The incidence and relative risk of major adverse cardiovascular events and hypertension in patients treated with immune checkpoint inhibitors plus tyrosine-kinase inhibitors for solid tumors: a systemic review and meta-analysis.

INTRODUCTION: Combinations of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) can be responsible for major adverse cardiovascular events (MACEs). We performed a meta-analysis to assess the relative risk (RR) of MACEs and hypertension in cancer patients treated with ICI+TKI combinations. RESEARCH DESIGN AND METHODS: We selected prospective trials through MEDLINE/PubMed, Cochrane Library, and ASCOMeeting abstracts. We calculated combined ORs, RRs, and 95% CIs using RevMansoftware for meta-analysis (v.5.2.3). RESULTS: Seven studies were selected for the analysis of MACEs (3849 patients). The incidence MACEs were 0.8% with ICI+TKI combinations, compared to 0.2% in the control arms for both any- and high-grade. ICI+TKI combinations significantly increased the risk of any- (OR = 3.21; p = 0.01) and high-grade MACEs (OR = 2.72; p = 0.05). Ten studies were selected for the analysis of hypertension (5744 patients). The incidence of treatment-related hypertension of any-grade and high-grade was41.3% (vs. 20.8%) and 26.1% (vs. 12.3%) with ICI+TKI combinations, respectively. ICI+TKI combinations significantly increased the risk of treatment-related hypertension of any-grade (RR = 2.10; p = 0.001), but not of high-grade (p = 0.11). CONCLUSIONS: ICI+TKI combinations increase the risk of MACEs compared to controls, although the absolute incidence is eventually low. Routine cardiovascular monitoring in asymptomatic patients is therefore not recommended.

Implementation of Artificial Intelligence in Personalized Prognostic Assessment of Lung Cancer: A Narrative Review.

Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep imaging data analysis. This could potentially improve precision and efficiency in staging, facilitating personalized treatment decisions. Furthermore, there are data suggesting the potential application of AI-based models in predicting prognosis in terms of survival rates and disease progression by integrating clinical, imaging and molecular data. In the present narrative review, we will analyze the preliminary studies reporting on how AI algorithms could predict responses to various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. There is robust evidence suggesting that AI also plays a crucial role in predicting the likelihood of tumor recurrence after surgery and the pattern of failure, which has significant implications for tailoring adjuvant treatments. The successful implementation of AI in personalized prognostic assessment requires the integration of different data sources, including clinical, molecular, and imaging data. Machine learning (ML) and deep learning (DL) techniques enable AI models to analyze these data and generate personalized prognostic predictions, allowing for a precise and individualized approach to patient care. However, challenges relating to data quality, interpretability, and the ability of AI models to generalize need to be addressed. Collaboration among clinicians, data scientists, and regulators is critical for the responsible implementation of AI and for maximizing its benefits in providing a more personalized prognostic assessment. Continued research, validation, and collaboration are essential to fully exploit the potential of AI in NSCLC management and improve patient outcomes. Herein, we have summarized the state of the art of applications of AI in lung cancer for predicting staging, prognosis, and pattern of recurrence after treatment in order to provide to the readers a large comprehensive overview of this challenging issue.

Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced nonsmall cell lung cancer.

BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced nonsmall cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

Response to first-line pembrolizumab in metastatic KRAS-mutated non-small-cell lung cancer.

Aims: This retrospective study aims to identify a possible predictive role of KRAS mutations in non-small-cell lung cancer in response to first-line pembrolizumab, either as monotherapy or combined with chemotherapy. Methods: Patients received pembrolizumab alone (n = 213) or associated with chemotherapy (n = 81). Results: A mutation in the KRAS gene was detected in 27% of patients. In patients on pembrolizumab alone, median progression-free survival in KRAS-mutated cases was longer than in wild-type cases (11.3 vs 4.4 months; p = 0.019), whereas median overall survival did not reach statistical significance (22.1 vs 12.5 months; p = 0.119). Patients receiving chemo-immunotherapy with KRAS-positive tumors had a similar progression-free survival (9.7 vs 7.3 months; p = 0.435); overall survival data were immature. Conclusion: This study suggests a correlation between KRAS status and response to pembrolizumab.

Atezolizumab Plus Carboplatin and Etoposide in Patients with Untreated Extensive-Stage Small-Cell Lung Cancer: Interim Results of the MAURIS Phase IIIb Trial.

BACKGROUND: MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation. MATERIALS AND METHODS: Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction. RESULTS: At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response. CONCLUSIONS: Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice. CLINICAL TRIAL REGISTRATION: Eudract No. 2019-001146-17, NCT04028050.

Leptin-mediated meta-inflammation may provide survival benefit in patients receiving maintenance immunotherapy for extensive-stage small cell lung cancer (ES-SCLC).

BACKGROUND: Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. METHODS: Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). RESULTS: In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18-0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25-1.29] p = 0.07). CONCLUSIONS: Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.

[Management of the patient with extensive stage microcytoma. The importance of collaboration between oncology and radiotherapy.] / Gestione del paziente con microcitoma a stadio esteso. L'importanza della collaborazione tra oncologia e radioterapia.

Small cell lung cancer (SCLC) represents one of the most complex challenges in the oncological field, with a very slow advancement in research, contrary to the rapid evolutionary of the disease. For nearly two years, the mainstay of treatment for extensive-stage disease (ES-SCLC) has been the combination of platinum-based chemotherapy and immunotherapy, following the approval of atezolizumab and subsequently durvalumab, based on a modest, but significant improvement in overall survival compared to chemotherapy alone. The poor prognosis after the failure of first-line treatment explains the need to maximize the duration and efficacy of up-front systemic therapies, in particular, the emerging role of radiotherapy, also in ES-SCLC. On 10 November 2022, a meeting concerning the integrated treatment of patients with ES-SCLC was held in Rome and was attended by 12 specialists in oncology and radiotherapy from various centers in Lazio, under the direction of Federico Cappuzzo, Emilio Bria and Sara Ramella. The aim of the meeting was to share their clinical experience and to provide a series of practical indications in order to support physicians in the correct integration between first-line chemo-immunotherapy and radiotherapy treatments in ES-SCLC.

Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer.

Lung cancer is one of the most aggressive malignancies, classified into two major histological subtypes: non-small cell lung cancer (NSCLC), that accounts for about 85% of new diagnosis, and small cell lung cancer (SCLC), the other 15%. In the case of NSCLC, comprehensive genome sequencing has allowed the identification of an increasing number of actionable targets, which have become the cornerstone of treatment in the advanced setting. On the other hand, the concept of oncogene-addiction is lacking in SCLC, and the only innovation of the last 30 years has been the introduction of immune checkpoint inhibitors in extensive stage disease. Dysregulation of cell cycle is a fundamental step in carcinogenesis, and Aurora kinases (AURKs) are a family of serine/threonine kinases that play a crucial role in the correct advance through the steps of the cycle. Hyperexpression of Aurora kinases is a common protumorigenic pathway in many cancer types, including NSCLC and SCLC; in addition, different mechanisms of resistance to anticancer drugs rely on AURK expression. Hence, small molecule inhibitors of AURKs have been developed in recent years and tested in several malignancies, with different results. The aim of this review is to analyze the current evidences of AURK inhibition in lung cancer, starting from preclinical rationale to finish with clinical trials available up to now.

[Management of small cell lung cancer patient in the regions of Lazio, Umbria and Sardinia.] / Gestione del paziente con microcitoma nelle regioni Lazio, Umbria e Sardegna.

Small cell lung cancer (SCLC) is an aggressive disease, difficult to treat. There have been no significant therapeutic advances over platinum and etoposide chemotherapy in the last 20 years until the introduction of immunotherapy. In 2020 atezolizumab, an immune checkpoint inhibitor against PD-L1 was approved in Italy in combination with carboplatin and etoposide for the first-line treatment of patients with extensive stage disease (ES-SCLC), becoming the new standard treatment. On May 20, 2021, a virtual meeting, directed by profs. Federico Cappuzzo and Emilio Bria, was held in which 14 clinicians from different oncology centers in Lazio, Umbria and Sardinia discussed the issues of ES-SCLC patients treatment, after the advent of immunotherapy. The aim of the meeting was to share their clinical experience and to provide a series of practical indications that can support clinicians in the management of ES-SCLC patients in first-line with chemo-immunotherapy.

Bend losses in flexible polyurethane antiresonant terahertz waveguides.

One important shortcoming of terahertz technology is the relative absence of convenient, flexible, and reconfigurable waveguides with low attenuation and small bend losses. While recent years have been marked by remarkable progress in lowering the impact of material losses using hollow-core guidance, such waveguides often have centimeter-scale diameter and are therefore not flexible. Here we experimentally and numerically investigate antiresonant dielectric waveguides made of thermoplastic polyurethane, a commonly used dielectric with a low Young's modulus. The hollow-core nature of antiresonant fibers leads to low transmission losses using simple structures, whereas the low Young's modulus of polyurethane makes them extremely flexible. The structures presented enable millimeter-wave manipulation in the same spirit as conventional (visible- and near-IR-) optical fibers, i.e. conveniently and reconfigurably, despite their centimeter-thick diameter. We investigate two canonical antiresonant geometries formed by one- and six-tubes, experimentally comparing their transmission, bend losses and mode profiles. The waveguides under investigation have loss below 1 dB/cm in their sub-THz transmission bands, increasing by 1 dB/cm for a bend radius of about 10 cm. We find that the six-tube waveguide outperforms its one-tube counterpart for smaller bend radii (here: 10cm); for larger bend radii, coupling to cladding tube modes can lead to a drop in transmission at specific frequencies in the six-tube waveguide that does not occur in the one-tube waveguide.

Early Progression in Non-Small Cell Lung Cancer (NSCLC) with High PD-L1 Treated with Pembrolizumab in First-Line Setting: A Prognostic Scoring System Based on Clinical Features.

BACKGROUND: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored. METHODS: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model. RESULTS: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9-4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0-13, with three-risk group stratification: 0-2 (good prognosis), 3-6 (intermediate prognosis), and 7-13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70-0.81). CONCLUSIONS: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.

Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.

Large Cell Neuro-Endocrine Carcinoma of the Lung: Current Treatment Options and Potential Future Opportunities.

Large-cell neuroendocrine carcinomas of the lung (LCNECs) are rare tumors representing 1-3% of all primary lung cancers. Patients with LCNEC are predominantly male, older, and heavy smokers. Histologically, these tumors are characterized by large cells with abundant cytoplasm, high mitotic rate, and neuroendocrine immunohistochemistry-detected markers (chromogranin-A, synaptophysin, and CD56). In 2015 the World Health Organization classified LCNEC as a distinct subtype of pulmonary large-cell carcinoma and, therefore, as a subtype of non-small cell lung carcinoma (NSCLC). Because of the small-sized tissue samples and the likeness to other neuroendocrine tumors, the histological diagnosis of LCNEC remains difficult. Clinically, the prognosis of metastatic LCNECs is poor, with high rates of recurrence after surgery alone and overall survival of approximately 35% at 5 years, even for patients with early stage disease that is dramatically shorter compared with other NSCLC subtypes. First-line treatment options have been largely discussed but with limited data based on phase II studies with small sample sizes, and there are no second-line well defined treatments. To date, no standard treatment regimen has been developed, and how to treat LCNEC is still on debate. In the immunotherapy and targeted therapy era, in which NSCLC treatment strategies have been radically reshaped, a few data are available regarding these opportunities in LCNEC. Due to lack of knowledge in this field, many efforts have been done for a deeper understanding of the biological and molecular characteristics of LCNEC. Next generation sequencing analyses have identified subtypes of LCNEC that may be relevant for prognosis and response to therapy, but further studies are needed to better define the clinical impact of these results. Moreover, scarce data exist about PD-L1 expression in LCNEC and its predictive value in this histotype with regard to immunotherapy efficacy. In the literature some cases are reported concerning LCNEC metastatic patients carrying driver mutations, especially EGFR alterations, showing targeted therapy efficacy in this setting of disease. Due to the rarity and the challenging understanding of LCNEC, in this review we aim to summarize the management options currently available for treatment of LCNEC.

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non-small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors.

BACKGROUND: Rapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population. MATERIALS AND METHODS: Archival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS). RESULTS: Fifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P < .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P < .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P < .0005). CONCLUSIONS: A low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.

Thermally drawn biodegradable fibers with tailored topography for biomedical applications.

There is a growing demand for polymer fiber scaffolds for biomedical applications and tissue engineering. Biodegradable polymers such as polycaprolactone have attracted particular attention due to their applicability to tissue engineering and optical neural interfacing. Here we report on a scalable and inexpensive fiber fabrication technique, which enables the drawing of PCL fibers in a single process without the use of auxiliary cladding. We demonstrate the possibility of drawing PCL fibers of different geometries and cross-sections, including solid-core, hollow-core, and grooved fibers. The solid-core fibers of different geometries are shown to support cell growth, through successful MCF-7 breast cancer cell attachment and proliferation. We also show that the hollow-core fibers exhibit a relatively stable optical propagation loss after submersion into a biological fluid for up to 21 days with potential to be used as waveguides in optical neural interfacing. The capacity to tailor the surface morphology of biodegradable PCL fibers and their non-cytotoxicity make the proposed approach an attractive platform for biomedical applications and tissue engineering.

The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures.

Non-small cell lung cancer (NSCLC) represents the perfect paradigm of 'precision medicine' due to its complex intratumoral heterogeneity. It is truly characterized by a range of molecular alterations that can deeply influence the natural history of this disease. Several molecular alterations have been found over time, paving the road to biomarker-driven therapy and radically changing the prognosis of 'oncogene addicted' NSCLC patients. Kirsten rat sarcoma (KRAS) mutations are present in up to 30% of NSCLC (especially in adenocarcinoma histotype) and have been identified decades ago. Since its discovery, its molecular characteristics and its marked affinity to a specific substrate have led to define KRAS as an undruggable alteration. Despite that, many attempts have been made to develop drugs capable of targeting KRAS signaling but, until a few years ago, these efforts have been unsuccessful. Comprehensive genomic profiling and wide-spectrum analysis of genetic alterations have only recently allowed to identify different types of KRAS mutations. This tricky step has finally opened new frontiers in the treatment approach of KRAS-mutant patients and might hopefully increase their prognosis and quality of life. In this review, we aim to highlight the most interesting aspects of (epi)genetic KRAS features, hoping to light the way to the state of art of targeting KRAS in NSCLC.

Towards subdiffraction imaging with wire array metamaterial hyperlenses at MIR frequencies.

We describe the fabrication of metamaterial magnifying hyperlenses with subwavelength wire array structures for operation in the mid-infrared (around 3 µm). The metadevices are composed of approximately 500 tin wires embedded in soda-lime glass, where the metallic wires vary in diameter from 500 nm to 1.2 µm along the tapered structure. The modeling of the hyperlenses indicates that the expected overall losses for the high spatial frequency modes in such metadevices are between 20 dB to 45 dB, depending on the structural parameters selected, being promising candidates for far-field subdiffraction imaging in the mid-infrared. Initial far-field subdiffraction imaging attempts are described, and the problems encountered discussed.

Thermal poling of multi-wire array optical fiber.

We demonstrate in this paper thermal poling of multi-wire array fibers, which extends poling of fibers with two anodes to ~50 and ~500 wire array anodes. The second harmonic microscopy observations show that second order nonlinearity (SON) layers are developed surrounding all the rings of wires in the ~50 anode array fiber with poling of 1.8kV, 250°C and 30min duration, and the outer rings of the ~500 anode array fiber at lower poling temperature. Our simulations based on a two-dimensional charge dynamics model confirm this can be explained by the self-adjustment mechanism, and show the SON layers are induced from the outer rings to the inner rings.