In patients with higher uric acid levels, the ARB of choice should be losartan. Irbesartan may also have a protective effect at therapeutic doses. Telmisartan is a neutral agent regarding uric acid excretion, while candesartan, olmesartan and valsartan may increase the risk of hyperuricemia.
Since 2018, FHU OncoAge (Nice, France) and the MD Anderson Cancer Center (MDACC) (Houston, Tx, USA) hosting annual meetings dedicated to recent advances in lung cancer. These meetings were held in person in Nice and then in Houston. This year, on October 4th, the third Joint Meeting on Lung Cancer (JMLC) will be virtually due to COVID-19. This meeting will be co-organized by George Calin, Sendurai Mani and Ignacio Wistuba from the MDACC and by Paul Hofman from the FHU OncoAge. At this third JMLC meeting, experts from the MDACC and for the FHU Oncoage will present the last advances in different fields of thoracic oncology, including new therapeutic options (in targeted therapy and immunotherapy fields), new predictive biomarkers, as well as new discoveries in lung carcinogenesis.
Therapeutic Choices 7th edition.torrent
The main objective of the Special Issue is to summarize the current trends and discuss different topics linked to lung cancer based on the presentations from the third JMLC meeting. Importantly, this Special Issue will promote understanding of new therapeutic options for lung cancer patients in the near future and decipher the mechanisms of lung carcinoma development and progression.
The drug discovery process has long been characterized by very low success rates in moving compounds from early-stage studies to clinically proven therapeutics. A confounding factor in the process is the inability to conduct high-throughput screening in an environment that truly mirrors human physiology. These early-stage tests are typically performed [ Read More ]
Consultation breaks and invitations for more information from clients allow for both the therapist and client to brainstorm on what might have been missed during the initial conversations. After this break, clients are complemented and given a therapeutic message about the presenting issue. The message is typically stated in the positive so that clients leave with a positive orientation toward their goals.
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.See related commentary by Rouanne et al., p. 1097.This article is highlighted in the In This Issue feature, p. 1079.
Low tumor cellularity, tumor heterogeneity, clonal evolution, treatment status, sample quality, and/or size of the sequencing panel accounted for a proportion of the differential detection of mutations at primary and metastatic sites. The therapeutic implications of the most frequently discordant alterations (TP53, APC, PIK3CA, and SMAD4) are discussed. Our meta-analysis indicates that a subset of patients who fail initial therapy may benefit from sequencing of additional sites to identify new actionable genomic abnormalities not present in the initial analysis. Evidence-based recommendations are proposed.
Over the past decade, our improved understanding of CRC biology has resulted in the identification of novel molecular targets with corresponding targeted therapies which improve survival and have fewer side effects [5]. The most important of these is the proto-oncogene epidermal growth factor receptor (EGFR), which is often overexpressed in CRC [6, 7]. Two monoclonal antibodies, cetuximab and panitumumab, which target the extracellular ligand-binding domain of EGFR, are FDA-approved for treating mCRC lacking KRAS- and NRAS-activating mutations [8]. CRCs that harbor RAS-activating mutations, however, are resistant to anti-EGFR antibodies, and these therapies are contraindicated in this setting. Similarly, CRCs that harbor BRAF-activating mutations are typically resistant to anti-EGFR antibodies; however, combining anti-EGFR therapy with the BRAF V600E inhibitor encorafenib has demonstrated efficacy [9]. Given the therapeutic relevance of KRAS, NRAS, and BRAF mutations, testing for all three is recommended in the metastatic setting [3, 4, 10]. Many have found mutations in these genes to be highly concordant in paired primary and metastatic colorectal cancers [11], leading to the NCCN guideline that either tumor is suitable for genotyping these markers [3, 4]. Conversely, others have found significant discordance in KRAS status between sites and after therapy [12,13,14,15].
Looking beyond RAS and BRAF mutations, about 15% of CRCs harbor DNA mismatch repair deficiency (dMMR), which results in microsatellite instability (MSI) [16]. The identification of this subset of CRCs is critical due to its prognostic and therapeutic implications [16]. First, patients with dMMR/MSI tumors tend to have significantly more favorable survival outcomes than those with MMR-proficient/microsatellite stable tumors. Second, dMMR/MSI tumors have poor response to standard CRC therapy with FOLFOX/FOLFIRI regimens but are exquisitely sensitive to immunotherapies targeting immune checkpoint molecules. Indeed, several immunotherapies are now FDA-approved for treating dMMR/MSI CRC [17]. Several studies have demonstrated a high degree of concordance in dMMR/MSI status between patient-matched primary and metastatic CRCs, but site-specific and treatment-induced differences were noted [18,19,20,21,22].
More recently, targeted next-generation sequencing (NGS) has entered the clinical arena as a cost-effective means of identifying additional actionable genetic abnormalities [23, 24]. Thus, for those CRC patients who are refractory to cytotoxic chemotherapy or are not candidates for anti-EGFR antibody therapy or checkpoint inhibitors, NGS may identify additional therapeutic targets beyond RAS, BRAF, and MSI and allow for placement in clinical trials. This raises the question of whether paired primary and metastatic CRCs will be concordant for these additional targets.
One reason to expect otherwise is that tumors evolve over time and after branching, continue to evolve over time independently. Therefore, genetic differences within different areas of a tumor mass (intratumoral heterogeneity) and between paired primary and metastatic tumors (intertumoral heterogeneity) are to be expected. While this phenomenon of genetic heterogeneity of tumors is generally accepted, the qualitative and quantitative extent of the heterogeneity between primary tumors (PTs) and their paired metastases to either distant organs (DMs) or regional lymph nodes (RLNs) is controversial. Metastases may potentially harbor a distinct spectrum of mutations compared to their PTs and therefore, may respond to a different set of drugs. Genetic discordance creates a challenge for the pathologist who must determine which formalin-fixed paraffin-embedded (FFPE) tissue block to select for NGS, a decision which may profoundly impact downstream therapeutics and ultimately patient outcomes.
A small sample size reflects the most important limitation of our work. However, as we incorporate our data into a meta-analysis, we are able to provide a robust estimate of the genetic similarity of patient-matched tumors. Furthermore, our comprehensive analysis of every patient, including multiple metastases and recurrences, further substantiates our conclusion that primaries and metastases are generally genetically similar. While our study only focused on 50 genes, we do not consider this to be a limitation of significant importance given that the objective of our study was to determine differences in actionable gene mutations in primary and metastatic CRCs. At this time, the number of therapeutically actionable genes is small, and the vast majority are reflected in the 50-gene panel, and those that are not, such as NTRK, are exceptionally rare in CRC. While this study was conducted at a single institution, we do not believe this to be a major shortcoming to the generalizability of our study due to the diversity of our patient population.
The clinical utility of KRAS, NRAS, and BRAF is certainly clear. In our meta-analysis, there were only rare RAS discordances and no BRAF discordances. However, rare differences in the mutational status of these genes could have a significant impact on treatment. For instance, patient 5 had an NRAS mutation in the PT but not in the DM and, therefore, would have potentially qualified for anti-EGFR therapy. Among significantly altered CRC genes, TP53, APC, PIK3CA, and SMAD4 were the most frequently discordant in our meta-analysis (Supplemental Table S2). Always a leader in frequency, mutated TP53 is a target of extremely high unmet need without well-established therapeutic options, but some inroads are in progress, including a phase 2 study of the antiviral agent lamivudine in patients with p53-mutant mCRC (NCT03144804). 2ff7e9595c
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