Abstract Background The androgen receptor splice variant 7 (AR-V7) is associated with resistance to hormonal therapy in castration-resistant prostate cancer (CRPC). Due to limitations of the methods ...available for AR-V7 analysis, the identification of a reliable detection method may facilitate the use of this biomarker in clinical practice. Objective To confirm AR-V7 as a predictor of resistance to hormonal therapy and develop a new approach to assess AR-V7 by highly sensitive digital droplet polymerase chain reaction (ddPCR) in plasma-derived exosomal RNA. Design, setting, and participants Plasma samples were collected from 36 CRPC patients before they began second-line hormonal treatment. Exosomes were isolated and RNA extracted for analysis of AR-V7 by ddPCR. Outcome measurements and statistical analysis The absolute target gene concentration as copies per milliliter (copies/ml) was determined by ddPCR. Statistical analyses were performed with SPSS software (IBM Corp., Armonk, NY, USA). Results and limitations A total of 26 patients received abiraterone and 10 enzalutamide; 39% of patients were found to be AR-V7 positive (AR-V7+ ). Median progression-free survival was significantly longer in AR-V7 negative (AR-V7− ) versus AR-V7+ patients (20 vs 3 mo; p < 0.001). Overall survival was significantly shorter in AR-V7+ participants at baseline compared with AR-V7− participants (8 mo vs not reached; p < 0.001). Conclusions This study demonstrates that plasma-derived exosomal RNA is a reliable source of AR-V7 that can be detected sensitively by ddPCR assay. We also showed that resistance to hormonal therapy may be predicted by AR-V7, making it a clinically relevant biomarker. Patient summary We report a first study on a method for androgen receptor splice variant 7 (AR-V7) detection in RNA extracted from cancer cell vesicles released in blood. Results confirmed the role of AR-V7 as a predictive biomarker of resistance to hormonal therapy. Our assay showed that vesicles are a reliable source of AR-V7 RNA and that the method is fast, highly sensitive, and affordable.
Immune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a ...considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.
Around 70 infectious agents are possible threats for blood safety.
The risk for blood recipients is increasing because of new emergent agents like West Nile, Zika and Chikungunya viruses, or ...parasites such as
and
in non-endemic regions, for instance.
Screening programmes of the donors are more and more implemented in several Countries, but these cannot prevent completely infections, especially when they are caused by new agents.
Pathogen inactivation (PI) methods might overcome the limits of the screening and different technologies have been set up in the last years.
This review aims to describe the most widely used methods focusing on their efficacy as well as on the preservation integrity of blood components.
Background
The role of image-derived biomarkers in recurrent oligometastatic Prostate Cancer (PCa) is unexplored. This paper aimed to evaluate
18
FFMCH PET/CT radiomic analysis in patients with ...recurrent PCa after primary radical therapy. Specifically, we tested intra-patient lesions similarity in oligometastatic and plurimetastatic PCa, comparing the two most used definitions of oligometastatic disease.
Methods
PCa patients eligible for
18
FFMCH PET/CT presenting biochemical failure after first-line curative treatments were invited to participate in this prospective observational trial. PET/CT images of 92 patients were visually and quantitatively analyzed. Each patient was classified as oligometastatic or plurimetastatic according to the total number of detected lesions (up to 3 and up to 5 or > 3 and > 5, respectively). Univariate and intra-patient lesions' similarity analysis were performed.
Results
18
FFMCH PET/CT identified 370 lesions, anatomically classified as regional lymph nodes and distant metastases. Thirty-eight and 54 patients were designed oligometastatic and plurimetastatic, respectively, using a 3-lesion threshold. The number of oligometastic scaled up to 60 patients (thus 32 plurimetastatic patients) with a 5-lesion threshold. Similarity analysis showed high lesions' heterogeneity. Grouping patients according to the number of metastases, patients with oligometastatic PCa defined with a 5-lesion threshold presented lesions heterogeneity comparable to plurimetastic patients. Lesions within patients having a limited tumor burden as defined by three lesions were characterized by less heterogeneity.
Conclusions
We found a comparable heterogeneity between patients with up to five lesions and plurimetastic patients, while patients with up to three lesions were less heterogeneous than plurimetastatic patients, featuring different cells phenotypes in the two groups. Our results supported the use of a 3-lesion threshold to define oligometastatic PCa.
Pancreatic metastases from renal cell carcinoma are uncommon and their prognostic significance is not well defined. In this analysis we evaluated the outcome of patients with pancreatic metastases ...treated with either targeted therapies or local treatment to the pancreas. Patients with pancreatic metastases from renal cell carcinoma treated between 1993 and 2014 were identified from 11 European centers. Clinical records were retrospectively reviewed. Kaplan-Meier method and log-rank test were used to evaluate progression-free survival and overall survival. Cox's proportional hazard models were used for survival analysis. In total, 276 PM patients were evaluated, including 77 (28%) patients treated by either surgery or radiotherapy to the pancreas, and 256 (93%) who received systemic therapy. Median time from nephrectomy to diagnosis of pancreatic metastases was 91 months (IQR 54-142). Disease control rate after first-line TTs was 84%, with a median progression-free survival of 12 months (95% CI 10-14). Median overall survival was 73 months (95% CI 61-86) with a 5-year OS of 58%. Median OS of patients treated with local treatment was 106 months (95% CI 78-204) with a 5-year overall survival of 75%. On multivariable analysis, nephrectomy (HR 5.31; 95%CI 2.36-11.92; p<0.0001), Memorial Sloan Kettering/International Metastatic RCC Database Consortium prognostic score (HR 1.45, 95% CI 0.94-2.23 for intermediate vs good vs risk; HR 2.76 95%, CI 1.43-5.35 for poor vs good risk p = 0.0099) and pancreatic local treatment (HR 0.48; 95%CI 0.30-0.78 p = 0.0029) were associated with overall survival. Difference in median OS between patients with PM and that reported in a matched-control group of mRCC patients with extrapancreatic metastases was statistically significant (p < .0001). Pancreatic metastases from renal cell carcinoma usually occur years after nephrectomy, are associated with an indolent behavior and a prolonged survival. Targeted therapies and locoregional approaches are active and achieve high disease control rate.
Background
The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; ...INT) and within the Italian Rare Cancer Network (“Rete Tumori Rari”; RTR).
Methods
We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for
WWTR1
rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15–20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria.
Results
Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic;
WWTR1
rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1–45), with four patients progression-free at 24 months. The clinical benefit (complete response CR + PR + SD
>
6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1–8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients.
Conclusions
A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.
Commissioning of liquid xenon gamma-ray detector for MEG II experiment Matsushita, Ayaka; Ban, Sei; Benmansour, Hicham ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2023, Letnik:
1047
Journal Article
Recenzirano
The liquid xenon (LXe) gamma-ray detector in the MEG II experiment measures the energy, position and timing of the gamma-ray from μ+→e+γ, and it is the key to the unprecedented sensitivity of the ...experiment. All the photo sensors of 4092 VUV MPPCs and 668 PMTs were read out for the first time and a physics data collection started in 2021. The detector response was monitored all through the beam time, and the LXe detector operated stably. The timing and energy resolution were measured using the gamma-rays from the π0 decays after charge exchange reaction of charged pions in a liquid hydrogen target. The detector has been successfully commissioned and is ready for the long physics run.
Abstract
Background
Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma ...(mccRCC).
Methods
Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings.
Results
A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004).
Conclusions
The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.
, a ubiquitous intracellular parasite, has a strong tropism for the brain tissue, where it forms intracellular cysts within the neurons and glial cells, establishing a chronic infection. Although ...latent toxoplasmosis is generally assumed to be asymptomatic in immunocompetent individuals, it is now clear that it can induce behavioral manipulations in mice and infected humans. Moreover, a strong relation has emerged in recent years between toxoplasmosis and psychiatric disorders. The link between
and schizophrenia has been the most widely documented; however, a significant association with bipolar disorder (BD) and suicidal/aggressive behaviors has also been detected.
may play a role in the etiopathogenesis of psychiatric disorders affecting neurotransmitters, especially dopamine, that are implicated in the emergence of psychosis and behavioral
-induced abnormalities, and inducing brain inflammation by the direct stimulation of inflammatory cytokines in the central nervous system. Besides this, there is increasing evidence for a prominent role of immune dysregulation in psychosis and BD. The aim of this review is to describe recent evidence suggesting a link between
and BD, focusing on the interaction between immune responses and this infectious agent in the etiopathogenesis of psychiatric symptoms.
This work presents a tectonic geomorphology analysis of a river bend in the middle Tavo River valley, in the piedmont area of the NE Apennines (Abruzzo Region), between the eastern slope of the chain ...(Gran Sasso Massif) and the Adriatic coast. The main map (1:15,000 scale) was obtained through a morphometric, geological, and geomorphological analysis, and was composed of four sections including orography and hydrography at basin scale, main map at local scale, geomorphological cross-section and longitudinal profiles, and morphoneotectonic analysis. This study provides a basis for the recognition of morphostructural and morphotectonic features that control the drainage evolution of the Tavo River. Specifically, the study is focused on the Tavo-Saline basin characterized by possible capture processes, and the evolution of the watershed with the Pescara basin. The results from this study can contribute to the understanding of the evolution of the NE Apennines piedmont area since the Middle Pleistocene.
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