Chips Shortage and Chips Acts: The Inside View Azzoni, Paolo; Galloni, Jean-Luc di Paola; Serpanos, Dimitrios ...
Computer (Long Beach, Calif.),
2023-Nov., 2023-11-00, Letnik:
56, Številka:
11
Journal Article
Recenzirano
International initiatives to remedy semiconductor chip shortage are rebuilding supply chains and restructuring value chains. Emerging technologies and ongoing digitalization lead to the need to Ie ...all stages of the supply and value chains in the initiatives.
In order to study alternatives at the tissue biopsy to study EGFR status in NSCLC patients, we evaluated three different liquid biopsy platforms (plasma, urine and exhaled breath condensate, EBC). We ...also reviewed the literature of the cfDNA biological sources other than plasma and compared our results with it about the sensitivity to EGFR mutation determination. Twenty-two EGFR T790M-mutated NSCLC patients in progression to first-line treatment were enrolled and candidate to osimertinib. Plasma, urine and EBC samples were collected at baseline and every two months until progression. Molecular analysis of cfDNA was performed by ddPCR and compared to tissue results. At progression NGS analysis was performed. The EGFR activating mutation detection reached a sensitivity of 58 and 11% and for the T790M mutation of 45 and 10%, in plasma and urine samples, respectively. Any DNA content was recovered from EBC samples. Considering the plasma monitoring study, the worst survival was associated with positive shedding status; both plasma and urine molecular progression anticipated the radiological worsening. Our results confirmed the role of plasma liquid biopsy in testing EGFR mutational status, but unfortunately, did not evidence any improvement from the combination with alternative sources, as urine and EBC.
Despite concerns on mental health problems related to lockdowns, recent reports revealed a reduction in psychiatric admissions in Emergency Departments (ED) during the lockdown period compared with ...the previous year in several countries. Most of the existing studies focused on the first lockdown not considering the different phases of the COVID-19 crisis. The present study aimed to analyze differences in ED admission for psychiatric consultation during three different phases of the COVID-19 health crisis in Italy.
Information on ED admission for psychiatric consultations were retrospectively collected at the ED of the Santo Spirito Hospital in Rome (Italy), and compared between the three periods: the lockdown (March-June 2020) and the post-lockdown period (June 2020-June 2021) compared to the pre-lockdown (January 2019-March 2020). Multinomial logistic regression was used to assess the risk of accessing ED for psychiatric consultation before, during, after the lockdown.
Three thousand and eight hundred seventy-one ED psychiatric consultations were collected. A significant reduction of psychiatric consultations in ED during the lockdown period and the post-lockdown (H 762,45; p < 0.001) was documented. Multinomial logistic regression analysis showed that compared to pre-lockdown during the lockdown and post-lockdown patients were more likely to be men (RRR 1.52; 95% CI 1.10-2.12) and more often diagnosed with non-severe mental illnesses (nSMI) (relative risk ratio RRR 1.53, 95% CI 1.10-2.15; and 1.72, 95% CI 1.42-2.08); during the lockdown, patients were also more often diagnosed with alcohol/substance abuse (A&S) (RRR 1.70; 95% CI 1.10-2.65).
several changes in the clinical characteristics of psychiatric consultations during and after the lockdown emerged from the present study; nSMI and A&S abuse patients were more likely to present at the ED in the lockdown and post-lockdown periods while SMI patients appeared to be less likely. These may inform clinicians and future preventive strategies among community mental health services.
•Plasmatic levels of EGFR activating mutations at baseline affect prognosis.•The plasmatic mutational load inversely correlates with outcome measures.•Therascreen selects patients with high ...mutational load sample and worst outcome.•T790M loss after progression is associated to EGFR-independent resistance mechanism.
Analysis of circulating tumor DNA (ctDNA) for the identification of T790M mutation in advanced EGFR-mutated NSCLC patients can replace tissue re-biopsy for resistance characterization and, being non-invasive, may be applied for disease monitoring. We analysed ctDNA during osimertinib treatment to correlate mutational levels with clinical outcome and to predict pattern of resistance.
Forty patients with advanced NSCLC receiving osimertinib for T790M + disease after previous EGFR-TKI were enrolled in a pilot study to collect plasma at baseline and every 12 weeks until progression. Molecular analysis of ctDNA was performed by ddPCR and Therascreen®. When feasible at progression, tissue re-biopsy and NGS analysis were performed.
Thirty-eight patients had baseline plasma samples suitable for molecular analysis. Patients with low levels of the EGFR activating mutation in ctDNA < 2200 copies/mL or allele frequency (AF) < 6.1% showed better progression-free survival (17.8 or 17.8 months vs. 4.3 or 2.7, p = 0.022 or p = 0.018, respectively) and overall survival (23.6 or 23.6 vs. 7.7 or 7.3, p = 0.016 or p = 0.013, respectively) than patients with high levels (≥ 2200 copies/mL or AF ≥ 6.1%). Patients with detectable EGFR mutations in plasma (shedders) presented worse outcome than negative subjects (non-shedders). Low levels of T790M, higher T790M/activating mutation ratio and complete clearance after 2 months were associated with a trend towards better outcome. Tissue re-biopsy at resistance showed 3 patients with EGFR C797S, 1 with MET amplification, 1 with MYC amplification, 1 with PTEN loss, 3 with SCLC transformation.
The mutational analysis performed on plasma plays a significant role in prognostic stratification, especially for the EGFR activating mutation, since patients with absence or low levels of mutations presented a better outcome to osimertinib. At progression, tissue re-biopsy remains a crucial issue for the identification of resistance mechanisms.
To evaluate the impact of faecal immunochemical test (FIT) screening on stage distribution at diagnosis, and to estimate relative incidence rates by stage in screened at first and subsequent rounds ...vs. unscreened. We included all incident cases occurring in 2000–2008 in 50‐ to 71‐year‐olds residing in areas with an FIT‐screening programme. Multinomial logistic models were computed to estimate the relative risk ratio (RRR) of stages I and IV, compared to stage II + III, adjusting for age, sex, geographical area, and incidence year. Proportions were then used to estimate incidence rate ratios (IRR) by stage for screened subjects at the first and at subsequent rounds vs. unscreened subjects, applying the expected changes in overall incidence during screening phases. 11,663 cancers were included: 5965 in not‐invited and 5,698 in invited subjects, 3,425 of whom attendees. Compared to not‐invited, invited subjects had RRR 2.04 (95% CI: 1.84; 2.46) of stage I and RRR 0.77 (95% CI: 0.69; 0.87) of stage IV. Differences were stronger comparing attendees vs. nonattendees. Interval cancers were more frequently stage I compared to non‐invited (RRR 1.54; 95% CI: 1.15; 2.04), but there was no difference for stage IV. IRRs in screened at first round vs. unscreened were 4.6 (95% CI: 4.2; 5.1), 1.4 (95% CI: 1.3; 1.5) and 0.7 (95% CI: 0.6; 0.9) for stages I, II + III and IV, respectively; in the following rounds the IRRs of screened vs. unscreened were 1.4 (95% CI: 1.2; 1.6), 0.8 (95% CI: 0.7; 0.9) and 0.3 (95% CI: 0.1; 0.4) for stages I, II + III and IV, respectively. FIT screening reduces the incidence of metastatic cancers by about 70% after the first round.
What's new?
Screening programs are intended to reduce mortality by early diagnosis. In this study, the authors evaluated the faecal immunochemical test (FIT) for colorectal cancer. They calculated the effect of FIT screening on stage at diagnosis, and estimated the relative incidence rates by stage. Individuals who attended screening had far higher incidence of stage I cancer, and lower incidence of stage IV, than those not screened. Metastatic cancer incidence, they found, decreased by about 70% at the first round of screening.
This paper reports a study of oxygen and redox conditions, trophic status, and phytoplankton community in the meromictic Lake Idro (Italy) from 2010 to 2014. The sequence of causes and effects of ...meromixis are also evaluated by comparing recent research with studies conducted from the late 1960s to the mid-1990s. In the last half century, Lake Idro was steadily meromictic due to solutes which accumulated in its deep waters, along with both dissolved nutrients and chemically reduced substances produced by the anaerobic microbial metabolism. These substances were retained in bottom waters and made unavailable to upper layers until stratification broke. Mixing episodes occurred in 2005–2006 altering stratification, and oxygen and nutrient distribution within the lake. The potential full overturn effects were also evaluated as potential oxygen consumption due to the oxidation of reduced substances to forecast possible oxygen exhaustion and collapse of biological communities. Finally, meromixis is discussed as a potential threat for deep perialpine lakes using Lake Idro as a reference to comparatively evaluate the present status and possible future trends.
Abstract Objectives An association between skin toxicity and outcome has been reported for NSCLC patients treated with erlotinib. Several explanations have been suggested, including pharmacokinetic ...and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic and to correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients. Methods Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line were enrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serum and urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC–MS/MS analysis, along with urinary 6β-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of the CYP3A4/5 enzyme. Results 56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were 3.90 2.13 μmol/l and 0.37 2.90 μmol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 4.05 μmol/l and 0.23 4.47 μmol/mol creat, respectively). Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade 0–2 (6.84 2.28 vs. 3.08 1.97 μmol/l, respectively, p = 0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6β-hydroxycortisol/cortisol ratio was observed in patients with grade 3 skin toxicity. Conclusions These findings suggest that the pharmacokinetics and metabolism of erlotinib are related to skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters.
ALK tyrosine kinase inhibitors (TKIs) are the standard treatment for advanced ALK-positive NSCLC. Nevertheless, drug resistance inevitably occurs. Here, we report a case of a patient with metastatic ...ALK-positive lung adenocarcinoma with an impressive resistance to sequential treatment with ALK TKIs mediated by YES1 and MYC amplification in a contest of epithelial-to-mesenchymal transition and high progressive chromosomal instability.
The patient received, after chemotherapy and 7 months of crizotinib, brigatinib and lorlatinib with no clinical benefit to both treatments. A study of resistance mechanisms was performed with whole exome sequencing on different biological samples; primary cell lines were established from pleural effusion after lorlatinib progression.
At whole exome sequencing analysis, YES1 and MYC amplifications were observed both in the pericardial biopsy and the pleural effusion samples collected at brigatinib and lorlatinib progression, respectively. Increasing chromosomal instability from diagnostic biopsy to pleural effusion was also observed. The addition of dasatinib to brigatinib or lorlatinib restored the sensitivity in primary cell lines; data were confirmed also in H3122_ALK-positive model overexpressing both YES1 and MYC.
In conclusion, YES1 and MYC amplifications are candidates to justify a rapid acquired resistance to crizotinib entailing primary brigatinib and lorlatinib resistance. In this context, a combination strategy of ALK TKI with dasatinib could be effective to overcome a rapid resistance.
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are the standard treatment for advanced ALK-positive non-small cell lung cancer (NSCLC) allowing survivals up to 5 years. However, ...duration of responses is limited by the almost certain occurrence of drug resistance. Here, we report a case of a never smoker, 59-year-old female with metastatic ALK-positive adenocarcinoma, solid and signet ring patterns, who developed resistance to alectinib, a second-generation ALK-TKI, mediated by
HER2
gene amplification. The patient received 22 months of crizotinib as first-line and subsequently 1-year of alectinib therapy. A study of resistance mechanism was performed with next generation sequencing (NGS) on tissue re-biopsy. A
HER2
-amplified emerging clone was identified by NGS in a liver metastasis and confirmed by fluorescent
in situ
hybridization (FISH) analysis. The resistant clone was detectable 2 months before disease progression in plasma cell-free DNA (cfDNA) using digital droplet PCR (ddPCR) copy number variation (CNV) assay and it was retrospectively traced in rare cells of the lung primary by FISH. To our best knowledge, this is first evidence of
HER2
gene amplification as a resistance mechanism to ALK-TKI in a NSCLC. Future strategies against oncogene-addicted NSCLC might benefit of combined drug treatments, such as ALK and HER2 inhibition.
PDF
