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The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross- resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an. In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC.

Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC. Update on options for treatment of metastatic castration-resistant prostate cancer. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28, per year.

Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen PSA testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer CRPC, the median survival is about 1—2 years, with improvements in survival seen mostly with docetaxel-based regimens.

The purpose of this article is to review the recent developments in the treatment of advanced CRPC. Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance , circulating tumor cells. Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands. Wissing, M. We report the results of. Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant hormone refractory prostate cancer.

Sipuleucel T improves overall survival and provides an additional treatment option for this patient population. Prostate cancer is one of the most common cancers in men in US and European countries. In patients with castration-resistant prostate cancer CRPC , the median survival is about years, with improvements in survival seen mostly with docetaxel-based regimens.

Whilst the novel biomarkers, 'circulating tumor cells', have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity DTH tests.

Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS. Immune responses were detected in approximately half of the patients investigated Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer. This approach has not been adequately tested. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations.

Unlike in clinical trials, in practice, clinicians may rely on PSA As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures.

Full Text Available Abstract Men with metastatic castration-resistant prostate cancer mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials.

Significant progress in the discovery of novel therapeutic agents has been made in the past few years. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Cabazitaxel significantly improves overall survival OS versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer.

To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel CA as second-line or third-line therapy in the everyday clinical setting. Common Terminology Criteria for Adverse Events were used to register grade nonhematological toxicity during treatment with CA.

Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen PSA percentage A median of 6 versus 5 treatment cycles was administered in patients treated Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date. Advances in therapies have led to the approval of six therapeutic agents since , each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer CRPC.

More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor AR , nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements.

Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer. Prior to , docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer mCRPC.

Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy cabazitaxel , androgen suppressive agents abiraterone acetate and enzalutamide , a cellular vaccine sipuleucel-T and radium for symptomatic bone metastases.

With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium.

Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation. Full Text Available Prostate cancer PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world.

Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. The interaction of androgen receptor and alternative phosphoinositidekinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

We developed a conceptual model to define key concepts associated with patients' experiences with the signs, symptoms, and impacts of non- metastatic castration-resistant prostate cancer M0-CRPC. A targeted review of peer-reviewed literature, and other publicly available information, identified and categorized symptoms and impacts related to early-stage prostate cancer.

Semi-structured interviews with five clinical experts helped determine the most relevant and important concepts for patients with M0-CRPC. The findings from these three lines of evidence were summarized in a conceptual model. Literature searches identified mainly urinary, intestinal, and sexual symptoms. Patient interviews confirmed the high frequency of erectile dysfunction, loss of libido, urinary urgency, and incontinence. Symptoms and impacts most frequently experienced by patients were typically not those with the greatest effects on their lives; rather, those with the greatest consequences were related to treatment.

The most relevant symptoms and impacts expressed by patients may be a consequence of therapy rather than of the disease. Androgen receptor variant-driven prostate cancer : clinical implications Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer mCRPC. The primary end point was overall survival OS. Bone scan response BSR at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival rPFS and effects on circulating tumor cells CTCs , bone biomarkers, serum prostate-specific antigen PSA , and symptomatic skeletal events SSEs were exploratory assessments.

Median OS was Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies.

Comparators included abiraterone acetate, sipuleucel-T, radium Ra dichloride, and docetaxel. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies.

Market shares were estimated for each comparator before and after adoption of enzalutamide. One-way sensitivity analyses were performed. Results were most sensitive to. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel- resistant cancers.

We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progre Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment.

Fischer's exact test A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer. Abiraterone acetate AA is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP enzyme system, which Treatment consisted of 1,mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate With the approval of several new treatments for metastatic castration-resistant prostate cancer mCRPC , budgetary impact is a concern for health plan decision makers.

Budget impact models BIMs are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.

A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium, with utilization rates derived from market research data.

Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment.

In the second scenario, all treatment costs were assumed to be paid by the plan. In a hypothetical 1 million-member health plan population, patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases.

Beer, T. Enzalutamide significantly improved radiographic progression-free survival rPFS and overall survival OS among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study.

We evaluated the. Rescigno, P. A decline in prostate-specific antigen PSA is widely used to monitor treatment response, but is not validated as an. Clinical activity and tolerability of enzalutamide MDV in patients with metastatic , castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Badrising, S.

Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.

All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen PSA progression were in favor of the enzalutamide arm. Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer. Hedgehog Hh pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state.

We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer mCRPC would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. This is a single-arm study of oral daily vismodegib in men with mCRPC. Ten patients were planned for enrollment. Nine patients were enrolled.

The median number of treatment cycles completed was three, with a median PFS of 1. No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity.

Vismodegib will not be developed further as monotherapy in mCRPC. Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions.

Patients were divided into 3 groups with low N numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of metastatic lesions mean 74, range 2— were identified. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases.

Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space. Full Text Available Abstract Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration , most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation.

This has been termed metastatic castrate-resistant prostate cancer mCRPC. Despite this designation, however, there is evidence that androgen receptor AR-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands.

The therapeutic options were limited and palliative in nature until trials in demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC.

After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel with prednisone, or treatment with the antiandrogen abiraterone with prednisone could improve survival for patients with mCRPC following docetaxel therapy.

Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space. Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations. To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer mCRPC.

Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for generic docetaxel introduction, while other costs were adjusted to values using the national average annual unit cost increase.

This study identified Medicare-insured and commercially insured men, with and docetaxel episodes, respectively. The average number of cycles unique docetaxel infusion days per episode was 6. The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium, and taxane chemotherapy.

The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate. Practical recommendations for radium treatment of metastatic castration-resistant prostate cancer.

Radium Ra dichloride radium, Xofigo registered is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium service provision.

An independent research consultancy agency observed radium procedures and conducted interviews with all key staff members involved in radium treatment delivery in 11 nuclear medicine centres across six countries Germany, Italy, the Netherlands, Spain, Switzerland and the UK experienced in administering radium The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined.

Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium service provision and improve patient care.

The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. A total of cycles were performed in 71 patients. Data for response and adverse events were available for all patients. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy.

Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy.

Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Median progression-free survival in this cohort was 8. Baseline clinical characteristics of the two groups were similar.

Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels.

The mean age of patients was The mean VASmax score decreased from 7. The mean analgesic score decreased from 2. The mean KPS score improved from The mean ECOG performance status improved from 2. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. Impact of body composition parameters on clinical outcomes in patients with metastatic castrate-resistant prostate cancer treated with docetaxel.

Body composition may influence clinical outcomes of certain chemotherapeutic agents. We examined the prognostic significance of skeletal muscle mass and adipose tissue on docetaxel toxicity and overall survival in patients with metastatic castrate resistant prostate cancer mCRPC. A retrospective review of patients medical records with mCRPC, treated with docetaxel was conducted.

Body composition parameters skeletal muscle mass, muscle attenuation [MA], visceral and subcutaneous adipose tissue were measured at L3 by computed tomography CT and defined using previously established cut points. Toxicity profile was assessed after 3 cycles of the drug and graded according to the National Cancer Institute Common Toxicity Criteria version 4.

Overall survival was analysed. Overall 63 patients, mean age 69 years SD 8. Common toxicities all grades observed included fatigue DLT occurred in 22 Measurements of adiposity were not predictive of DLT, however Skeletal muscle index and MA were significantly lower in patients who experienced neutropenia grade I-II Neither sarcopenia nor sarcopenic obesity was associated with overall survival.

We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety.

According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. Published by Elsevier B. All rights reserved. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men.

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: development of a prognostic model through a crowdsourced challenge with open clinical trial data. Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies.

In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM Dialogue for Reverse Engineering Assessments and Methods challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease.

Datasets consisting of more than clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Methods were evaluated using the integrated time-dependent area under the curve iAUC. The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance.

Further validation was done using data from a. Full Text Available In contrast to bone scan and computed tomography CT, which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging WB-MRI may be able to directly detect viable tumors. A year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital.

Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores.

In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer.

Phenotypic and genetic heterogeneity of tumor tissue and circulating tumor cells in patients with metastatic castration-resistant prostate cancer: A report from the PETRUS prospective study. Molecular characterization of cancer samples is hampered by tumor tissue availability in metastatic castration-resistant prostate cancer mCRPC patients. Molecular screening of metastatic biopsies is achievable in a multicenter context.

Close attention must be paid to CTC characterization since neither approach tested here fully reflects the tremendous phenotypic and genetic heterogeneity present in CTCs from mCRPC patients. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer SYNERGY trial : a phase 3, multicentre, open-label, randomised trial.

Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer.

Patients were randomly assigned centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression.

Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen mg intravenously after three loading doses of mg. The primary endpoint was overall survival analysed in the intention-to-treat population.

Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials. The trial is completed and final analyses are reported here. Between Dec 10, , and Nov 7, , patients were enrolled to the trial, of whom were assigned docetaxel, prednisone, and custirsen and were allocated docetaxel and prednisone. Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival OS.

PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled chemotherapy-naive men with metastatic castration-resistant prostate cancer from September through September The data were analyzed in November Patients were randomized to enzalutamide mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment.

Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events SA3 , clinical progression SA4 , a confirmatory scan for soft-tissue disease progression SA5 , and all deaths regardless of time after study drug discontinuation SA6.

In the men mean age, Circulating tumor cells CTCs expressing AR-V7 protein localized to the nucleus nuclear-specific identify metastatic castration-resistant prostate cancer mCRPC patients with improved overall survival OS on taxane therapy relative to the androgen receptor signaling inhibitors ARSi abiraterone acetate, enzalutamide, and apalutamide. To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization "nuclear-agnostic" identifies more patients who would benefit from a taxane over an ARSi.

The study used a cross-sectional cohort. Between December and March , pretherapy blood samples, of which were evaluable, were collected and processed from unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane hazard ratio 0.

This interaction was not significant when nuclear-agnostic criteria were used. To reliably inform treatment selection. Enzalutamide was well tolerated in patients with or without visceral disease. Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy.

Spinal cord compression had the largest impact on HRQoL. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival rPFS and overall survival OS only.

All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. In patients with liver metastases, enzalutamide was associated with an improvement in rPFS hazard ratio [HR], 0. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

Enzalutamide was well tolerated in patients with visceral disease. Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment.

Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer. All patients received continuous daily oral abiraterone acetate 1, mg plus prednisone 10 mg starting on cycle 1, day 1. Ratios of geometric means for maximum plasma concentration C max The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone.

Ratios of geometric means [C max ; The safety profile of abiraterone acetate was consistent with reported toxicities. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone. A genetic variant in SLC28A3, rs, is associated with progression to castration-resistant prostate cancer in a Korean population with metastatic prostate cancer.

Genetic variation which related with progression to castration-resistant prostate cancer CRPC during androgen-deprivation therapy ADT has not been elucidated in patients with metastatic prostate cancer mPCa. The top five polymorphisms were statistically significantly associated with metastatic disease.

We assessed genetic variation among patients with PCa with or without metastasis, using , single nucleotide polymorphisms SNPs on the custom HumanExome BeadChip v1. Genetic data were analyzed using unconditional logistic regression and odds ratios calculated as estimates of relative risk of metastasis. Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer.

Retrospective analyses suggest some cross- resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer mCRPC who progressed following abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required.

The primary endpoint was radiographic progression-free survival. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Median radiographic progression-free survival was 8. Median time-to-PSA progression was 5. No seizures were reported. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy.

Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting. Men treated with enzalutamide had improved OS hazard ratio, 0. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development.

However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer ; Cancer published by Wiley Periodicals, Inc. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy CA : a multicentre, randomised, double-blind, phase 3 trial.

Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a ratio to receive bone-directed radiotherapy 8 Gy in one Patients were randomly Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer.

We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic , castration -sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients to receive either androgen-deprivation therapy plus abiraterone acetate mg daily, given once daily as four mg tablets plus prednisone 5 mg daily the abiraterone group or androgen-deprivation therapy plus dual placebos the placebo group.

The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of Full Text Available The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio NLR and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial.

Coprimary end points were centrally assessed radiographic progression-free survival rPFS and overall survival OS. A PSA response was observed in At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients geometric mean ratio, 1. Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer CRPC. The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature.

No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation pharmaceutical or surgical indefinitely. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk.

Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens eg, bicalutamide, flutamide, nilutamide may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or.

An analysis of leukapheresis and central venous catheter use in the randomized, placebo controlled, phase 3 IMPACT trial of Sipuleucel-T for metastatic castrate resistant prostate cancer. Sipuleucel-T is an autologous cellular immunotherapy. A total of patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were enrolled in the study.

All patients were scheduled to undergo 3 standard 1. Leukapheresis related adverse events and those related to venous catheter use were reviewed. Immune cell counts were examined throughout the treatment course. Of enrolled patients underwent 1 or more leukapheresis procedures and were included in this analysis.

Adverse events were comparable between the sipuleucel-T and control arms. Leukapheresis related adverse events were primarily associated with transient hypocalcemia Median white blood cell count and absolute monocyte and lymphocyte counts were stable and within normal ranges throughout the treatment course. Of all patients Patients with vs without a central venous catheter had a higher risk of infection potentially related to catheter use Adverse events related to leukapheresis are manageable and quickly reversible.

The majority of patients can undergo leukapheresis without a central venous catheter. Central venous catheters are associated with an increased risk of infections and venous vascular events. Peripheral intravenous access should be used when feasible. Published by Elsevier Inc. PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

To evaluate the association between prostate-specific antigen PSA response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer mCRPC treated with cabazitaxel. After four cycles, Median progression-free survival was 7. Median progression-free survival was longer in PSA responders versus non-responders With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required.

To illustrate the usability of two such techniques, timed automata TA and discrete event simulation DES , for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes e. Qualitatively, among others, model structure, agent interactions, data management i.

Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure.

Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems.

All rights. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic , castration-resistant prostate cancer. We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer mCRPC. Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned to receive sunitinib Patients also received oral prednisone 5 mg twice daily.

The primary end point was overall survival OS ; secondary end points included progression-free survival PFS. Two interim analyses were planned. The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.

PFS was significantly improved in the sunitinib arm median 5. This two-part study assessed the safety and tolerability of combined treatment with zibotentan ZD , a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel.

Patients were randomized to receive zibotentan at the highest tolerated dose identified in part A plus docetaxel or placebo plus docetaxel. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. A total of patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. No formal statistical analysis was carried out.

The incidences of neutropenic sepsis 6. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

Androgen receptor splice variant 7 AR-V7 has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer mCRPC. Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR AR-FL and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies.

Positive AR-V7 signals were detected in Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to. Budgetary impact on a U. Abiraterone acetate, an androgen biosynthesis inhibitor, received FDA approval in for metastatic castration-resistant prostate cancer mCRPC patients who have received prior chemotherapy containing docetaxel.

A decision analytic model compared mCRPC treatment cost before and after abiraterone acetate adoption based on a hypothetical 1,,member plan. Treatment costs were computed using prescribing information, treatment duration from phase III trials, and drug costs considering common U. Prevalence and costs of managing treatment-related toxicities were estimated from literature, treatment guidelines, and expert clinical opinion.

The model evaluated the perspectives of a commercial payer with no Medicare beneficiaries and a commercial payer with a subset of Medicare beneficiaries. Sensitivity analyses were conducted to assess changing input values. In each modeled scenario, 57 patients with prior docetaxel therapy received treatment for mCRPC. When testing key sensitivity. The aim was to evaluate quality of life QoL , pain, and fatigue in patients with metastatic castration-resistant prostate cancer mCRPC treated with different regimens after first-line docetaxel, as well as disease progression.

Patients with mCRPC having received first-line chemotherapy with docetaxel were eligible. Second-line treatment choice was at the discretion of the local investigator. One hundred thirty-eight patients were included in 36 oncology centers across Switzerland. The 47 Society. Travel Addicts. The Electrostar Appreciation Group. To The Trees. Denver and Rio Grande Western Railroad. The Secret Library Natural Trees Of The Rainforest.

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Patients with both liver and lung metastases were included in the liver subset. In patients with liver metastases, enzalutamide was associated with an improvement in rPFS hazard ratio [HR], 0. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

Enzalutamide was well tolerated in patients with visceral disease. Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment. Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

All patients received continuous daily oral abiraterone acetate 1, mg plus prednisone 10 mg starting on cycle 1, day 1. Ratios of geometric means for maximum plasma concentration C max The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C max ; The safety profile of abiraterone acetate was consistent with reported toxicities.

Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

A genetic variant in SLC28A3, rs, is associated with progression to castration-resistant prostate cancer in a Korean population with metastatic prostate cancer. Genetic variation which related with progression to castration-resistant prostate cancer CRPC during androgen-deprivation therapy ADT has not been elucidated in patients with metastatic prostate cancer mPCa.

The top five polymorphisms were statistically significantly associated with metastatic disease. We assessed genetic variation among patients with PCa with or without metastasis, using , single nucleotide polymorphisms SNPs on the custom HumanExome BeadChip v1. Genetic data were analyzed using unconditional logistic regression and odds ratios calculated as estimates of relative risk of metastasis. Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer.

Retrospective analyses suggest some cross- resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer mCRPC who progressed following abiraterone acetate plus prednisone treatment.

All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. The primary endpoint was radiographic progression-free survival. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Median radiographic progression-free survival was 8. Median time-to-PSA progression was 5.

No seizures were reported. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy. Clinical outcomes and survival surrogacy studies of prostate-specific antigen declines following enzalutamide in men with metastatic castration-resistant prostate cancer previously treated with docetaxel.

The goal of this post hoc analysis was to associate levels of PSA decline from baseline after enzalutamide with clinical outcomes in the postchemotherapy mCRPC setting. Men treated with enzalutamide had improved OS hazard ratio, 0. Surrogacy of PSA decline for OS was not fully established, possibly due to lack of PSA declines with placebo, and discordant results between PSA and imaging responses over time, and because some declines were not durable due to rapid resistance development.

However, a lack of PSA decline by 90 days following enzalutamide treatment was a poor prognosis indicator in this setting. Conclusions from sensitivity analyses of maximal PSA decline from baseline over the entire treatment period are consistent with PSA declines restricted to the first 90 days. Cancer ; Cancer published by Wiley Periodicals, Inc. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy CA : a multicentre, randomised, double-blind, phase 3 trial.

Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a ratio to receive bone-directed radiotherapy 8 Gy in one Patients were randomly Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer.

We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic , castration -sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned patients to receive either androgen-deprivation therapy plus abiraterone acetate mg daily, given once daily as four mg tablets plus prednisone 5 mg daily the abiraterone group or androgen-deprivation therapy plus dual placebos the placebo group.

The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of Full Text Available The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio NLR and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial.

Coprimary end points were centrally assessed radiographic progression-free survival rPFS and overall survival OS. A PSA response was observed in At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients geometric mean ratio, 1. Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer CRPC. The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation pharmaceutical or surgical indefinitely.

For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens eg, bicalutamide, flutamide, nilutamide may be offered, accompanied by discussion of limited known clinical benefit.

Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or. An analysis of leukapheresis and central venous catheter use in the randomized, placebo controlled, phase 3 IMPACT trial of Sipuleucel-T for metastatic castrate resistant prostate cancer.

Sipuleucel-T is an autologous cellular immunotherapy. A total of patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer were enrolled in the study. All patients were scheduled to undergo 3 standard 1.

Leukapheresis related adverse events and those related to venous catheter use were reviewed. Immune cell counts were examined throughout the treatment course. Of enrolled patients underwent 1 or more leukapheresis procedures and were included in this analysis.

Adverse events were comparable between the sipuleucel-T and control arms. Leukapheresis related adverse events were primarily associated with transient hypocalcemia Median white blood cell count and absolute monocyte and lymphocyte counts were stable and within normal ranges throughout the treatment course. Of all patients Patients with vs without a central venous catheter had a higher risk of infection potentially related to catheter use Adverse events related to leukapheresis are manageable and quickly reversible.

The majority of patients can undergo leukapheresis without a central venous catheter. Central venous catheters are associated with an increased risk of infections and venous vascular events. Peripheral intravenous access should be used when feasible. Published by Elsevier Inc. PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

To evaluate the association between prostate-specific antigen PSA response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer mCRPC treated with cabazitaxel. After four cycles, Median progression-free survival was 7. Median progression-free survival was longer in PSA responders versus non-responders With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required.

To illustrate the usability of two such techniques, timed automata TA and discrete event simulation DES , for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed.

Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes e. Qualitatively, among others, model structure, agent interactions, data management i. Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software.

Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems.

All rights. Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic , castration-resistant prostate cancer. We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer mCRPC.

Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned to receive sunitinib Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival OS ; secondary end points included progression-free survival PFS.

Two interim analyses were planned. The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8. PFS was significantly improved in the sunitinib arm median 5. This two-part study assessed the safety and tolerability of combined treatment with zibotentan ZD , a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer.

Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized to receive zibotentan at the highest tolerated dose identified in part A plus docetaxel or placebo plus docetaxel.

The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. A total of patients participated at 12 UK cancer centres. All had mCRPC with disease progression during or after docetaxel. No formal statistical analysis was carried out.

The incidences of neutropenic sepsis 6. Neutropenic sepsis episodes, though low, occurred only in patients who did not receive prophylactic granulocyte-colony stimulating factor. The UK EAP experience indicates that cabazitaxel might improve QoL in mCRPC and represents an advance and a useful addition to the armamentarium of treatment for patients whose disease has progressed during or after docetaxel. In view of the potential toxicity, careful patient selection is important.

Androgen receptor splice variant 7 AR-V7 has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer mCRPC. Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR AR-FL and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies.

Positive AR-V7 signals were detected in Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance.

Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to. Budgetary impact on a U. Abiraterone acetate, an androgen biosynthesis inhibitor, received FDA approval in for metastatic castration-resistant prostate cancer mCRPC patients who have received prior chemotherapy containing docetaxel. A decision analytic model compared mCRPC treatment cost before and after abiraterone acetate adoption based on a hypothetical 1,,member plan. Treatment costs were computed using prescribing information, treatment duration from phase III trials, and drug costs considering common U.

Prevalence and costs of managing treatment-related toxicities were estimated from literature, treatment guidelines, and expert clinical opinion. The model evaluated the perspectives of a commercial payer with no Medicare beneficiaries and a commercial payer with a subset of Medicare beneficiaries. Sensitivity analyses were conducted to assess changing input values. In each modeled scenario, 57 patients with prior docetaxel therapy received treatment for mCRPC.

When testing key sensitivity. The aim was to evaluate quality of life QoL , pain, and fatigue in patients with metastatic castration-resistant prostate cancer mCRPC treated with different regimens after first-line docetaxel, as well as disease progression. Patients with mCRPC having received first-line chemotherapy with docetaxel were eligible.

Second-line treatment choice was at the discretion of the local investigator. One hundred thirty-eight patients were included in 36 oncology centers across Switzerland. QoL analysis was available for all patients 59 who received cabazitaxel; 79 who received other therapy [OT] including 75 who received abiraterone. No significant differences for any of the end points were found between groups.

A similar but minor improvement of fatigue was noted in both groups. Some degree of QoL decrease was seen in most patients regardless of second-line treatment. Cost per median overall survival month associated with abiraterone acetate and enzalutamide for treatment of patients with metastatic castration-resistant prostate cancer. Sensitivity analyses were performed to understand how variations in treatment duration and treatment-related monitoring recommendations influenced cost per median OS month.

Cost-effectiveness estimates of other Phase 3 trial outcomes were also explored: cost per month of chemotherapy avoided and per median radiographic progression-free survival rPFS month. The findings were robust to sensitivity analyses.

These results have important implications. To evaluate the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients. Coprimary end-points were centrally assessed radiographic progression-free survival and overall survival. Prostate-specific antigen responses were observed in Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Prostate cancer disproportionately affects older men.

In the elderly subgroup, OS was greater with enzalutamide than with placebo [ The aim of this evaluation was to identify the first indicators of efficacy for Ac-labeled prostate-specific membrane antigen PSMA therapy in a retrospectively analyzed group of patients. Prostate-specific antigen PSA and blood cell count were measured every 4 wk. Follow-up included the duration of PSA response and radiologic progression-free survival at month 6.

Patient histories were reviewed for the duration of previous treatment lines, and a swimmer plot was used to intraindividually compare the duration of tumor control by PSMA therapy versus prior treatment modalities. Results: Thirty-one of 40 patients were treated per protocol. Five patients discontinued treatment because of nonresponse, and 4 because of xerostomia. Because all patients had advanced disease, this result compares favorably with the tumor control rates associated with earlier-phase disease; the most common preceding first-, second-, third-, and fourth-line therapies were abiraterone median duration Conclusion: A positive response for surrogate parameters demonstrates remarkable antitumor activity for Ac-PSMA Swimmer-plot analysis indicates a promising duration of tumor control, especially considering the unfavorable prognostic profile of the selected advanced-stage patients.

Xerostomia was the main reason patients discontinued therapy or refused. Third-line treatment and Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review. There is a controversy as to the relative efficacy of Lu prostate specific membrane antigen PSMA radioligand therapy RLT and third-line treatment for patients with metastatic castration-resistant prostate cancer mCRPC.

Searches in Pubmed and Embase selected articles up to September A search in ClinicalTrials. The meta-analysis used the random-effects model. Sixteen studies including patients reported third-line treatment. Treatment patterns for metastatic castration-resistant prostate cancer mCRPC have changed substantially in the last few years.

Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen PSA values were available. The median docetaxel treatment duration among these patients was 4.

Docetaxel was the most common FST among older and younger patients from each treatment arm. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced.

A retrospective analysis of overall survival. Rahbar, K. Prostate specific antigen PSA changes after the first cycle of therapy were documented prior to a second cycle. Patients were followed-up for overall survival OS. All patients were treated with at least one line of chemotherapy.

The median OS was This Guideline is intended to provide a rational basis for the management of patients with castration-resistant prostate cancer based on currently available published data. A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance.

The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded articles published from through that were used to form a majority of the guideline statements.

Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. Guideline statements were created to inform clinicians on the appropriate use of observation, androgen-deprivation and antiandrogen therapy, androgen synthesis inhibitors, immunotherapy, radionuclide therapy, systemic chemotherapy, palliative care and bone health.

These were based on six index patients developed to represent the most common scenarios encountered in clinical practice. As a direct result of the significant increase in FDA-approved therapeutic agents for use in patients with metastatic CRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex.

Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, patients' preferences and personal goals should be considered when choosing management strategies.

The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here.

The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including a not using the intention-to-treat ITT population; b inconsistencies in estimating prediction equations; c not fully incorporating the impact of adverse events; d incorrectly incorporating the new patient access scheme PAS ; and e the assumption that AA non-compliance leads to recoverable drug costs.

Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer VENICE : a phase 3, double-blind randomised trial. Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer.

Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries sites.

Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status vs 2. Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis.

This is the primary analysis of the completed trial. The study is registered with ClinicalTrials. At final analysis, median follow-up was 35 months IQR and men had died. Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone 55 patients and enzalutamide 33 patients in a post hoc analysis of COU-AA Prostate-specific antigen PSA response was assessed.

The median time to PSA progression was 3. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone.

Castration-resistant prostate cancer: systemic therapy in Full Text Available Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients.

Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy.

Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration-resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone.

Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer. The androgen receptor splice variant-7 AR-V7 has been implicated in the development of castration-resistant prostate cancer CRPC and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer HSPC to CRPC.

A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Overview of treatment of castration-resistant prostate cancer. Prostatic cancer is a very heterogenic disease. Initial treatment of metastatic disease is androgen deprivation therapy, however upon the time eventually all cases develop castrate resistant disease CRCP.

In CRPC the combination of docetaxel with prednisone is considered to be the gold standard first line therapy with prolongation of overall survival. Until recently there was not standardly defined second line treatment. According to the international guidelines of today cabazitaxel and abirateron is recommended as second line therapy. We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles.

The second aim of this study was to calculate the median overall survival OS of responders and non-responders after the first cycle and after all three cycles of RLT. The tumour marker prostate-specific antigen PSA was used as the marker for response evaluation.

Fifty-two patients underwent a total of cycles of RLT cycles per patient. Of these, When compared to baseline PSA, The median OS was 60 weeks in all patients. There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA.

Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer. Full Text Available Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer CRPC; however, its effects vary.

An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival OS. We retrospectively analyzed a cohort of patients.

Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 The C-index of external validation of Chi model was 0. Univariate and multivariate analyses identified low hemoglobin concentrations Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [Lu]Lu-PSMA Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer-updated results.

A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population.

Published by Oxford University Press. Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer—updated results. Abstract A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population.

Castration-Resistant Prostate Cancer 5a. Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects. Androgen receptor AR signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy ADT remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer CRPC has changed dramatically in the last several years.

Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution.

The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. Circulating tumor cell counts are prognostic of overall survival in SWOG S a phase III trial of docetaxel with or without atrasentan for metastatic castration-resistant prostate cancer. Circulating tumor cell CTC enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer.

We assessed the prognostic value of CTCs for overall survival OS and disease response in S, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline day 0 and before cycle two day 21 using CellSearch. Median day-0 CTC count was five cells per 7. Prostate cancer is currently known as the most common cancer and the second leading cause of death from cancer in men in Western population.

Advanced prostate cancer is initially sensitive to androgen-deprivation therapy ADT but later on progresses to castration resistant state. Understanding the mechanisms that transform prostate cancer PCA into a castration-resistant state enables investigators to explore suppression of extraresticular andronegs and other critical pathways to suggest appropriate and rational therapeutic design.

Docetaxel based chemotherapy is established as the standard first line chemotherapy in patients with metastatic castration-resistant advanced prostate cancer with improved survival. However, prognosis remains poor and median survival is usually not longer than 2 years. Several Phase III studies have been completed recently, e.

Multidisciplinary management and optimization of their role and and the most appropriate timing is the most important task in the treatment of advanced prostate cancer. Common Terminology Criteria for Adverse Events, version 4. Logistic and Cox regression models were used to predict toxicity and survival. NOTES Castration-resistant prostate cancer was subjected to a paradigm switch from hormone resistance to androgen deprivation therapy resistance during the last decade.

Indeed, new therapeutics targeting the androgen receptor showed clinical efficacy in patients with progressive disease under castration. Thus, it is a proof that the AR remains a dominant driver of oncogenesis in earlier-called hormone resistant prostate cancer. This review summarizes the molecular mechanisms involved in castration-resistant prostate cancer. The optimal degree of testosterone suppression in patients with prostate cancer undergoing androgen deprivation therapy remains in question.

Furthermore, serum free testosterone, which is the active form of testosterone, seems to correlate with intraprostatic testosterone. Here we compared free and total serum testosterone as predictors of survival free of castration resistance. During a mean follow-up of 67 months , 75 Metastatic spread was the most powerful predictor of castration resistance , HR: 2.

Gleason score, baseline PSA and PSA at 6 months were also independents predictors, but not free and total testosterone. Stratified analysis was conducted on the basis of the status of metastatic diseases and free testosterone was found to be an independent predictor of survival free of castration resistance in the subgroup of patients without metastasis, HR: 2.

The lowest threshold of free testosterone which showed significant differences was 1. Free testosterone at 6 months of LHRH agonist treatment seems to be a better surrogate than total testosterone to predict castration resistance in no metastatic prostate cancer patients. Prostate , The primary and secondary endpoints were safety and immune responses, respectively.

Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p. Aldara creme was applied at the site of injection during a one-year period. The median OS was 19 months, whereas the predicted median OS was We observed a significant decrease in Tregs in the peripheral blood. We did not identify any immunological parameter that significantly correlated with better OS. Concomitant chemotherapy. Castration Resistant prostate cancer 5b.

Health-related quality of life effects of enzalutamide in patients with metastatic castration-resistant prostate cancer: an in-depth post hoc analysis of EQ-5D data from the PREVAIL trial. Average decline in EQ-5D index In baseline and time-dependent multivariate analyses, OS was independently associated with multiple HRQoL measures across both studies. Enzalutamide is an androgen receptor AR inhibitor that acts on different steps in the AR signaling pathway. Centrally assessed radiographic progression-free survival rPFS and overall survival OS were coprimary endpoints.

Of patients, patients were enrolled at sites in East Asia enzalutamide 73, placebo The enzalutamide plasma concentration ratio East Asian:non-Asian patients was 1. Treatment effects and safety of enzalutamide in East Asian. The objective of the present study was to assess the oncologic outcomes of patients receiving second-line therapy against metastatic castration-resistant prostate cancer mCRPC. However, no significant differences were found in the remaining parameters between the 2 groups.

Similar trends were confirmed by comparing these outcomes among 4 therapy groups, with significant differences PSA response rate, Enz-to-AA vs. Patient-reported outcomes PROs are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood.

We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer mCRPC. Cox proportional hazard regression modeled time to death or radiographic progression. The month analysis confirmed the 6-month results. PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression.

DGP, maximum of eight courses, until progression or unacceptable toxicity. Imaging response during therapy with radium for castration-resistant prostate cancer with bone metastases. We aimed to describe the imaging response to radium treatment. Imaging by CT scan should be considered after three and six doses of radium to rule out extraskeletal disease progression Prostate radiation in non- metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer.

Full Text Available Abstract Background The natural history of non- metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. Findings Median PSA response following prostate radiation was Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was Median survival from castration resistance to date of death or November was 60 months, with median survival from RT 42 months.

Conclusion Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.

Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer PREVAIL : results from a randomised, phase 3 trial.

Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer.

We report the effect of enzalutamide on health-related quality of life HRQoL , pain, and skeletal-related events observed during this trial. The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event.

Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Full Text Available Medications increasing the survival of patients with metastatic castration -refractory prostate cancer CRPC are lacking today.

In the past 3 years, in the pharmaceutical market there have been a few novel drugs to treat progressive prostate cancer. Abiraterone acetate is an androgen synthesis inhibitor, which is also used to increase the survival of patients with metastatic CRPC that progresses after chemotherapy. The results of treatment for metastatic CRPC depend on a number of factors. Visceral metastases are poor predictors of the course of the disease.

The results of abiraterone acetate treatment were analyzed in CRPC patients with visceral metastases. Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients. Patients received weekly infusions of AA week 1, 5 g Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events AEs were recorded. Eleven were graded as "serious".

Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did Conclusions: Infusion Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains.

Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells.

Using LNCaP C cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents. Prostate cancer PCa is the second leading cause of cancer-related death afflicting United States males.

Castration resistant prostate cancer in the year Prostate cancer PC is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problems of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy ADT , which is resistant to any hormonal therapy.

Objectives of article: provide information to the general medical community and especially urologists and oncologists mainly about a treatment of complicated issues of CRPC. The basic data on the current and future. The article presented basic data on the current and future possibilities of such therapy and increasing basic knowledge about treating CRPC should improve the care of patients with advanced PC.

Denis-Bacelar, Ana M. To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.

Clinical data from 57 patients who received 2. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival OS and correlation analyses.

A statistically significantly longer OS was associated with administered activities above 3. A total of bone lesions were identified in 22 patients. This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated. Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

Prostate cancer cells express the androgen receptor AR and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer CRPC stage is often mediated by AR signalling.

Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

Castration resistant prostate cancer - something new in the year ? Prostate cancer PC is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problem of the male population. This state probably arises from either clonal selection of androgen — independent cell lines or increased ligand — independent activation of androgen receptors.

Survival can range from only a few months to 4 years or more. Historically, therapy had little effect beyond modest palliation. Army Col. That, truly, is performance of the highest order. During the war years and those that followed, C. Morris added new equipment, extended floor space, installed air-conditioning, and bricked the exterior of the building.

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William D. Hollis, S. Watkins, John H. Thomas W. Hughes, B. Johnson, John A. Wilkerson, B. Submitted by Stanley Bailey Scanned by CamScanner Ak was the custom around , women, out of necessity, combined their household chores with their social life. These women were photographed displaying a quilt that had been quilted. Sometimes three or four quilts would be quilted at a quilting party. These women are shown on the front porch of Mrs. Mattie Robinson. They are left to right: Mrs. Mattie Robinson, Mrs.

Cath Jackson. Siddie Keith, Mrs. Tom Shell, Mrs. Hattie Robinson, and Mrs. Susan Seymour. Mayors of Palmetto Thomas P. Dullard: Joseph A. Dennis: Thomns E. Arnold: Thomns P. Bullard: Thomas B. Harper: Irvin T. Broadus Bradley: James T. Bullard: Murray D. Bradley: James A.

Bentley: L. Watkins Mary G Bunch. Swann Charles Jackson William H. Astin Mrs Annelle S. Johnson Eli B. Cotton Mrs Elizabeth A. Turner Mrs Clara J. So, they took him in tow and spoiled him to begin with. The bad boy named them Bill and Mary. In a few years Bill and Mary had a family of their own which numbered seven, including Bill and Mary, The little boy sheared the wool from his flock until he had saved more than 50 pounds. He also took out all of the cockle-burrs and other foreign matter from the wool and washed it.

The Misses Powells were expert weavers. The work was all done by hand, and Mother spun the most of the yarns on the wheel that is now in the living room. This was her own wheel, which was also made by hand in Uncle Tom Barns' shop at Newnan, Ga, All the carving on this wheel was done with a foot power lathe nearly years ago. William H, Astin, so she would have the history of the coverlets. It shows two of the coverlets, one belonging to her, the other to Sara Astin Davis, In the picture also is the spinning wheel on which the yarns were spun for the making of these coverlets.

Astin Dr. William H, Astin was reared and educated by his Grandparents. He graduated with honors from medical college but did not enjoy practicing medicine. At age twenty-four, while he was working in C. B, Moseley's store in Palmetto, Mr.

Daniel Wiley Gentry came in to shop and announced that he had a new baby girl at his home. In jest, Dr. A number of years later Dr. Will Astin eloped. They were active members of Ramah Baptist church where he taught a Sunday school class for about fifty-two years. Known us Ihe Captain [ftckson Homo, Mr. This holisi? The Carlton family owned this home for over years. Coorge Redding Sims homeplace. At the beginning nr the Civil War, Mr.

Griffith ran a post office at the same time that he operated Griffith s Tavern in the house. During the War, Confederate soldiers were billeted there. This house on Main Streel was hull! J his was the old Nathaniel Harrison home at Fumpkintown on the 1 hat la hoochee River, The house was built ahoul and it burned in the early 's.

Nalhoniel Harrison had two daughters. Cochran, [lie Bollard home was built in and was a copy of the houst Mrs. Ballard grew up in. Having begun the digging of a well for their water supply, they quickly discovered the granite. An Irishman from Atlanta was employed for this purpose. Then began the work of drilling holes in the rock, lowering the Irishman into the well to set the charge, pouring live coals into the well to ignite the powder, the lowering of slaves into the well to remove the rock.

When they reached a depth of feet, disaster befell them. During the winter months, water from the housetop was directed into the cistern by system of guttering and was used for the year. On 1 hot August day in the writer enjoyed a cold drink of water from this cistern. An unusual feature of this two-and-one-half story colonial home has been lost in its modernization by subsequent owners. Florence Devine, who married the youngest son of the family, attended this school.

Submitted by William J. Sims, Jr. Our service for the department was to raise monies for items like protective clothing, F. Receiving Units, and a Hydraulic Jack. The means of raising this money was by rummage, bake, Christmas Card, and Stanley sales. We always served at the annual Steak Supper held in February for the community. The auxiliary dissolved in November of Students photographed at Riley School in First row.

Billy Shell. Jerry Hubbard Reed, Billy Duncan. Harvey Melear, Joyce Braswell. Fourth row: Ned Peek. Ronnie Turner, Harry Deal. Joyce Mobley. Patsy Dowdy. Irene Dingier. Clarice Kearns. It is a member of the Fairbum Missionary Baptist Association. Key as the first pastor, and thirteen charter members as follow's: Mrs. Sarah Boggs; Mr. David Hataway; Mr.

Tom Chastain; Mr. Cook; Mrs. Stevie Docia Kidd Garrett; Mr. Emanuel Hataway; Mrs. William Betty Kidd Nix; Mr. Smith; Mr. The first church services were held in the school house. In the first white frame church building was constructed. The present granite church building was under construction from to The beauty of the auditorium is enhanced by th natural granite walls and the stained glass memory 6 windows.

Old pews, although not the original, are still used. The church has had thirty-four pastors, with the Reverend H. Buddy Waldron as present pastor. The present membership of the church is Active deacons are Fred Driver, W. Submitted by Mrs. Brother Sumlin let the group use his home.

Coming from a split congregation, the members asked the Reverend R. Ridley to be their pastor and leader. Carter Day Care Center. After a few months God blessed them with a juilding at Park Street. They moved in and began t ij'IIl there November They held their worship services in this building until the membership of decided to build a placf for worship. Bethsadia Baptist Church, Mt. Pleasant and Hams Chapel Methodist Church opened their doors for the group to hold their worship slices while preparing to build.

This lot is sacred to the church because on that very spot the late Reverend J. Hammonds moved into a house that stood there in the year He decided to move to Palmetto from Atlanta to be near his members an the Church which he pastored fifty-two years unti God called him away.

God sent the church another leader and pastor, t ie Reverend R. He never knew Reverend Scanned by CamScanner Hammonds, but he had heard wonderful things about him and said that he could almost imagine knowing him. Our church is located on Beckman Street and is named the J. Hammonds Baptist Church. This name was suggested by the Reverend Ridley. Members are planning to go into the building August 12, Thank God for the contractor, Mr.

Melvin Lowery of Villa Rica, Georgia, for making this possible. Thank God! The present building is the third structure to sit here. In November of the membership moved into the structure it now occupies. From a meager beginning at the corner of Ray Street and Fayetteville Road, where it was known as the African Church, it has developed into a modern structure today.

Over the past years the church has had many pastors. Twice during its long history it was honored to have one of her own as pastor, the Reverend W. For forty of her years Clyde E. Smith served as Sunday School Superintendent.

Others who served in this office were J. New Hope Methodist Church taken in Services were held once a month with the Reverend George W. Colquitt as pastor. Whorton, editor of the Christian Index, preaching the sermon. At this time, the Sunday School was organized and later the weekly prayer meeting. Brittain as its first president. In a new church was built on Center Street. Some of the officers over the past years were Daniel Virgal, John W.

Submitted by James W. Smith Sunday School rooms were added later. In following years, the addition of dining-kitchen area, choir loft and nursery were great assets to the fellowship of a growing congregation. In the building was enlarged with a vestibule and balcony, the outside was bricked and a beautiful steeple was added.

The church has grown to resident members and non-resident members. Among the many activities enjoyed are trips in the church Greyhound Bus. The pastor, Tom Daugherty, and his family also take part in the town activities, and this participation endears them to all. Later that year the church services were changed to the school house. On June 9, , Willis P. Menefee deeded a one and one-half acre lot to the Church Trustees, and in a neat wooded building was erected on the ground where the present brick building stands.

A brick building was completed in on the original one and one-half acres. This brick church was dedicated by Bishop Wightman. In money was raised for building the vestibule and towers. While attending this conference, Mrs. Harper as pastor. The church began with only eight members. There are now sixty-five members.

The Reverend Harper pastored the church until October of The Reverend James R. Daniel is now the pastor. Submitted by Lois M. Harper ganized in , and in the Wesleyan Service Guild had its first meeting. During a Church School annex was erected and the entire church sanctuary was renovated. The parsonage was built and paid for in full June 17 Hodges, Jr.

Maeser, Jr. Bur- ans, Garretts, and others are buried. On one side of this burial ground the Negro slaves of these families, as the custom was at that time, are buried. Scanned by CamScanner This first church was Primitive Baptist or Hardshell, j j j fl very interesting to read the old minutes which date well back before the War Between the As the years went by, many of the members of this little church changed their Scriptural viewpoint and became Missionary Baptists at heart.

They decided to procure a tract of land and build a Missionary Baptist Church. This they did, and in this Church whore the members now worship was built on land deeded by Mrs. Buran, who lived at what was later the old Shannon place. In later years, Jewett Shannon deeded one-half acre, and later another half acre, to be used as a cemetery for the Methodists and Baptists of the community.

Three more Sunday School rooms were added during Dr. During the Reverend C. Mowell's pastorate more Sunday School rooms were added, the heating system was changed, and memorial windows were put in. In an educational building was added, and in the sanctuary was renovated. This was during the pastorate of the Reverend Searcy Jack- son. Submitted by Mannie Clifford Reeves, Jr.

The Reverend Rice was traveling by horseback. During his first revival at Ramah twenty-eight people were baptized. In George W. Colquitt was called as pastor and served a few years. He left to pastor Palmetto Baptist Church, but returned to Ramah as pastor in In J. Monday became pastor and in two years baptized forty-nine people. In the year R. Rhodes, one of the best loved men ever to pastor Ramah, became pastor and served until He planted the magnolia tree that stands in front of the sanctuary.

Ramah has been blessed by the great men God has sent to lead her, among them W. Lewis Fowler , J. Bunnell, J. Alex Shores, Judson Jones. Roy Davis, F. Garrard, Jr.. Ramah climaxed her th year with the traditional homecoming on the third Sunday in August and a week of revival following. Lewis D. Robert Headdon, while he was at Cartersville. Headdon was reared in Ramah Church.

Bishop W, A. Candler was the Bishop- Mr. W, Shannon gave an acre of land to build the church on. Members and friends donated materials, furnishings and labor to build the church. Camp, Luther F. Gaddy and Rowland G. They are still in use. There is no record of how much it cost or if there was a contractor. The church was dedicated on May 3, , Bishop Key presiding.

The bell was brought from Libery Hill some years later. Recently the entire annex has been refurbished, tiled floors and Sardis Baptist Church Sardis Baptist Church was established in As the area seven miles west of Palmetto became more populated, residents felt the need of a more localized church.

Brown as pastor. Earliest membership records show sixty-five members on roll. Many came from Ramah Baptist Church, in Palmetto. Harry V. Smith, Jack Tatum, N. Most of the work has always been done by members. People of Rico are proud of our church and what it has stood for these seventy-six years. God grant that it may continue to be a beacon light to those who pass by for many more years. In a new church building was constructed by the members themselves in the southwest corner of the intersection.

In services were changed to two Sundays each month. In records show that the church was called Sardis Baptist Church, and in the church began holding services every Sunday. Some members recall that as late as horses and wagons were still used by some people as a means of transportation to church.

Turner, Sr. In a larger pastorium was built where the original church had been located. Since its beginning, thirty- three ministers have pastored Sardis. This building was formerly used for a Christian Church. By fall of that year a new brick building with a full basement had been finished, with most of the work being done by the members of the church. This was down behind the church at the "Pond.

Mae Bailey, unknown, Gertrude Collins. Nell Roberts. Genia Carter unknown, unknown, unknown. The southernmost high school in Fulton County began op- eration in August of , on double. The school moved into the newly completed Palmetto High School on February 22 , I he school opened with only three grades—eighth, ninth, and tenth—with an enrollment of students. Ten years later the school has five grades—eighth through twelfth—and a student body of approximately The first faculty had twenty-eight members, and today's faculty has grown to forty.

Shields, Tom T. Through the efforts of Mrs. Concheta Carter and the P. This came about when the P. Graduates of the first graduating class in the new building in were Mrs. Mattie Sue Amos Hines, Mrs. Nancy Bellamy and Mrs. Harry Reese. Submitted by Sondra A. Wingo, P. Two principals have served the present Palmetto Elementary School since its construction in , they are Mr.

John T. Gibson and Miss Jemmie L. Jane Holland Charles E. The Board of Education engaged the services of Robert and Company, Architects, to build a new school building in the city of Palmetto on six acres of land on Turner Avenue. Because a large donation toward the cost of the building was made by Mr. Charles E. Riley, President of the Palmetto Cotton Mill, the school was named for him.

The student capacity was for children, with ten original classrooms, clinic, auditorium, lunchroom, office rooms, and the Science and Library Room. The new school was quite an advancement over the old ones and one of the most satisfying and interesting features was the school lunch program.

In the past many of the ladies of the community used to make large containers of soup, divide it into smaller containers and carry them to the teachers in each classroom, who would place the food on the coa heater to be served to the children at the noon. Second row: Edna Condor. Raymond Steed. Ruby Thompson served from September until her resignation in April Miss Nellie Keith became principal at this time and erved until her retirement in Third row standing; Embard Hopkins, Grady Keith. Effie Shell.

Mattie Watkins. The building is in a T-shape with three larp rooms. The first principal was Mr. Other known teachers were Mrs. Fronnie Hubbard, Mrs. Janie Mae Swanson, Miss Clements. Some of those who attended the school were, Mrs. John Edward Creel. Harold Bowen deceased , and Mrs.

Myrtle Bates, and Mildred Creel; front row T left to right. At that time, the county extension service provided a home demonstrator to attend each meeting to bring such new ideas in homemaking as methods for canning and freezing vegetables and fruits, tailoring, interior decorating, crafts, gardening and nutrition.

For many years, the club met once a month in homes of members with an enrollment of some twenty-five to thirty-five members. Once a year at Christmas a covered dish dinner for husbands would be given with exchanging of presents, singing of Christmas carols, and playing of games to liven the affair. As time passed, with affirmative action and equal opportunity, the County Extension Agent could meet with the Club only in public buildings.

When the Rico Homemakers Club dissolved in , the County Line Club eventually extended its boundaries to all of Rico for membership. It now has an enrollment of approximately thirty-four ladies who do not only meet monthly but on occasions have work-days for quilt making and special projects. Many of the members have been attending twenty years or longer. Two special projects for raising funds are the sweet shops.

For the sweetshop, members bake from scratch such cakes as fresh apple, coconut, Italian cream, caramel pound, chocolate layer, sheath cake, and lemon cheese. They also make brownies, cookies, divinity candy, homemade bread, and such pies as sweet potato, lime, and coconut.

The club also has turned its energies toward the community with goals of providing a luncheon for senior citizens once a year and redecorating the Rico Civic Club Building—the Old Masonic Lodge. Easter Maddox. Cleophas Williams. Johnnie Slaughter, Ruby Kemp. Ruthie Kemp. Dona Knox. Irene Merritt. Emma Elder, Rentha Williams.

Evelylene [ones. Louvenia Williams. Dorothy Roquemore. Lucile Brown, who is now deceased. At that time, Mrs. August 3. T elected our President. Later, Mrs. Louvenia Williams joined. As the years passed, the club has grown to fourteen members. Our growth has also added strength. Merritt has served as president for twenty-one years and Mrs.

Carter for one year. The club has sincerely enjoyed the leadership of the two presidents. On Christmas we give a basket of fruit to the elderly and also to the shut-ins. We always remember the deceased in the community. Dora Knox. Carter is our Honorary Member.

Submitted by Louvenia Williams club was formed and officers were elected: Lena Landers. President; J. A name for the club was discussed. The name "Life Lighters. The club seeks to live up to its name by doing something to bring life and joy to the hearts of other people.

At Ghristmas, gifts are carried to some of the nursing homes. Pads have been made for the Cancer Home in Atlanta. McMillan, President; Mrs. Hudson, Secretary; Mrs. Arnold, Press. Twenty-four charter members were enrolled. The principal speaker of the afternoon was Mrs. The members of our Lodge have played a prominent part in its peace and in its wars. This activity was very interesting. A group of the ladies, along with Pastor Kelley, enjoyed a fishing trip after one of the club meetings, proving that there are many things to enjoy as a Senior Citizen.

Three are over sixty years old, and all are still identified with the same families. Of these gardens, the old Beckman Garden is still cared for by Mr. Bill Beckman; the old Walthall Garden by Mrs. Vena Smith Redwine. Article taken from the minutes of the year book Submitted by Carole Harper The Palmetto Garden Club are photographed as they celebrate their twenty-fifth anniversary.

Standing left to right are: Mrs. LnTrelle Jackson. Mary Lee Morris, Mrs. Nelle Aslin, Mrs. Beltv Thornton, Mrs. Elizabeth Hearn, and Mrs. Evelyn Chirk. First table: Mrs. Louise Gibbs, Mrs. Marian Bruns, and Mrs. Charles Grifhe. Second table: Mrs. Zenobia Morris. Blanche Mo well. Burma Abercrombie. Margaret Steed, Mrs. Clairman Condor, Mrs. Elizabeth Swanson. Through the years, our members have gone quietly about obeying the laws of God and of their government, keeping their heads in troubled times, and always ready to lend a hand to those in distress.

I loin, in the shadow of our Lodge have lived and worked for a century, men and women who were guided and protected by its principles. Indeed, the history of America has been the history of Palmetto Lodge No. Kellog, WM, C. Taliaferro, SW, and Willis P.

Menefee, JW. After five or six years the meeting place was moved to a building erected by Dr. Cabe Johnson, near the home of Winston Eberhart. In the Lodge home was moved to Palmetto and on November 1, the name of the Lodge was changed to Palmetto No. These men were: Brothers J. Zellars, and Arthur Hutcheson. Left to right: Slim Grubbs. Bradley, B. Barronton, Fred Davidson, and T. At that time, it moved into the Reid building from which it moved to its present location, about Coggin is now Worshipful Master.

Meeting nights are the first and third Tuesday of each month. The individual clubs met monthly with as many as members attending the quarterly meetings held at different club locations throughout South Fulton. Such issues as paved roads, a bridge across the Chat- tachoochee in South Fulton, and fire protection were discussed.

At that time there were no paved roads, no fire protection, and no bridge across the river south of Ben Hill. However, at a quarterly meeting in Rico in , a motion was made and passed to dissolve the Federation. And that, no doubt, broke the solidarity of the people in South Fulton, as little progress has been made in twenty-five years toward paved roads, fire protection, or two bridges only two had been built.

The Rico Civic Club continued to meet and eat monthly. The land upon which the Community House was built was given by a person who stated that no dancing or gambling would be permitted. Geraldine Longino as the first president. They met in the home of Mrs. Ruth Barnes. But much of the meeting time was spent on a variety of programs about travel, politics, gardening, cattle raising, and a few parties.

Of course delicious food was uncovered at each meal. Then, in , a new generation came into the community, and a need for community action arose. To give freedom of direction, the club members worked out a trade of land between the two churches. Restoration began immediately. The club sponsored the construction of the sign. She worked hard end spent many oxhe hums helping the Indies to learn to make or arrange I urn islilnyts to u room or work out a color scheme.

Jolyn ttnd ti helper would go to tho county work shops wham county agents mid assist tints would teach them how to go hack to tUolv own uhdw, ,imt give demonstrations on what they learned at those work shops At this time tho county agents voulj not moot with oil tho clubs in tho South and North 1 'niton ureas. Mrs Teresa Daugherty is tho president now. This club was to be made up from itll churches and community citizens fifty yours and older.

Lucy Seymour. Jackson, and Miss Willie Johnson. When the club was first organized. Allmri int-r Aslin. Hack row, boys: Dim: As! Paul Penisimi. Hslut I liir Nir. Jmihu Cunlon, Hilly t. Roy lulHSoltur. I tn, i Purr, Hull lllmiuilcr. HusU IVuk. Iviiuut Ittiiloy. In it was closed because of financial problems. The Home is no longer an orphanage. Organized and led by the first chief of the department, Johnny Smith, much progress has been made in the eleven year history of the department.

The men had no prior training, so they immediately began taking a sixty-hour course in "fire supression" provided by the Georgia Tech Fire Institute. Improvements then came year after year. Today there is a three-bay station with a day room, rimlees wore asked to sell to the City of Atlanta. The move ana! Approxi- lolved? The archway entrance to the Hapeville campus bridges tho past to the present as it rests on the Pal- metto campus.

Stained glass windows that graced the Hapeville Chapel continue to inspire boys and girls where they are now placed in the library. All the efforts made on that hot August day have been worth it to the residents of the new Palmetto Campus. The children have more space in which to grow and mature. Large spots for gardens behind each cottage are just one of the many advantages for the boys and girls.

Two lakes also offer the opportuni- ty for fishing and relaxation. This station was officially opened and dedicated on December 27, The present equipment includes a G. In June of the department, with the aid of the city and its citizens, purchased the Hurst "Jaws of Life" to be used in rescue extrication. The department, headed by volunteer chief Roger D. Front row: Ralph Wingo. Ellis Sims. Ray Lassetter. Second row: Bill Landers. Robert Johnston, unknown. Left to right: Ray Lasselter.

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Larmoyer, I7a 3 c Same r. Holborn District Board of Works. Seyd and another. Aubyu p. Scott- Hall 0. Hilron, Union Bank of Manchester. Sissons r. Smith V, Anderson, 80; 18 a V. Spier V. General Pablic Works and As- sets Company. Atlas Permanent Benefit Building Society. Unirao Uegaba v. Irshad Husain and another. United Alkali Company t;. Universal Automatic Machines Company, 81 m 12 b Wasmuth o. Manser and Blome.

Davisi 8 : 13e — — Wilkinson v. Medical Battery Company. Knight, 10 m 18 t p. Vere, I? Fletcher, Son and FearnalU 29 in 1 1 e Wilson 0. Passmore-E'i wards, 11 m 14 6 — Wise and others o. Foreign, American and General invest- ments Trust. Annual Meeting. Jftmes, Norlands 27 a 14f — St.

Mary Magdalene, Enfleldi, 27 a 14 e — St Saviour. Hammersmith, 27a 14r Conistory Court of St. Aiban's— St. Sir G. Ort Crete. Mark, for Stealing, 27 a U d Brown, J. Alice, for Assault. U mlid — Collins, C. Duyal 'hunder, for Fraud, 1 m 8 s Elkins. John, for Fraud. SmSd Grubb. Fn for Embezzlement. C, and another, for Fraud, 26 m 14 c — Lumley. John, fur Stealing, 4 a 4 a. Samuel, and ot hers, for Unlawful Possission, 27 ; 12 d Sharp.

Frank, for Attempted. Archibald, for Forgery. Henry, for Stealing, 22 j lid ' Wells. C on the Teaching Uni- versity of London. Proposed, for Notes on. Daldy F. S on Ladas. Times Ackrill, Robt.. Count von, 11 m 10 a Bisset. Sir J. Valentine dr. Auguste, 24 a 10 a — Coward. Major 8. Lord, 28 1 14 a Foucaux, M. Gill, Rev. Joseph, 18 m 4s Hewketh. Alice, the Blind Novelist 9 w 10 rf Kinsman, Rev. Prebendary, 81 m 6 e Kossuth, M.. Brough, 8 a 10 c Marignac.

C, 19 ; 10 a Masoch, M. Henry, 15 m8 e - Letter on, 15 m 8 Morocco. Kb Noel. H ; 6 A Parrot, M. Fleet- Master W. Vice- Adm. Pullin, C. Funeral of. Lieut -Gen. Rear Adm.. EL, 1 ; 86 Trumbull. Josiah, 8 ; 10 i Col. Estrup, 17 ab e — — Miscellaneous News. Allen and Bell, 4 m 18 c Bastard v.

DnioHnond, 24 a 3 c ntinhill If. GlanviUe and another, 12 m 15 s Grant u. Owle and another. Degrees, Mark Wilks. Bmlding Rulea. North, 2 a 7 6—28 m 1 1 6 — - Cambridge Borough. Six, ki Baroelonak 22 m 6 6 Fenton, F. Art Salea. Bernard Mancon's Livery Stables Destroyed. New Town. Firs Road. Talmage's Tabernacler Destroyed by. City, Fireman Injured, 1 m 11 d at Sutton. Goggia, 20 a 6 6 44 Flramoe ronf Ina'cf. Arreat of Comte Elie de Talleyrand and If. Blaise de Bury's Lectures in, 26 a 5 6 Mme.

Laguerre, 5 m 9 a of M. TouMRint, 7 ; 6 e M. Casimir-Perier on French Politics, 80 a 5d M. Progress of. Decrais' Speech. Delonde on English Foreign Policy, 25 9 6 a Disturbanceain. Meeting, Aa b r — Funeral of Gen. Gladstone, 7 m 5 " Polytechnic Sdiooi. Centenary Celebration, 18 m. Ueinach's Bill. Blount, 28 a bo — Sale of Property to Foreigners.

Letiii Stiy'd Address, I i a 6 6 Mme. Amoruise Thomas. Sa Hb Gladstone Herbert in Marylebone. Selwyn and KeUgious Kdu- eatton. Letter on SO i S d Earthquakes in. Haileybury College, Speech Day. Hamilton Loid G. Proposed Memorial to. Annual Meetini.

Letter oo, 1 t? II a Hornby Adm. Royal Commission on. Legal Cases, see Civil Actions, Meetiiixs. Paul's School. Demonstiation of the. Building Trades Federation in, 2. Reports of, 30 a A b Rupee Debt. Opening of, 6j 3 b Indian-Tibet Treaty. Annual Uojtini:. Grand Day of Easter Tenh, Dinner. James on the r. J,, who Committed Suicide, 20 a llr Paget, T. Killed through his Horse Fallinfi on him. Sophia F. Aocidentalld Killed on the Railway.

Kicked to Death, 10 a 10 6 Inqueeti rontinrnd. C, who Committed 8idcide,29 Walker, Mrs. Mails 'ontract. Trade Union Congress. O'Brien's Letter in Reply to Mr. Vesey Knox. Sails Outrages in. Meeting, 9j 11 i — Mail Service. Bomb Etploatdn In. Annual Dinner, 22 mb d - Trade of. Report, 1 2 a 5 a Treatment of Foreif? Treaty between, 2 m5 d Japanese Diet. Condition of. Keturn of. Sir F. Karslake J. Temple Of Phiia;.

Bankruptcy Court CsiseSj. Jbaw fonthiued'. Bfdfour on. Newnes, 26 w 13 s M. Fowler at Wolverhampton. Harcsonrt on the Budget, 1 ar9 3 on Trade. Morley at Newcastle. Navy Kstimates. Tolls Queen's Uniform. SUte of. Osborne Morgaaand Mr. Stanley Leighton, 22 in 8 a on Dr. Lou Leslie Major F. Negro Migration to. Ha 10 o Movement, 1 j hj — Service. Watford, 81 st Anniver- sary Festival.

Annual Meeting of Diocesan Socie- ties at. Fowler, 27 a 15a Chamber of Commerce,. Kid Marchant E. Right Hon. Beatrice, 29 ; 10 6 Cecil Lofd E. Duke of Madrid. Marquis Ugo. C, i a ' a Skilbeck, VV. Dinner to, 18 a 10 f M'Larney ReT. Lecture on Moorish Life, 7 f7d Mearns. Stanley Leighton and Sir G. Charles, by her Husband, 24 a 13a — Guttman. Elizabeth, ImUd — Stephens, C. Clarke, A. Police- OfBcers. Napier T. Distribution of Medals by Prince.

James's, 8 m 3 6 -9 m 1 1 c Society. Mfixim'it Cuirass. Relist Tiial. New Royal Warrant and Regulations for. John and George, 25 a 1 6 Benpmin. Sophie Marie, 18 m I 6 — Colly er. Harriet L.. John, 19 a 1 c — Evett. Will of, 8 ; 1 c Gunter E. Grace Paige, 25 a 1 6 — — Harding, Eleanor Jane. Hannah, 2 m 1 6 — Joyce. Bei j.. John, 2 m 1 6 — Lindesay.

Mary Ross, 24 a 1 c — Livingstone. Adam, 16 7 1 6 — Micklethwait. Jeremiah, 24 a 1 c — Robinson, G. Henrietta Charlotte, 7. State of. An-' nual Dinner. Sir Hope Grant. Asquiih's Wehh Dis establisih- ment Bill. Paul's School 81 m 6 r — on Public School Holidays. V3 m 10 r — the Aubrey Moore Memorial. Grants of Books to Public Libraries, 28 m 10 r. Fige T. Percirai and Welsh Dis- establishment. Rising in, 19 j 5 e ' Falestine Exploration Fund. Htoms Act.

Ballot tor Kiiday Siitingn. Brennan and his Colleagues. London and North Western Railway. John Herkless. Mundella's Explanation, 25 mHd. Scottish Fishery Board, 18 a 6 e.. Mackness of Work at Enfield, 17 a Sir O.. Sir E.. Lord G.. Sir E. Sir A.. Earl of, 80 J 10 a - Lewis, J.

H , 4 tf 7 r Lloyd- George, —. Earl of. Viscount, 8 m 66 Smith, Parker, 10 a 7 e— 28 m 7 a S.. Annual Meeting, 28m 7 f Pease f J. Peterborough Bp. Attempt of a Convict to Escape from, 21 o 12 r Petroleum in Somerset. Outbreak of, 28 a 12 6 Plumbers' Company, Dinner.

John for Libel. Jane, for Drunkenness, G a lij — 18; a. Claiage, Wm.. John, fur Misdemeanour, 19 m 18 s — ;larke, F. C, for Threats. Harriett, for Assault. Annie, for Stealing. John, lor Stenling, 2 a 14 6—9 a 4e Fitzgerald, J. James, foi Assault, 8 m 1 1 Garland W.

Hailing, Wm.. Ualngrove, George, for Murder, 26 r 4 a. Hewston, Gen. John, for Assault. Paul, and another, for Murder, 5 Kn utzer. Mme Elise. Henry, for Assault. Lucy, and another, for Assault. Sanders, A. Shaw, John, for Fraud. Annie, and another, for Mis- demeanour. Frank, for Attempted Murder, 19m 18 s Geo. John, for Intimidation. Clifford, for Assault, 7 a 15 e - Stanley, Chas. C, for Debtors Act Offence. Heury, for Assault. Harry, for Abuse. Sir W.

C, fir Misdemeanour, 10 m 14 r Rich. Memorial to, 80a 6 6 Port Said. Rngged School Union, Jubilee of. Opening of. History of English Lot- teries, 14 jtri 14 6. Select Specimens of the Great Fri-uch Writer-.

IJecollectiunsof Oil Counrty Life. Discourses BioIogi Ml and Geological. Vieux Souvenirs. Eugene, Sonnets of the Win. Memoirs of Napoleon I. Studies in Forestry, 24 m 12 c Palmer. Gilbert A. Fever's Diarv. I 7 in 6 rf Portal Sir G. Humphry, MarellA,. Rochester Bp. AthelsUn Riley, 30 ; 19 i. Second Spring Show, 19 a i. Meeting, 80 a 6. Asylum, 79th.

Anoand and Mr. Natiice Peasantry of,. Morley's Shuffling, ;12a Note on, 80 j 7 c SaunderBon Col. HeadiuKton, Bp. Asaph Bp. George's Hospital II alls St. Helena ondition of, 5 m 20 a St. John the KvMi. Peter's 1 hurch. Thomas' Hosp. Trial of. Annual Report. Next Sixteen. Auch unseren Hol- und Bringservice haben wir erweitert.

Dezember - Uhr Dezember - Uhr Dezember - Uhr. Mein Sohn Marcel hat sich gestern mit seiner er auf den Weg zu seiner Freundin gemacht. Um ca. Und jetzt kommts!! Die Maschine ist allerdings Totalschaden siehe Fotos. Und jetzt noch an das Arschl Mein Junge hat sich das Moped vom Munde abgespart und auch noch einiges reingesteckt.

Denn im Winter er Wichtiges Thema!!! Termine leider erst ab Auf ein Wiedersehen im neuen Jahr in unserer Werkstatt. Jump to. Sections of this page. Accessibility help. Email or phone Password Forgotten account? Log In. Forgotten account? Not Now. Visitor Posts. Jessica Schulz. See more. Dezember und