While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. ...MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment.
We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported.
27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months).
MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Niclosamide, an FDA-approved anti-helminthic drug, has activity in preclinical models of castration-resistant prostate cancer (CRPC). Potential mechanisms of action include degrading constitutively ...active androgen receptor splice variants (AR-Vs) or inhibiting other drug-resistance pathways (e.g., Wnt-signaling). Published pharmacokinetics data suggests that niclosamide has poor oral bioavailability, potentially limiting its use as a cancer drug. Therefore, we launched a Phase I study testing oral niclosamide in combination with enzalutamide, for longer and at higher doses than those used to treat helminthic infections.
We conducted a Phase I dose-escalation study testing oral niclosamide plus standard-dose enzalutamide in men with metastatic CRPC previously treated with abiraterone. Niclosamide was given three-times-daily (TID) at the following dose-levels: 500, 1000 or 1500mg. The primary objective was to assess safety. Secondary objectives, included measuring AR-V expression from circulating tumor cells (CTCs) using the AdnaTest assay, evaluating PSA changes and determining niclosamide's pharmacokinetic profile.
20 patients screened and 5 enrolled after passing all screening procedures. 13(65%) patients had detectable CTCs, but only one was AR-V+. There were no dose-limiting toxicities (DLTs) in 3 patients on the 500mg TID cohort; however, both (N = 2) subjects on the 1000mg TID cohort experienced DLTs (prolonged grade 3 nausea, vomiting, diarrhea; and colitis). The maximum plasma concentration ranged from 35.7 to 182 ng/mL and was not consistently above the minimum effective concentration in preclinical studies. There were no PSA declines in any enrolled subject. Because plasma concentrations at the maximum tolerated dose (500mg TID) were not consistently above the expected therapeutic threshold, the Data Safety Monitoring Board closed the study for futility.
Oral niclosamide could not be escalated above 500mg TID, and plasma concentrations were not consistently above the threshold shown to inhibit growth in CRPC models. Oral niclosamide is not a viable compound for repurposing as a CRPC treatment.
Clinicaltrials.gov: NCT02532114.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug ...development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
MSH2 Loss in Primary Prostate Cancer Guedes, Liana B; Antonarakis, Emmanuel S; Schweizer, Michael T ...
Clinical cancer research,
11/2017, Volume:
23, Issue:
22
Journal Article
Peer reviewed
Open access
Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
A total of 1,133 primary ...prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).
Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (
< 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed
loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in
Tumors with MSH2 loss had a higher density of infiltrating CD8
lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm
;
= 0.008), and CD8
density was correlated with mutation burden among cases with MSH2 loss (
= 0.72,
= 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.
Loss of MSH2 protein is correlated with
inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
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MAGIC is a system of two Imaging Atmospheric Cherenkov Telescopes located in the Canary island of La Palma, Spain. During summer 2011 and 2012 it underwent a series of upgrades, involving the ...exchange of the MAGIC-I camera and its trigger system, as well as the upgrade of the readout system of both telescopes. We use observations of the Crab Nebula taken at low and medium zenith angles to assess the key performance parameters of the MAGIC stereo system. For low zenith angle observations, the standard trigger threshold of the MAGIC telescopes is ∼ 50GeV. The integral sensitivity for point-like sources with Crab Nebula-like spectrum above 220GeV is (0.66 ± 0.03)% of Crab Nebula flux in 50h of observations. The angular resolution, defined as the σ of a 2-dimensional Gaussian distribution, at those energies is ≲ 0.07°, while the energy resolution is 16%. We also re-evaluate the effect of the systematic uncertainty on the data taken with the MAGIC telescopes after the upgrade. We estimate that the systematic uncertainties can be divided in the following components: < 15% in energy scale, 11%–18% in flux normalization and ± 0.15 for the energy spectrum power-law slope.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
There is a growing body of literature using functional MRI to study the acute and long-term effects of concussion on functional brain networks. To date, studies have largely focused on changes in ...pairwise connectivity strength between brain regions. Less is known about how concussion affects whole-brain network topology, particularly the "small-world" organization which facilitates efficient communication at both local and global scales. The present study addressed this knowledge gap by measuring local and global efficiency of 26 concussed athletes at acute injury, return to play (RTP) and one year post-RTP, along with a cohort of 167 athletic controls. On average, concussed athletes showed no alterations in local efficiency but had elevated global efficiency at acute injury, which had resolved by RTP. Athletes with atypically long recovery, however, had reduced global efficiency at 1 year post-RTP, suggesting long-term functional abnormalities for this subgroup. Analyses of nodal efficiency further indicated that global network changes were driven by high-efficiency visual and sensorimotor regions and low-efficiency frontal and subcortical regions. This study provides evidence that concussion causes subtle acute and long-term changes in the small-world organization of the brain, with effects that are related to the clinical profile of recovery.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
On January 14, 2019, the Major Atmospheric Gamma Imaging Cherenkov telescopes detected GRB 190114C above 0.2 TeV, recording the most energetic photons ever observed from a gamma-ray burst. We use ...this unique observation to probe an energy dependence of the speed of light in vacuo for photons as predicted by several quantum gravity models. Based on a set of assumptions on the possible intrinsic spectral and temporal evolution, we obtain competitive lower limits on the quadratic leading order of speed of light modification.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Clinical trials in men with biochemically recurrent prostate cancer (BRPC) have been hampered by long survival times, making overall survival (OS) a difficult end point to reach. Intermediate end ...points are needed in order to conduct such trials within a more feasible time frame.
This is a retrospective analysis of 450 men with BRPC following prostatectomy treated at a single institution between 1981 and 2010, of which 140 developed subsequent metastases. Androgen deprivation therapy (ADT) was deferred until after the development of metastases. Cox regression models were developed to investigate factors influencing OS.
Median metastasis-free survival (MFS) was 10.2 years 95% confidence interval (CI) 7.6–14.0 years; median OS after metastasis was 6.6 years (95%CI 5.8–8.4 years). Multivariable Cox regressions identified four independently prognostic variables for OS: MFS (HR 0.77; 95% CI 0.63–0.94), number of metastases (≤3 versus ≥4; HR 0.50; 95% CI 0.29–0.85), pain (absent versus present; HR 0.43; 95% CI 0.25–0.72), and bisphosphonate use (yes versus no; HR 0.60; 95% CI 0.37–0.98).
MFS emerged as an independent predictor of OS in men with BRPC treated with deferred ADT after the development of metastases. MFS may be a reasonable intermediate end point in future clinical trials. This observation requires prospective validation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the 1940s Charles Huggins reported remarkable palliative benefits following surgical castration in men with advanced prostate cancer, and since then the androgen receptor (AR) has remained the ...main therapeutic target in this disease. Over the past couple of decades, our understanding of AR-signaling biology has dramatically improved, and it has become apparent that the AR can modulate a number of other well-described oncogenic signaling pathways. Not surprisingly, mounting preclinical and epidemiologic data now supports a role for AR-signaling in promoting the growth and progression of several cancers other than prostate, and early phase clinical trials have documented preliminary signs of efficacy when AR-signaling inhibitors are used in several of these malignancies. In this article, we provide an overview of the evidence supporting the use of AR-directed therapies in prostate as well as other cancers, with an emphasis on the rationale for targeting AR-signaling across tumor types.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
The coincident detection of GW170817 in gravitational waves and electromagnetic radiation spanning the radio to MeV gamma-ray bands provided the first direct evidence that short gamma-ray ...bursts (GRBs) can originate from binary neutron star (BNS) mergers. On the other hand, the properties of short GRBs in high-energy gamma-rays are still poorly constrained, with only ∼20 events detected in the GeV band, and none in the TeV band. GRB 160821B is one of the nearest short GRBs known at
z
= 0.162. Recent analyses of the multiwavelength observational data of its afterglow emission revealed an optical-infrared kilonova component, characteristic of heavy-element nucleosynthesis in a BNS merger. Aiming to better clarify the nature of short GRBs, this burst was automatically followed up with the MAGIC telescopes, starting from 24 s after the burst trigger. Evidence of a gamma-ray signal is found above ∼0.5 TeV at a significance of ∼ 3
σ
during observations that lasted until 4 hr after the burst. Assuming that the observed excess events correspond to gamma-ray emission from GRB 160821B, in conjunction with data at other wavelengths, we investigate its origin in the framework of GRB afterglow models. The simplest interpretation with one-zone models of synchrotron-self-Compton emission from the external forward shock has difficulty accounting for the putative TeV flux. Alternative scenarios are discussed where the TeV emission can be relatively enhanced. The role of future GeV–TeV observations of short GRBs in advancing our understanding of BNS mergers and related topics is briefly addressed.
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