from two academic ILD centres. Test characteristics for HRCT patterns as predictors of UIP on surgical lung biopsy were derived and validated in independent cohorts. Results In the derivation cohort, 64/385 (17%) had possible UIP pattern on HRCT; 321/385 (83%) had inconsistent with UIP pattern. 113/385 (29%) patients had histopathological UIP pattern in the derivation cohort. Possible UIP pattern had a specificity of 91.2% (95% CI 87.2% to 94.3%) and a positive predictive value (PPV) of 62.5% (95% CI 49.5% to 74.3%) for UIP pattern on surgical lung biopsy. The addition of age, sex and total traction bronchiectasis score improved the PPV. Inconsistent with UIP pattern demonstrated poor PPV (22.7%, 95% CI 18.3% to 27.7%). HRCT pattern specificity was nearly identical in the validation cohort (92.7%, 95% CI 82.4% to 98.0%). The substantially higher prevalence of UIP pattern in the validation cohort improved the PPV of HRCT patterns. Conclusions A possible UIP pattern on HRCT has high specificity for UIP on surgical lung biopsy, but PPV is highly dependent on underlying prevalence. Adding clinical and radiographic features to possible UIP pattern on HRCT may provide sufficient probability of histopathological UIP across prevalence ranges to change clinical decision-making.

Precision medicine is defined by the National Institute of Health's Precision Medicine Initiative Working Group as an approach to disease treatment that takes into account individual variability in genes, environment, and lifestyle. There has been increased interest in applying the concept of precision medicine to idiopathic pulmonary fibrosis, in particular to search for genetic and molecular biomarker-based profiles (so called endotypes) that identify mechanistically distinct disease subgroups. The relevance of precision medicine to idiopathic pulmonary fibrosis is yet to be established, but we believe that it holds great promise to provide targeted and highly effective therapies to patients. In this manuscript, we describe the field's nascent efforts in genetic/molecular endotype identification and how environmental and behavioral subgroups may also be relevant to disease management.

Objectives The interpretation of radiographic findings in renal tumors treated with minimally invasive modalities, such as radiofrequency ablation (RFA), is critical for assessing treatment adequacy. Magnetic resonance imaging (MRI) is commonly used for patients with renal insufficiency or contrast allergy. Because the MRI experience with renal RFA is limited, we reviewed our experience and report the unique MRI characteristics of RFA-treated renal tumors. Methods A single-institution database of renal RFA was reviewed to identify patients followed up with MRI. A radiologist and urologist retrospectively reviewed all MRI scans to identify the characteristic lesion findings after RFA. Results Eleven patients (12 tumors) treated by RFA were followed up with MRI examinations. The mean follow-up was 10 months. The mean tumor size at ablation was 2.4 cm, with minimal reduction over time. Ablated lesions were characterized by high signal intensity on T 1 -weighted images, low signal intensity on T 2 -weighted images, and an absence of contrast enhancement. Of the patients treated by percutaneous RFA, 71% developed a characteristic peritumor halo, seen as a rim of low signal intensity on T 1 -weighted and T 2 -weighted images, surrounding a zone of perinephric fat just external to the ablated area. Two lesions demonstrated enhancement on the initial postablation MRI scan, indicating incomplete ablation. Conclusions The MRI characteristics of successfully ablated renal tumors include the absence of enhancement, minimal size reduction over time, and high and low signal intensity on T 1 -weighted and T 2 -weighted imaging, respectively. Knowledge of these findings can aid radiologists and urologists in correctly assessing the success of RFA for kidney lesions.

Background: Respiratory isolation of inpatients during evaluation for TB is a slow and costly process in low-burden settings. Xpert MTB/RIF (Xpert) is a novel molecular test for tuberculosis (TB) that is faster and more sensitive but substantially more expensive than smear microscopy. No previous studies have examined the costs of molecular testing as a replacement for smear microscopy in this setting. Methods: We conducted an incremental cost–benefit analysis comparing the use of a single negative Xpert versus two negative sputum smears to release consecutive adult inpatients with presumed TB from respiratory isolation at an urban public hospital in the United States. We estimated all health-system costs and patient outcomes related to Xpert implementation, diagnostic evaluation, isolation, hospitalization, and treatment. We performed sensitivity and probabilistic uncertainty analyses to determine at what threshold the Xpert strategy would become cost-saving. Results: Among a hypothetical cohort of 234 individuals undergoing evaluation for presumed active TB annually, 6.4% had culture-positive TB. Compared to smear microscopy, Xpert reduced isolation bed utilization from an average of 2.7 to 1.4 days per patient, leading to a 48% reduction in total annual isolation bed usage from 632 to 328 bed-days. Xpert saved an average of $2,278 (95% uncertainty range $1582–4570) per admission, or $533,520 per year, compared with smear microscopy. Conclusions: Molecular testing for TB could provide substantial savings to hospitals in high-income countries by reducing respiratory isolation usage and overall length of stay.

296^ Background: DN24-02 is an investigational autologous cellular immunotherapy (ACI) consisting of antigen presenting cells (APCs) cultured with BA7072, a recombinant HER2-derived antigen (HER500) linked to granulocyte-macrophage colony-stimulating factor. In the ongoing NeuACT (N10-1; NCT01353222) trial, patients (pts) with high-risk, HER2+ urothelial cancer (UC) are randomized 1:1 to either adjuvant DN24-02 or surveillance. Updated analyses are presented. Methods: Eligibility criteria include radical surgical resection of primary ≥pT2 or pN+ UC (bladder or upper tract) with HER2 expression ≥1+ by immunohistochemistry. Pts randomized to DN24-02 undergo 3 cycles of leukapheresis and infusion at 2-week intervals. Product potency is assessed at each infusion. Immune responses and adverse events (AEs) are measured at multiple time points. Results: By July 2013, tumor specimens from 226 pts had been screened. Of these, 75% (95% CI 69–81%) had HER2 expression of ≥1+ in the primary tumor, 32% had ≥2+ and 8% had 3+. In pts with available lymph node samples (n=83), 84% (95% CI 75–91%) had a HER2 score of ≥1+ in the lymph nodes; 49% and 14% had ≥2+ and 3+, respectively. Pts with 1+ HER2 expression had similar immune responses to BA7072 as those with higher HER2 levels. APC activation (CD54 upregulation) was observed at each infusion in the first 30 pts who had completed the 3 infusions, but was typically greater at infusions 2 (median 15.56; range: 6.42–23.97) and 3 (14.69; 8.24–30.86) than infusion 1 (7.35; 4.04–14.34). In the 5 pts with available data, BA7072 and HER500 specific antibody responses increased from baseline for at least 12 months. Most (92.3%) AEs were grade 1–2 in severity, including all AEs that occurred ≤1 day after infusion. Conclusions: The high frequencies (≥75%) of ≥1+ HER2 scores in primary tumor and lymph node samples confirm that HER2 expression is common in muscle-invasive and node+ UC. DN24-02 product potency data suggest an immunologic prime-boost effect. The observed humoral responses are the first data suggesting prolonged immune responses with an ACI in UC. Most AEs were grade 1–2 in severity. Clinical trial information: NCT01353222.

148 Background: Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T prepared using 10μg/mL PA2024 (PAP-GM-CSF antigen) stimulates immune responses and prolongs overall survival (OS). ProACT is an ongoing phase 2 study to evaluate immune responses and OS of sipuleucel-T when manufactured using 3 different concentrations of PA2024. Here we report data from the FDA-approved concentration, 10μg/mL PA2024 (n=40). Methods: Pts with asymptomatic or minimally symptomatic mCRPC (n=120) received sipuleucel-T manufactured using 2, 5 or 10μg/mL PA2024 for a total of 3 infusions with 2-wk intervals. Peripheral immune responses were evaluated 2, 4 and 6 mo after 1st infusion by serum ELISA (n=40), and B cell activation phenotype was characterized during the manufacture of the product by flow cytometry (n=19). Results: During product manufacture both mature and memory B cells were activated; the percentage of B cells that had a mature phenotype (defined as CD20+ IgD+ CD27+ CD86+) was increased only after culture of each successive treatment. Activated memory B cells (defined as CD20+ IgD- CD27+ CD86+) were also increased after culture of each successive treatment and in pre-culture cells at the 3rd treatment. At mo 2, median serum anti-PA2024 and anti-PAP titers (IgG and IgM combined) were 128 and 32-fold higher vs baseline respectively, compared to median serum anti-GM-CSF titers, which were 16-fold higher vs baseline. Median serum anti-PA2024 titers (IgG and IgM combined) were significantly higher than those for anti-GM-CSF (p12,800) were 79% and 47% of pts, respectively. Anti-tetanus titers were predominantly IgG and did not differ between timepoints. Conclusions: These data indicate that sipuleucel-T induces an activated memory phenotype, evident after each culture in vivo after the first two treatments. Sipuleucel-T also appears to generate robust, long lasting anti-PA2024 and anti-PAP responses. Analyses comparing the 3 dosing cohorts will be reported in future publications. Clinical trial information: NCT00715078.

292 Background: HER2 overexpression has been suggested as a poor prognostic factor in pts with high-risk urothelial carcinoma (UC). Published data note a wide range of HER2 overexpression in UC, with some reports showing 50% of cases with ≥2+ HER2 expression by immunohistochemistry (IHC). NeuACT (N10-1; NCT01353222) is a phase 2 trial to determine whether DN24-02, an autologous cellular immunotherapy targeting HER2 based on the same platform used for sipuleucel-T, given as adjuvant therapy following surgical resection can prolong survival (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples from this study. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ≥pT2 or pN+ staging, and HER2 expression ≥1+ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest scoring system. Results: As of August 2012, tumor specimens from 61 pts have been screened for HER2 expression. Of these pts, 49 (80%; 95% CI: 68–89%) had a HER2 expression score of ≥1+ in the primary tumor, with 27 (44%) having ≥2+ score and 3 (5%) having a 3+ score. Twenty-three pts (38%) also had HER2 expression levels evaluated in tumor from involved lymph nodes. A total of 20 (87%; 95% CI: 66–97%) of these pts had a HER2 expression score of ≥1+ in the lymph nodes, with 12 (52%) having a ≥2+ score and 3 (15%) having a 3+ score. Two pts had primary tumor samples that expressed HER2 but were negative for HER2 expression in the lymph nodes submitted for analysis. Conclusions: Although preliminary, a high frequency (≥80%) of HER2 expression score of ≥1+ in primary tumor and lymph node samples was observed. These data highlight the prevalence of HER2 protein expression in high-risk UC. Furthermore, the HER2 expression data are consistent with previously published data in pts with invasive UC. Clinical trial information: NCT01353222.

181 Background: Sipuleucel-T is an FDA-approved autologous cellular therapy that has been demonstrated to prolong overall survival in patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To better understand the immunologic effects of sipuleucel-T, an open-label Phase 2 study (P07‐1; NCT00715104 ) of sipuleucel-T prior to radical prostatectomy (RP) was undertaken in patients with localized prostate cancer. Methods: Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6–7 weeks prior to RP. Prostate biopsies (pre-treatment) and tissue from RP (post-treatment) were assessed for the presence of lymphocytes by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP infusions of sipuleucel-T. To date, tissue IHC analysis has been completed in 19 patients. Treatment-related AEs were manageable and reversible. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (>10% of patients) were fatigue, headache, and myalgia. Significant increases (>2‐fold) in CD3+ and CD4+ T cells populations were observed at the tumor rim (where benign and malignant glands interface), compared with the pre-treatment biopsy (ANOVA post hoc Newman-Keuls test: p=0.0002, 0.0002, respectively). CD8+ T cells or CD56+ cells were not significantly increased at the tumor rim compared with benign biopsy regions. Conclusions: Neoadjuvant sipuleucel-T treatment appears to result in an increased frequency of T cells in prostate cancer tissue at the rim between the benign and malignant glands. These data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response within the prostate tumor tissue and in the peripheral blood.