Exceptional response to immunotherapy in association with radiotherapy in patient with breast metastasis from urothelial carcinoma: A case report

Most common sites of metastasis of urothelial carcinoma (UC) are lungs, liver, lymph nodes and bone. Pembrolizumab, a humanized monoclonal antibody directed against programmed cell death protein-1 (PD-1), represents an effective second-line therapy for advanced UC. Radiotherapy has been shown to induce a mechanism of immunogenic cell death (ICD) resulting in immune memory and advantageous systemic effects. We present the first case of breast metastasis (BM) from a UC described in literature who had an exceptional response to second-line therapy with pembrolizumab in association with radiotherapy, showing the efficacy of combining immunotherapy and radiotherapy even in patients with atypical metastatic sites

Resolving the cosmic X-ray background with a next-generation high-energy X-ray observatory

The cosmic X-ray background (CXB), which peaks at an energy of ~30 keV, is produced primarily by emission from accreting supermassive black holes (SMBHs). The CXB therefore serves as a constraint on the integrated SMBH growth in the Universe and the accretion physics and obscuration in active galactic nuclei (AGNs). This paper gives an overview of recent progress in understanding the high-energy (>~10 keV) X-ray emission from AGNs and the synthesis of the CXB, with an emphasis on results from NASA's NuSTAR hard X-ray mission. We then discuss remaining challenges and open questions regarding the nature of AGN obscuration and AGN physics. Finally, we highlight the exciting opportunities for a next-generation, high-resolution hard X-ray mission to achieve the long-standing goal of resolving and characterizing the vast majority of the accreting SMBHs that produce the CXB.Comment: Science White paper submitted to Astro2020 Decadal Survey; 5 pages, 3 figures, plus references and cover pag

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort

Background: Reliable and affordable prognostic and predictive biomarkers for urothelial carcinoma treated with immunotherapy may allow patients' outcome stratification and drive therapeutic options. The SAUL trial investigated the safety and efficacy of atezolizumab in a real-world setting on 1004 patients with locally advanced or metastatic urothelial carcinoma who progressed to one to three prior systemic therapies.Patients and methods: Using the SAUL Italian cohort of 267 patients, we investigated the prognostic role of neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) and the best performing one of these in combination with programmed death-ligand 1 (PD-L1) with or without lactate dehydrogenase (LDH). Previously reported cut-offs (NLR >3 and NLR >5; SII >1375) in addition to study-defined ones derived from receiver operating characteristic (ROC) analysis were used.Results: The cut-off values for NLR and SII by the ROC analysis were 3.65 (sensitivity 60.4; specificity 63.0) and 884 (sensitivity 64.4; specificity 67.5), respectively. The median overall survival (OS) was 14.7 months for NLR <3.65 [95% confidence interval (CI) 9.9-not reached (NR)] versus 6.0 months for NLR >= 3.65 (95% CI 3.9-9.4); 14.7 months for SII <884 (95% CI 10.6-NR) versus 6.0 months for SII >= 884 (95% CI 3.7-8.6). The combination of SII, PD-L1, and LDH stratified OS better than SII plus PD-L1 through better identification of patients with intermediate prognosis (77% versus 48%, respectively). Multivariate analyses confirmed significant correlations with OS and progression-free survival for both the SII + PD-L1 + LDH and SII PD-L1 combinations.Conclusion: The combination of immune-inflammatory biomarkers based on SII, PD-L1, with or without LDH is a potentially useful and easy-to-assess prognostic tool deserving validation to identify patients who may benefit from immunotherapy alone or alternative therapies

NuSTAR observations of water megamaser AGN

Aims. We study the connection between the masing disk and obscuring torus in Seyfert 2 galaxies. Methods. We present a uniform X-ray spectral analysis of the high energy properties of 14 nearby megamaser active galactic nuclei observed by NuSTAR. We use a simple analytical model to localize the maser disk and understand its connection with the torus by combining NuSTAR spectral parameters with the available physical quantities from VLBI mapping. Results. Most of the sources that we analyzed are heavily obscured, showing a column density in excess of ~10^(23) cm^(-2); in particular, 79% are Compton-thick (N_H > 1.5 × 10^(24) cm^(-2)). When using column densities measured by NuSTAR with the assumption that the torus is the extension of the maser disk, and further assuming a reasonable density profile, we can predict the torus dimensions. They are found to be consistent with mid-IR interferometry parsec-scale observations of Circinus and NGC 1068. In this picture, the maser disk is intimately connected to the inner part of the torus. It is probably made of a large number of molecular clouds that connect the torus and the outer part of the accretion disk, giving rise to a thin disk rotating in most cases in Keplerian or sub-Keplerian motion. This toy model explains the established close connection between water megamaser emission and nuclear obscuration as a geometric effect

FIRST LINE AVELUMAB IN PD-L1+VE METASTATIC OR LOCALLY ADVANCED UROTHELIAL CANCER (AUC) PATIENTS UNFIT FOR CISPLATIN (CIS): THE ARIES TRIAL

Background: Avelumab (ave) was approved as maintenance therapy after platinum-based first line (1L) therapy for patients (pts) with aUC based on ph. 3 Javelin Bladder 100 study (NCT02603432), showing significant overall survival (OS) improvement. Here we tested the activity of ave as 1L of therapy in pts with aUC and PD-L1+ve expression. Methods: ARIES is a single-arm, multi-site, open-label phase II trial. Enrolled pts had aUC, were cis-unfit (at least one of: ECOG-PS=2, CrCl <60 mL/min, grade ⩾2 peripheral neuropathy/hearing loss, progression within 6-mos before the end of neo/adj chemo), had not previously received chemo for aUC and PD-L1⩾5% (SP263) centrally assessed. Pts received ave 10 mg/Kg IV Q2W until progression, unacceptable toxicity and withdrawal, whichever occurred first. The primary endpoint was the 1-year OS. Key secondary endpoints were median-OS, -PFS, ORR, DOR and safety. The outcome based on PDL1 expression >10 has also been investigated. Results: A total of 198 eligible cis-unfit pts have been tested for PD-L1 and 71 (35.6%) have been found positive. Among enrolled patients (N=71), median age was 75 y, 35 (49.3%) had visceral disease, and 22 (31.0%) had ECOG-PS=2; 50 (70.4%) had CrCl <60 mL/min and 9 (12.7%) progressed within 6-mos from the end of neo/adj chemo. At the cut-off data (Feb 2, 2022), median follow up was 10.0 mos and 14 patients are still on treatment. The median OS was 10.0 mos (95% CI, 5.5-14.5), and 43.0% of patients were alive at 1-year. The ORR for all patients was 24.0%; complete response, 8.5% (n=6); partial response, 15.5% (n=11). Clinical benefit was 43.6% (n=31). Median PFS was 2.0 mos (95% CI, 1.7-2.3). Among the 17 pts who had tumour response 13 had DOR > 1y and 5 > 2y. A total of 67 patients have been evaluated for CPS and among these 56 (83.6%) have been classified as high expression. The median OS was 11.0 mos (95%CI, 0.1 – 22.9) for those with high CPS and 7.0 mos (95%CI 2.8 – 11.2) for low CPS (p=0.13). The median PFS was 2.0 mos for both high and low CPS (p=0.34). Five (7.0%) grade 3 ave-related adverse events, and no treatment-related death were reported. Conclusions: Ave is active and safe in pts with cis-unfit, PD-L1+ve aUC and poor baseline characteristics

<i>NuSTAR </i>reveals the extreme properties of the super-Eddington accreting supermassive black hole in PG 1247+267

PG1247+267 is one of the most luminous known quasars at z similar to 2 and is a strongly super-Eddington accreting supermassive black hole (SMBH) candidate. We obtained NuSTAR data of this intriguing source in December 2014 with the aim of studying its high-energy emission, leveraging the broad band covered by the new NuSTAR and the archival XMM-Newton data. Several measurements are in agreement with the super-Eddington scenario for PG1247+267: the soft power law (Gamma = 2.3 +/- 0.1); the weak ionized Fe emission line; and a hint of the presence of outflowing ionized gas surrounding the SMBH. The presence of an extreme reflection component is instead at odds with the high accretion rate proposed for this quasar. This can be explained with three different scenarios; all of them are in good agreement with the existing data, but imply very different conclusions: i) a variable primary power law observed in a low state, superimposed on a reflection component echoing a past, higher flux state; ii) a power law continuum obscured by an ionized, Compton thick, partial covering absorber; and iii) a relativistic disk reflector in a lamp-post geometry, with low coronal height and high BH spin. The first model is able to explain the high reflection component in terms of variability. The second does not require any reflection to reproduce the hard emission, while a rather low high-energy cutoff of similar to 100 keV is detected for the first time in such a high redshift source. The third model require a face-on geometry, which may affect the SMBH mass and Eddington ratio measurements. Deeper X-ray broad-band data are required in order to distinguish between these possibilities

Treatment Outcome of metastatic lesions from renal cell carcinoma underGoing Extra-cranial stereotactic body radioTHERapy: The together retrospective study

Objectives: stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients. Methods: all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion. Results: 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions (&lt;14 mm). SBRT was safe and the 1-year local disease control was 87.7%. After SBRT, 18 patients (37.5%) permanently interrupted systemic therapy. Conclusions: consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients