Amivantamab in the Treatment of Metastatic NSCLC: Patient Selection and Special Considerations

: Amivantamab is a bispecific antibody that recognizes epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET). In May 2021, the Food and Drug Administration gave an accelerated approval of amivantamab for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (Exon20ins) who progressed after platinum-based chemotherapy. Amivantamab prevents ligand binding to EGFR and MET and the dimerization of the receptors suppressing the downstream signal transduction. Moreover, amivantamab determines antibody dependent cellular cytotoxicity and down regulation of cell surface proteins through internalization of the receptor and trogocytosis. Preliminary results of the Phase I/IB CHRYSALIS trial demonstrated an objective response rate of 40% with a median duration of response of 11.1 months (95% CI 9.6-not reached) in 81 patients treated with amivantamab with pretreated NSCLC with Exon20ins EGFR mutations. In a different cohort of the CHRYSALIS trial, patients with Ex19del and L858R EGFR mutations were enrolled after progression on osimertinib. 121 and 45 patients received amivantamab or a combination with lazertinib, a third-generation tyrosine kinase inhibitor, respectively. The objective response rate was 19% and 36% in patients treated with amivantamab alone or in combination with lazertinib, with a median progression-free survival of 6.9 (95% CI: 3.2-5.3) and 11.1 (95% CI: 3.7-9.5) months, respectively. All 20 patients with Ex19del and L858R EGFR mutations who received amivantamab and lazertinib as their first line treatment achieved an objective response. Amivantamab is currently under evaluation in Phase III clinical trials for the first line treatment of NSCLCs with Exon20ins EGFR mutations in combination with chemotherapy (PAPILLON), for the first line therapy of Ex19del and L858R mutated NSCLCs in combination with lazertinib (MARIPOSA) and in combination with chemotherapy and lazertinib in NSCLCs who progressed on osimertinib (MARIPOSA-2)

The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells

Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms

Plantar erythrodysesthesia with bullous otitis externa, toxicities from sorafenib: a case report

Lung cancer is the leading cause of cancer death worldwide and the use of novel agents, such as sorafenib has now demonstrated activity in Non Small Cell Lung Cancer. We present a case of a 77-year-old Caucasian male with advanced adenocarcinoma of the lung, who was being treated on clinical trial with single agent sorafenib. After seven weeks of treatment the patient presented to clinic with difficulty walking. Physical exam revealed acral erythema with bollous formation on bilateral soles of his feet. Otoscopic exam revealed bilateral external canal bullous lesion. The patient was diagnosed with plantar erythrodysesthesia with bullous otitis externa, a new toxicities in patients being treated with sorafenib

Designing Probabilistic Flow Counting over Sliding Windows

Probabilistic approaches allow designing very efficient data structures and algorithms aimed at computing the number of flows within a given observation window. The practical applications are many, ranging from security to network monitoring and control. We focus our investigation on approaches tailored for sliding windows, that enable continous-time measurements independently from the observation window. In particular, we show how to extend standard approaches, such as Probabilistic Counting with Stochastic Averaging (PCSA), to count over an observation window. The main idea is to modify the data structure to store a compact representation of the timestamp in the registers and to modify coherently the related algorithms. We propose a timestamp-augmented version of PCSA, denoted as TS-PCSA, and compare it with state-of-the-art solutions based on Hyper-LogLog (HLL) counters that evaluate the cardinality over a sliding window, but without storing the timestamps. We will show that TS-PCSA with a limited memory footprint is achieving a different tradeoff between memory and accuracy with respect to HLL-based solutions

La Vegetazione marina bentonica sciafila del Mediterraneo: 3.: Infralitorale e Circalitorale: proposte di aggiornamento

Sono stati esaminati criticamente 19 Aggruppamenti vegetali sciafili dell'Infralitorale e del Circalitorale; di questi 10 (9 Associazioni ed 1 Subassociazione) sono stati ritenuti validi. A phytosociological revision of 19 sciafilic algae assemblages located in the infralittoral and circalittoral zones is presented. At all 9 associations and 1 association can be recognized

A novel missense mutation in PSEN2 gene associated with a clinical phenotype of frontotemporal dementia

Background: In Familial Alzheimer's disease defects in three genes - the amyloid precursors protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14 and the presenilin 2 (PSEN2) on chromosome 1- have been identified. More than 160 pathogenic missense mutations have been described in PSEN1, with wide clinic phenotypic variability. In PSEN2 only 11 missense mutations are known, in two of which (M239V and T122R) the clinical phenotype may be frontotemporal dementia-like. Methods: We present a novel PSEN2 mutation (Y231C) in an Italian patient who seven years ago, at age 55, manifested mood and behavioural disorders characterized by apathia, delusions, physical aggressive behaviour and psychomotor agitation. Language disturbances appeared one year later and mild memory loss three years later. The neuropsychological pattern suggested a main dysfunction in posterior temporal and parietal cortex. MRI showed diffuse atrophy, especially in posterior regions. Results: The genetic study showed an A-to-G mutation in exon seven of PSEN2 gene, resulting in tyrosine to cysteine substitution at residue 231. Conclusions: This new mutation confirms the variability of the phenotypes associated with PSEN2 mutations and justified the analysis of this gene in behavioural disturbances associated with degenerative dementia, at least in Italy in which PSEN2 mutations seems more frequent than in other countries

Studio di impatto ambientale nell'area portuale antistante lo stabilimento industriale EniChem di Porto Torres

This paper reports environmental study carried out in the seaport wear Petro-chemical Plant of Porto Torres (North-Western Sardinia) eight years after study where four areas at different level of pollution were described. In the meantime specific, ecological plants are realized i.e. liquid effluent collectors, biological water treatment plant and a stelling basin of depurated effluents. The present work shows a general improvement of the harbour area, as water quality and transparency, heavy metals content of sediments and aquatic flora. In this way two different methods are used (synecological and chemical), i.e. mapping of biotic community, density of Posidonia oceanica seagrass, chemical analysis of oysters, posidonia's rhizome and leaf, water and sediments