Optimal MRI sequences for 68Ga-PSMA-11 PET/MRI in evaluation of biochemically recurrent prostate cancer.

BackgroundPET/MRI can be used for the detection of disease in biochemical recurrence (BCR) patients imaged with 68Ga-PSMA-11 PET. This study was designed to determine the optimal MRI sequences to localize positive findings on 68Ga-PSMA-11 PET of patients with BCR after definitive therapy. Fifty-five consecutive prostate cancer patients with BCR imaged with 68Ga-PSMA-11 3.0T PET/MRI were retrospectively analyzed. Mean PSA was 7.9 ± 12.9 ng/ml, and mean PSA doubling time was 7.1 ± 6.6 months. Detection rates of anatomic correlates for prostate-specific membrane antigen (PSMA)-positive foci were evaluated on small field of view (FOV) T2, T1 post-contrast, and diffusion-weighted images. For prostate bed recurrences, the detection rate of dynamic contrast-enhanced (DCE) imaging for PSMA-positive foci was evaluated. Finally, the detection sensitivity for PSMA-avid foci on 3- and 8-min PET acquisitions was compared.ResultsPSMA-positive foci were detected in 89.1% (49/55) of patients evaluated. Small FOV T2 performed best for lymph nodes and detected correlates for all PSMA-avid lymph nodes. DCE imaging performed the best for suspected prostate bed recurrence, detecting correlates for 87.5% (14/16) of PSMA-positive prostate bed foci. The 8-min PET acquisition performed better than the 3-min acquisition for lymph nodes smaller than 1 cm, detecting 100% (57/57) of lymph nodes less than 1 cm, compared to 78.9% (45/57) for the 3-min acquisition.ConclusionPSMA PET/MRI performed well for the detection of sites of suspected recurrent disease in patients with BCR. Of the MRI sequences obtained for localization, small FOV T2 images detected the greatest proportion of PSMA-positive abdominopelvic lymph nodes and DCE imaging detected the greatest proportion of PSMA-positive prostate bed foci. The 8-min PET acquisition was superior to the 3 min acquisition for detection of small lymph nodes

Improving SWE Estimation with Data Assimilation: The Influence of Snow Depth Observation Timing and Uncertainty

Snow depth observations can be leveraged with data assimilation (DA) to improve estimation of snow density and snow water equivalent (SWE). A key consideration for mission and campaign design is how snow depth retrieval characteristics (including observation timing/frequency and sampling error) influence SWE accuracy and uncertainty in a DA framework. To quantify these effects, we implement a particle filter (PF) assimilation technique to assimilate depth and validate this approach against observed snow density and SWE at 49 snow telemetry sites across 9 years. We sample from continuous in-situ snow depth records to test a range of measurement timing scenarios and two sampling error scenarios representative of remote sensing capabilities. Assimilation reduces density bias by over 40% and SWE bias by over 70% across climate zones and in both wet and dry years. There is little incremental benefit to SWE accuracy when assimilating more than one depth observation near peak accumulation. SWE estimates are less sensitive to observation timing than sampling error. Alternatively, more frequent depth observations improve melt-out date timing and reduce SWE uncertainty, a key consideration when evaluating the operational utility of DA. In matching depth observations, the PF mostly acts to increase precipitation inputs to the model, while not systematically shifting other parameter values or forcings across the climate zones represented with the study sites. This demonstrates that precipitation is the largest source of model error. With DA, density errors are still nontrivial, illuminating the need for further improvements to modeled density to achieve SWE error targets.</div

Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer.

BackgroundSipuleucel-T is a US Food and Drug Administration-approved immunotherapy for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Its mechanism of action is not fully understood. This prospective trial evaluated the direct immune effects of systemically administered sipuleucel-T on prostatic cancer tissue in the preoperative setting.MethodsPatients with untreated localized prostate cancer were treated on an open-label Phase II study of sipuleucel-T prior to planned radical prostatectomy (RP). Immune infiltrates in RP specimens (posttreatment) and in paired pretreatment biopsies were evaluated by immunohistochemistry (IHC). Correlations between circulating immune response and IHC were assessed using Spearman rank order.ResultsOf the 42 enrolled patients, 37 were evaluable. Adverse events were primarily transient, mild-to-moderate and infusion related. Patients developed T cell proliferation and interferon-γ responses detectable in the blood following treatment. Furthermore, a greater-than-three-fold increase in infiltrating CD3(+), CD4(+) FOXP3(-), and CD8(+) T cells was observed in the RP tissues compared with the pretreatment biopsy (binomial proportions: all P &lt; .001). This level of T cell infiltration was observed at the tumor interface, and was not seen in a control group consisting of 12 concurrent patients who did not receive any neoadjuvant treatment prior to RP. The majority of infiltrating T cells were PD-1(+) and Ki-67(+), consistent with activated T cells. Importantly, the magnitude of the circulating immune response did not directly correlate with T cell infiltration within the prostate based upon Spearman's rank order correlation.ConclusionsThis study is the first to demonstrate a local immune effect from the administration of sipuleucel-T. Neoadjuvant sipuleucel-T elicits both a systemic antigen-specific T cell response and the recruitment of activated effector T cells into the prostate tumor microenvironment

Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist

The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the AR antagonist flutamide, and these mutant ARs were strongly stimulated by flutamide. In contrast, the single mutant AR found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs. These findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment

Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study.

BackgroundHyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.MethodsSix patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.ResultsWe observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s-1) and 0.026 ± 0.000 (s-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).ConclusionsHP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer

The ion seeps tonight: Assessing ionic transport in multilayered nanocomposites

Figure 6 – Schematic of cation (M+) transport through an organized multilayered composite. Controlling ion transport across membranes and interfaces is one of the central themes challenging technological pursuits ranging from corrosion to energy storage and chemical separations. Here, we present several examples in which we have studied the application of multilayer nanocomposites to regulate ion transport. These composites comprise organized layers of functional or structural elements, integrated within composites such that the specific nanostructure and composition of the materials play important roles in defining ionic interactions and mobility. In cases such as corrosion inhibition, thin film composite coatings are intended to block ionic transport, retarding deleterious corrosion reactions. We show that by manipulating the materials chemistry of highly organized polymer clay nanocomposite thin film barriers, it is possible to significantly increase corrosion resistance of steel samples in a simulated sea water environment. In contrast, for energy storage applications such as batteries, composite separators capable of rapid ionic diffusion are desired for high current performance. We explore how layered composite structures may provide effective ion diffusion planes, leading to promising ionic conductivity in new solid state separators. Finally, in chemical separations, the selective transport of ions becomes important. We examine how manipulating the chemical and electrostatic composition of layered polyelectrolyte materials leads to preferential cation transport through these composite structures, a key property for an effective separations membrane. These different technologies exemplify how the principles governing ion transport through multilayered materials can be adapted for widely varied applications, and they illustrate the potential for this materials development strategy to enable new classes of functional composite materials. Please click Additional Files below to see the full abstract

Impacts of an environmental disaster on psychosocial health and wellbeing in Karakalpakstan.

Abstract The people of Karakalpakstan, along with those of the entire Aral Sea region, are facing a multitude of health problems corresponding to the drying of the Aral Sea and accompanying ecological consequences. In case studies of other environmental disasters, research has shown that environmental exposures may impact not only the physiological but also the psychosocial health of individuals. This research aims to determine the contribution of the environmental disaster to the psychosocial health of people living in Karakalpakstan, a semi-autonomous Republic in Uzbekistan. An interview survey was carried out by M! edecins Sans Fronti&quot; eres, with the assistance of the McMaster Institute of Environment and Health, local Universities and local health care workers, on a random sample of 1118 individuals aged 18 years and older in three communities in Karakalpakstan in May/June 1999. The communities were chosen according to distance from the former seashore, urban/rural characteristics and ethnic composition. The survey included questions about perceived general health, the General Health Questionnaire, the somatic symptom checklist of the Symptom Check List-90, questions about perceptions of the environmental disaster, social support as well as sociodemographic and socio-economic characteristics. Findings show that 41% of all respondents reported environmental concern while 48% reported levels of somatic symptoms (SCL-90) associated with emotional distress, above the normalized cut-point. Significant differences in levels of emotional distress were reported between men and women as well as between ethnic groups. Environmental problems are commonly perceived to be the cause of somatic symptoms and are significantly related to self-rated health status.

The effect of prior androgen synthesis inhibition on outcomes of subsequent therapy with docetaxel in patients with metastatic castrate-resistant prostate cancer: results from a retrospective analysis of a randomized phase 3 clinical trial (CALGB 90401) (Alliance).

BACKGROUND: Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel. METHODS: In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm. RESULTS: Baseline characteristics between patients who did (N=277) and did not (N=728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P=.635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P=.342), the proportion achieving a decline ≥ 50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P=.129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P=.366). CONCLUSIONS: As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC

Induction of \u3cem\u3eIL19\u3c/em\u3e Expression through JNK and cGAS-STING Modulates DNA Damage–Induced Cytokine Production

Cytokine production is a critical component of cell-extrinsic responses to DNA damage and cellular senescence. Here, we demonstrated that expression of the gene encoding interleukin-19 (IL-19) was enhanced by DNA damage through pathways mediated by c-Jun amino-terminal kinase (JNK) and cGAS-STING and that IL19 expression was required for the subsequent production of the cytokines IL-1, IL-6, and IL-8. IL19 expression was stimulated by diverse cellular stresses, including inhibition of the DNA replication checkpoint kinase ATR (ataxia telangiectasia and Rad3-related protein), oncogene expression, replicative exhaustion, oxidative stress, and DNA double-strand breaks. Unlike the production of IL-6 and IL-8, IL19 expression was not affected by abrogation of signaling by the IL-1 receptor (IL-1R) or the mitogen-activated protein kinase p38. Instead, the DNA damage–induced production of IL-1, IL-6, and IL-8 was substantially reduced by suppression of IL19 expression. The signaling pathways required to stimulate IL19 expression selectively depended on the type of DNA-damaging agent. Reactive oxygen species and the ASK1-JNK pathway were critical for responses to ionizing radiation (IR), whereas the cGAS-STING pathway stimulated IL19 expression in response to either IR or ATR inhibition. Whereas induction of IL1, IL6, and IL8 by IR depended on IL19 expression, the cGAS-STING–dependent induction of the immune checkpoint gene PDL1 after IR and ATR inhibition was independent of IL19. Together, these results suggest that IL-19 production by diverse pathways forms a distinct cytokine regulatory arm of the response to DNA damage