Enzalutamide: a new prostate cancer targeted therapy against the androgen receptor

[Abstract] Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients. In this article, most relevant data published in the literature have been reviewed, with special attention to the therapeutic alternatives currently available for postdocexatel mCRPC patients, emphasising the mechanisms of action of the different drugs, efficacy and quality of life-related aspects

Radium-223 dichloride: a new paradigm in the treatment of prostate cancer

Review[Abstract] Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies

A new scenario in metastatic renal cell carcinoma: a SOG‑GU consensus

[Abstract] Background This article describes and compares approved targeted therapies and the newer immunotherapy agents. Materials and methods This article especially performs an in-depth review of currently available data for tivozanib, explaining its mechanism of action, its safety profle and its role as an efcacy drug in the management of renal cancer. Results Despite the fact that the treatment of advanced RCC has been dramatically modifed in recent years, durable remissions are scarce and it remains a lethal disease. For frst- and second-line therapy, there is now growing evidence to guide the selection of the appropriate treatment. Conclusions Several TKIs are standard of care at diferent settings. Among those approved TKIs, tivozanib has similar efcacy than others with a better safety profle. The use of prognostic factors is critical to the selection of optimal therapy

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016

Impact on clinical practice of the implementation of guidelines for the toxicity management of targeted therapies in kidney cancer. The protect-2 study.

Journal Article;BACKGROUND The impact of such recommendations after their implementation of guidelines has not usually been evaluated. Herein, we assessed the impact and compliance with the Spanish Oncology Genitourinary Group (SOGUG) Guidelines for toxicity management of targeted therapies in metastatic renal cell carcinoma (mRCC) in daily clinical practice. METHODS Data on 407 mRCC patients who initiated first-line targeted therapy during the year before and the year after publication and implementation of the SOGUG guideline program were available from 34 Spanish Hospitals. Adherence to SOGUG Guidelines was assessed in every cycle. RESULTS Adverse event (AE) management was consistent with the Guidelines as a whole for 28.7 % out of 966 post-implementation cycles compared with 23.1 % out of 892 pre-implementation cycles (p = 0.006). Analysis of adherence by AE in non-compliant cycles showed significant changes in appropriate management of hypertension (33 % pre-implementation vs. 44.5 % post-implementation cycles; p < 0.0001), diarrhea (74.0 % vs. 80.5 %; p = 0.011) and dyslipemia (25.0 % vs. 44.6 %; p < 0.001). CONCLUSIONS Slight but significant improvements in AE management were detected following the implementation of SOGUG recommendations. However, room for improvement in the management of AEs due to targeted agents still remains and could be the focus for further programs in this direction.This study was funded by Pfizer, S.L.U. Medical writing assistance was provided by Esther Tapia, PhD and was founded by Pfizer.Ye

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure