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.

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.

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.

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.

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.

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.

Temperature insensitive hysteresis free highly sensitive polymer optical fiber Bragg grating humidity sensor.

The effect of humidity on annealing of poly (methyl methacrylate) (PMMA) based microstructured polymer optical fiber Bragg gratings (mPOFBGs) and the resulting humidity responsivity are investigated. Typically annealing of PMMA POFs is done in an oven without humidity control around 80°C and therefore at low humidity. We demonstrate that annealing at high humidity and high temperature improves the performances of mPOFBGs in terms of stability and sensitivity to humidity. PMMA POFBGs that are not annealed or annealed at low humidity level will have a low and highly temperature dependent sensitivity and a high hysteresis in the humidity response, in particular when operated at high temperature. PMMA mPOFBGs annealed at high humidity show higher and more linear humidity sensitivity with negligible hysteresis. We also report how annealing at high humidity can blue-shift the FBG wavelength more than 230 nm without loss in the grating strength.

Single mode step-index polymer optical fiber for humidity insensitive high temperature fiber Bragg grating sensors.

We have fabricated the first single-mode step-index and humidity insensitive polymer optical fiber operating in the 850 nm wavelength ranges. The step-index preform is fabricated using injection molding, which is an efficient method for cost effective, flexible and fast preparation of the fiber preform. The fabricated single-mode step-index (SI) polymer optical fiber (POF) has a 4.8µm core made from TOPAS grade 5013S-04 with a glass transition temperature of 134°C and a 150 µm cladding made from ZEONEX grade 480R with a glass transition temperature of 138°C. The key advantages of the proposed SIPOF are low water absorption, high operating temperature and chemical inertness to acids and bases and many polar solvents as compared to the conventional poly-methyl-methacrylate (PMMA) and polystyrene based POFs. In addition, the fiber Bragg grating writing time is short compared to microstructured POFs.

Real-time Doppler-assisted tomography of microstructured fibers by side-scattering.

We introduce the concept of Doppler-assisted tomography (DAT) and show that it can be applied successfully to non-invasive imaging of the internal microstructure of a photonic crystal fiber. The fiber is spun at ~10 Hz around its axis and laterally illuminated with a laser beam. Monitoring the time-dependent Doppler shift of the light scattered by the hollow channels permits the azimuthal angle and radial position of individual channels to be measured. An inverse Radon transform is used to construct an image of the microstructure from the frequency-modulated scattered signal. We also show that DAT can image sub-wavelength features and monitor the structure along a tapered fiber, which is not possible using other techniques without cutting up the taper into several short pieces or filling it with index-matching oil. The non-destructive nature of DAT means that it could potentially be applied to image the fiber microstructure as it emerges from the drawing tower, or indeed to carry out tomography on any transparent microstructured cylindrical object.

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.

High-Tg TOPAS microstructured polymer optical fiber for fiber Bragg grating strain sensing at 110 degrees.

We present the fabrication and characterization of fiber Bragg gratings (FBGs) in an endlessly single-mode microstructured polymer optical fiber (mPOF) made of humidity-insensitive high-Tg TOPAS cyclic olefin copolymer. The mPOF is the first made from grade 5013 TOPAS with a glass transition temperature of Tg = 135°C and we experimentally demonstrate high strain operation (2.5%) of the FBG at 98°C and stable operation up to a record high temperature of 110°C. The Bragg wavelengths of the FBGs are around 860 nm, where the propagation loss is 5.1 dB/m, close to the fiber loss minimum of 3.67 dB/m at 787 nm.

[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.

Highly sensitive and simple method for refractive index sensing of liquids in microstructured optical fibers using four-wave mixing.

We present both experimental measurements and simulations for a simple fiber-optical liquid refractive index sensor, made using only commercially available components and without advanced postprocessing of the fiber. Despite the simplicity, we obtain the highest sensitivity experimentally demonstrated to date for aqueous solutions (refractive index around 1.33), which is relevant for extensions to biosensing. The sensor is based on measuring the spectral shift of peaks arising from four-wave mixing (FWM), when filling the holes of a microstructured fiber with different liquid samples and propagating nanosecond pulses through the silica-core of the fiber. To the best of our knowledge, this is also the first experiment where a liquid is filled into the holes of a solid-core microstructured fiber to control the phase-match conditions for FWM.

Humidity insensitive TOPAS polymer fiber Bragg grating sensor.

We report the first experimental demonstration of a humidity insensitive polymer optical fiber Bragg grating (FBG), as well as the first FBG recorded in a TOPAS polymer optical fiber in the important low loss 850 nm spectral region. For the demonstration we have fabricated FBGs with resonance wavelength around 850 nm and 1550 nm in single-mode microstructured polymer optical fibers made of TOPAS and the conventional poly (methyl methacrylate) (PMMA). Characterization of the FBGs shows that the TOPAS FBG is more than 50 times less sensitive to humidity than the conventional PMMA FBG in both wavelength regimes. This makes the TOPAS FBG very appealing for sensing applications as it appears to solve the humidity sensitivity problem suffered by the PMMA FBG.

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.

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.

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.