Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Unifying Frequency Combs in Active and Passive Cavities: Temporal Solitons in Externally Driven Ring Lasers.

Frequency combs have become a prominent research area in optics. Of particular interest as integrated comb technology are chip-scale sources, such as semiconductor lasers and microresonators, which consist of resonators embedding a nonlinear medium either with or without population inversion. Such active and passive cavities were so far treated distinctly. Here we propose a formal unification by introducing a general equation that describes both types of cavities. The equation also captures the physics of a hybrid device-a semiconductor ring laser with an external optical drive-in which we show the existence of temporal solitons, previously identified only in microresonators, thanks to symmetry breaking and self-localization phenomena typical of spatially extended dissipative systems.

Evidence for swine and human papillomavirus in pig slurry in Italy.

AIMS: The diversity and the geographical distribution of swine papillomaviruses (PVs) are virtually unknown. The occurrence and the diversity of swine PV were therefore investigated in pig slurry collected in Italy, to contribute towards filling this gap in knowledge. METHODS AND RESULTS: Twenty-two slurry samples underwent analysis by nested PCR and DNA sequencing using published and newly designed specific primer pairs for Sus scrofa papillomavirus (SsPV) type 1 and 2 (SsPV1 and 2), along with degenerate PV-specific primers targeting the major coat protein L1 and the helicase protein E1. Overall, three samples (13·6%) were positive for SsPV1 by specific primers, and nucleotide (nt) sequences showed 99-100% nt identity with SsPV1 variant a (EF395818), while SsPV2 was not found in any sample. Using generic primers, eight samples (36·4%) were tested positive for human papillomavirus (HPV), and were characterized as follows: ß1-HPV8, ß1-HPV14, ß1-HPV206, ß2-HPV113, ß2-HPV120 and γ1-HPV173. Moreover, one unclassified γ-type was detected. CONCLUSIONS: Both swine and human PVs were detected in pig slurry in this study. The unexpected presence of HPV in pig waste could be explained as the result of an improper use of the sewage collection pits and/or with improper procedures of the operators. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reports the first detection of SsPV1 in Italy, along with the first detection of HPVs in pig slurry samples in Italy, and expands our knowledge about PV diversity and geographic distribution.

[Secondary labiaplasty: Retrospective study about 44 cases. Annual report SOFCPRE 2019]. / Nymphoplastie secondaire : étude rétrospective à propos de 44 cas. Rapport annuel de la SOFCPRE 2019.

INTRODUCTION: Labiaplasty is a surgery currently booming. The number of publications on this subject is also increasing significantly. With the increase of the operated cases, we see more and more consultations for revisions after a labiaplasty, called secondary labiaplasty. The author reports here his experience with secondary labiaplasties in 44 cases. MATERIAL AND METHOD: The study carried out by the author reports 44 cases divided into two categories of secondary labiaplasties. The first category is characterized by a wound dehiscence, including those following the author's lambda laser procedures, which are easily repaired under local anesthesia after border cutting and suture. The second category is characterized by over-resections or real amputations or even remains of atypical flaps. DISCUSSION: The over-resection is a technical fault. In this case, the technique used to improve the aesthetic, functional and psychological aspect is the use of the remains of labia minora in the form of a flap to avoid a dog-ear appearance at the anterior and posterior part. The use of lipofilling of the labia majora is to mask the area and improve the function. The future of this surgery is probably the reconstruction of the labia minora by local flaps. CONCLUSION: The conclusion of the study is that it is imperative that surgeons performing labiaplasties be trained in both anatomy and labiaplasty techniques and avoid as much as possible over-resections and amputations, mending being often difficult.

Dynamics of a broad-band quantum cascade laser: from chaos to coherent dynamics and mode-locking.

The dynamics of a multimode quantum cascade laser, are studied in a model based on effective semiconductor Maxwell-Bloch equations, encompassing key features for the radiation-medium interaction such as an asymmetric frequency dependent gain and refractive index as well as the phase-amplitude coupling provided by the linewidth enhancement factor. By considering its role and that of the free spectral range, we find the conditions in which the traveling wave emitted by the laser at the threshold can be destabilized by adjacent modes, thus leading the laser emission towards chaotic or regular multimode dynamics. In the latter case our simulations show that the field oscillations are associated to self-confined structures which travel along the laser cavity, bridging mode-locking and solitary wave propagation. In addition, we show how a RF modulation of the bias current leads to active mode-locking yielding high-contrast, picosecond pulses. Our results compare well with recent experiments on broad-band THz-QCLs and may help in the understanding of the conditions for the generation of ultrashort pulses and comb operation in mid-IR and THz spectral regions.

Modulating risky decision-making in Parkinson's disease by transcranial direct current stimulation.

BACKGROUND AND PURPOSE: Performance on gambling tasks in Parkinson's disease (PD) is of particular interest, as pathological gambling is often associated with dopamine replacement therapy in these patients. We aimed to evaluate the effects of transcranial direct current stimulation (tDCS) over the right dorsolateral prefrontal cortex (DLPFC) in modulating gambling behaviour in PD. METHODS: We assessed the effects of cathodal tDCS over the right DLPFC during the Iowa Gambling Task in 20 patients with PD, compared with sham stimulation. We then conducted a second experimental design, assessing the effects of anodal tDCS over the right DLPFC. RESULTS: We observed that cathodal tDCS over the right DLPFC increased Iowa Gambling Task scores compared with sham stimulation. In the second experimental design, we did not find significant differences between anodal and sham tDCS. CONCLUSIONS: Cathodal tDCS over the right DLPFC possibly reduces the pathological overdrive in frontostriatal networks in patients with PD on dopaminergic medication, thus modulating impulsive and risky decision-making.

Nutrition in the first 1000 days and respiratory health: A descriptive review of the last five years' literature.

The aim of this paper is to discuss the current evidence regarding short and long-term health respiratory effects of nutrients and dietary patterns during the first 1000 days from conception. Population of interest included children from birth to two years and their mothers (during pregnancy and lactation). Studies were searched on MEDLINE® and Cochrane database, inserting individually and using the Boolean ANDs and ORs, 'nutrients', 'micronutrients', 'LC-PUFA', 'Mediterranean Diet', 'human milk', 'complementary food', 'pregnancy', 'respiratory disease', 'pulmonary disease', 'asthma', 'epigenetics', 'first 1000 days', 'maternal diet' and 'respiratory health'. All sources were retrieved between 01-09-2015 and 07-12-2016. While unhealthy maternal dietary patterns (high fat intake) during pregnancy can result in alteration of foetal lung development, with increased risk of respiratory disorders, Mediterranean diet has been associated with a lower risk of allergic sensitisation and allergic rhinitis. Breastfeeding has beneficial effects on respiratory infections while evidences about its protective effect on allergic disorders are unclear. During complementary feeding there is no evidence to avoid or encourage exposition to 'highly allergenic' foods to have modification of tolerance development. In children from birth to two years of age, Mediterranean diet has been associated with a lower risk of atopy, wheezing and asthma. Micronutrients, antioxidant and LCPUFA supplementation is not recommended and a whole food approach should be preferred, except for Vitamin D.

Human skin-derived fibroblasts used as a 'Trojan horse' for drug delivery.

BACKGROUND: Drug toxicity currently represents the main challenge of tumour chemotherapy. Our group recently developed a new method for drug delivery inspired by the 'Trojan Horse' concept. Human mesenchymal stem cells (hMSCs) have been shown to play the role of new 'horses' in delivering anti-tumour agents, without involving any genetic manipulation. As human stromal dermal fibroblasts (hSDFs) represent an interesting alternative to hMSCs, being easy to isolate, they could be an ideal candidate for this kind of procedure. AIM: To investigate whether hSDFs can take up and deliver paclitaxel (PTX) in sufficient concentrations to inhibit a very aggressive melanoma tumour (IgR39) in vitro. METHODS: hSDFs were primed with high doses of PTX, and then the effect of drug delivery on IgR39 melanoma proliferation in vitro was evaluated using several assays (antiproliferation, transwell cocultures, rosette assays and colony growth assays). Furthermore, the cell cycle and PTX uptake/release mechanism of hSDFs were studied both under both normal and hypoxic conditions. RESULTS: hSDFs incorporated PTX and then released it with unaffected pharmacological activity, inhibiting human IgR39 melanoma growth in vitro. The hypoxic conditions did not induce changes in cell cycle pattern and the uptake-release mechanism with PTX was not affected. CONCLUSIONS: hSDFs can be used as a Trojan horse, as the released drug was functionally active. These results indicated that these cells could be used for clinical treatment as the drug was released into the cellular environment and the primed cells underwent apoptosis.

Dissipative Phase Solitons in Semiconductor Lasers.

We experimentally demonstrate the existence of nondispersive solitary waves associated with a 2π phase rotation in a strongly multimode ring semiconductor laser with coherent forcing. Similarly to Bloch domain walls, such structures host a chiral charge. The numerical simulations based on a set of effective Maxwell-Bloch equations support the experimental evidence that only one sign of chiral charge is stable, which strongly affects the motion of the phase solitons. Furthermore, the reduction of the model to a modified Ginzburg-Landau equation with forcing demonstrates the generality of these phenomena and exposes the impact of the lack of parity symmetry in propagative optical systems.

Left parietal cortex transcranial direct current stimulation enhances gesture processing in corticobasal syndrome.

BACKGROUND AND PURPOSE: Corticobasal syndrome (CBS) is a clinical entity characterized by higher cortical dysfunctions associated with asymmetric onset of levodopa-resistant parkinsonism, dystonia and myoclonus. One of the most typical and distressful features of CBS is limb apraxia, which affects patients in their everyday life. Transcranial direct current stimulation (tDCS) is a non-invasive procedure of cortical stimulation, which represents a promising tool for cognitive enhancement and neurorehabilitation. The present study investigated whether anodal tDCS over the parietal cortex (PARC), would improve ideomotor upper limb apraxia in CBS patients. METHODS: Fourteen patients with possible CBS and upper limb apraxia were enrolled. Each patient underwent two sessions of anodal tDCS (left and right PARC) and one session of placebo tDCS. Ideomotor upper limb apraxia was assessed using the De Renzi ideomotor apraxia test that is performed only on imitation. RESULTS: A significant improvement of the De Renzi ideomotor apraxia test scores (post-stimulation versus pre-stimulation) after active anodal stimulation over the left PARC was observed (χ(2) = 17.6, P = 0.0005), whilst no significant effect was noticed after active anodal stimulation over the right PARC (χ(2) = 7.2, P = 0.07). A post hoc analysis revealed a selective improvement in the De Renzi ideomotor apraxia score after active anodal stimulation over the left PARC compared with placebo stimulation considering both right (P = 0.03) and left upper limbs (P = 0.01). CONCLUSIONS: These findings indicate that tDCS to the PARC improves the performance of an ideomotor apraxia test in CBS patients and might represent a promising tool for future rehabilitation approaches.

Multimode regimes in quantum cascade lasers with optical feedback.

We study the instability thresholds of the stationary emission of a quantum cascade laser with optical feedback described by the Lang Kobayashi model. We introduce an exact linear stability analysis and an approximated one for an unipolar lasers, who does not exhibit relaxation oscillations, and investigate the regimes of the emitter beyond the continuous wave instability threshold, depending on the number and density of the external cavity modes. We then show that a unipolar laser with feedback can exhibit coherent multimode oscillations that indicate spontaneous phase-locking.

QCL-based nonlinear sensing of independent targets dynamics.

We demonstrate a common-path interferometer to measure the independent displacement of multiple targets through nonlinear frequency mixing in a quantum-cascade laser (QCL). The sensing system exploits the unique stability of QCLs under strong optical feedback to access the intrinsic nonlinearity of the active medium. The experimental results using an external dual cavity are in excellent agreement with the numerical simulations based on the Lang-Kobayashi equations.

A concomitant and complete set of nonvolatile all-optical logic gates based on hybrid spatial solitons.

We theoretically demonstrate the realization of a complete canonical set of all-optical logic gates (AND, OR, NOT), with a persistent (stored) output, by combining propagative spatial solitons in a photorefractive crystal and dissipative cavity solitons in a downstream broad-area vertical cavity surface emitting laser (VCSEL). The system uses same-color, optical-axis aligned input and output channels with fixed readout locations, while switching from one gate to another is achieved by simply varying the potential applied to the photorefractive crystal. The inputs are Gaussian beams launched in the photorefractive crystal and the output is a bistable, persistent soliton in the VCSEL with a 'robust' eye diagram and large signal-to-noise ratio (SNR). Fast switching and intrinsic parallelism suggest that high bit flow rates can be obtained.

Observation of electro-activated localized structures in broad area VCSELs.

We demonstrate experimentally the electro-activation of a localized optical structure in a coherently driven broad-area vertical-cavity surface-emitting laser (VCSEL) operated below threshold. Control is achieved by electro-optically steering a writing beam through a pre-programmable switch based on a photorefractive funnel waveguide.

Activity of osimeRTInib in non-small-cell lung Cancer with UNcommon epidermal growth factor receptor mutations: retrospective Observational multicenter study (ARTICUNO).

BACKGROUND: Osimertinib represents the standard of care for the treatment of advanced non-small-cell lung cancer (NSCLC) harboring classical epidermal growth factor receptor (EGFR) mutations, constituting 80%-90% of all EGFR alterations. In the remaining cases, an assorted group of uncommon alterations of EGFR (uEGFR) can be detected, which confer variable sensitivity to previous generations of EGFR inhibitors, overall with lower therapeutic activity. Data on osimertinib in this setting are limited and strongly warranted. PATIENTS AND METHODS: The ARTICUNO study retrospectively evaluated data on osimertinib activity from patients with advanced NSCLC harboring uEGFR treated in 21 clinical centers between August 2017 and March 2023. Data analysis was carried out with a descriptive aim. Investigators collected response data according to RECIST version 1.1 criteria. The median duration of response, progression-free survival (mPFS), and overall survival were estimated by the Kaplan-Meier method. RESULTS: Eighty-six patients harboring uEGFR and treated with osimertinib were identified. Patients with 'major' uEGFR, that is, G719X, L861X, and S768I mutations (n = 51), had an overall response rate (ORR) and mPFS of 50% and 9 months, respectively. Variable outcomes were registered in cases with rarer 'minor' mutations (n = 27), with ORR and mPFS of 31% and 4 months, respectively. Among seven patients with exon 20 insertions, ORR was 14%, while the best outcome was registered among patients with compound mutations including at least one classical EGFR mutation (n = 13). Thirty patients presented brain metastases (BMs) and intracranial ORR and mPFS were 58% and 9 months, respectively. Amplification of EGFR or MET, TP53 mutations, and EGFR E709K emerged after osimertinib failure in a dataset of 18 patients with available rebiopsy. CONCLUSION: The ARTICUNO study confirms the activity of osimertinib in patients with uEGFR, especially in those with compound uncommon-common mutations, or major uEGFR, even in the presence of BMs. Alterations at the E709 residue of EGFR are associated with resistance to osimertinib.

Intrinsic stability of quantum cascade lasers against optical feedback.

We study the time dependence of the optical power emitted by terahertz and mid-IR quantum cascade lasers in presence of optical reinjection and demonstrate unprecedented continuous wave (CW) emission stability for strong feedback. We show that the absence of coherence collapse or other CW instabilities typical of diode lasers is inherently associated with the high value of the photon to carrier lifetime ratio and the negligible linewidth enhancement factor of quantum cascade lasers.

Dysphagia after definitive radiotherapy for head and neck cancer. Correlation of dose-volume parameters of the pharyngeal constrictor muscles.

BACKGROUND: Dysphagia is a complication of head and neck cancer patients undergoing radiotherapy (RT). We analysed frequency and severity of swallowing dysfunction and correlated these findings with dose-volume histograms (DVHs) of the pharyngeal constrictor muscles. METHODS: A total of 50 patients treated by radical RT were enrolled. DVHs of constrictor muscles were correlated with acute and late dysphagia and with the items of three quality of life questionnaires. RESULTS: Mean dose to superior and middle constrictor muscles (SCM, MCM), partial volume of SCM and MCM receiving a dose ≥ 50 Gy dose to the whole constrictor muscles ≥ 60 Gy and tumour location were associated to late dysphagia at univariate analysis. Mean dose to the MCM was the only statistically significant predictor of late dysphagia at the multivariable analysis. CONCLUSION: The study shows a significant relationship between long-term dysphagia and mean doses to SCM, MCM, whole constrictor muscles, and oropharyngeal tumour. This finding suggests a potential advantage in reducing the RT dose to swallowing structures to avoid severe dysphagia.

Perfusion computed tomography assessments of peri-enhancing brain tissue in high-grade gliomas.

PURPOSE: This study was undertaken to identify tumoural infiltration of peri-enhancing brain tissue in patients with glioblastoma by means of perfusion computed tomography (PCT) parameters, cerebral blood volume (CBV) and permeability surface (PS). MATERIALS AND METHODS: Eight patients with surgically treated glioblastoma who were eligible for radiotherapy and nine patients with brain metastases from lung and breast cancer underwent CT before and after injection of contrast medium. CBV and PS were calculated in the contrast-enhancing lesion area, in the area of perilesional oedema and in the normal-appearing white matter (NAWM), normalised to contralateral symmetrical areas. RESULTS: No significant differences were found for normalised CBV (nCBV) and nPS in NAWM regions between metastasis and glioma. Significant differences in nPS (p<0.005) were found between the typically vasogenic oedema surrounding the metastases and signal alteration surrounding the glial neoplasm. On the contrary, no significant differences were detected in the same areas for nCBV. CONCLUSIONS: PCT can analyse the histopathological substrate underlying the hypodense peritumoural halo and differentiate between vasogenic oedema and neoplastic infiltration on the basis of the PS parameter. In our study, PS was more informative than CBV. These findings can be used to integrate plans for radiation therapy and/or surgery.

Diagnostic accuracy and agreement between whole-body diffusion MRI and bone scintigraphy in detecting bone metastases.

PURPOSE: This study was done to determine the diagnostic value of whole-body magnetic resonance using diffusion-weighted imaging with background suppression (WB-DWIBS) for detecting bone metastases compared with whole-body bone scintigraphy (WB-BS). MATERIALS AND METHODS: Twenty-three patients with solid tumours underwent both WB-DWIBS imaging and WBBS. A nuclear medicine specialist interpreted WB-BS images and two blinded radiologists, first independently and then jointly, interpreted the WB-DWIBS images by completing a reading grid categorising the skeletal segments. Cohen's k statistic was used to determine interobserver agreement in reading the WB-DWIBS images and the agreement between WB-BS and WB-DWIBS. Sensitivity and specificity were calculated per patient and per lesion. RESULTS: Interobserver agreement in reading the WBDWIBS images was substantial or good, with κ=0.68. Analysis of agreement between the nuclear physician's and the radiologists' readings provided κ=0.87 [95% confidence interval (CI)=0.76-0.98)] Per-lesion analysis gave a sensitivity of 80% (95% CI=75-85) and a specificity of 98.2% (95% CI=96.5-99.8). CONCLUSIONS: We found a good level of interobserver agreement for the WB-DWIBS images and an excellent level of agreement in the subjective judgement of presence or absence of disease between WB-BS and WB-DWIBS after consensual double reading. WB-DWIBS has the same specificity as WB-BS in detecting bone metastases. The anatomical sites exhibiting the highest level of disagreement between WB-DWIBS and WB-BS are the pelvis, the coccyx, and the sternum, all sites at which detection with WB-BS has the greatest limitations.

Unraveling the complexity of anti-doping analysis: reassessing meldonium detection and doping verdicts in a case study.

BACKGROUND: The precision and accuracy of mass spectrometry (MS) made it a fundamental tool in anti-doping analysis. High-resolution (HR) mass spectrometers significantly improved compound identification. This study systematically analyzes data from an athlete (Subject 1) who tested positive for meldonium and compares it with data from a healthy volunteer (Subject 2) to examine the correctness of the doping verdict. CASE PRESENTATION: The documentation related to Subject 1 was thoroughly processed and analyzed. A study involving a volunteer (Subject 2) replicated Subject 1 regimen and urine sample collection for data alignment with anti-doping results, with Subject 2 reporting not using meldonium. The anti-doping agency's analysis of Subject 1 showed the presence of meldonium at a concentration close to the established cut-off level. However, a closer examination revealed that one specific ion, crucial for meldonium identification, was absent from the mass spectra. Analyzing Subject 2 data, using the same methodology, the absence of the specific ion was confirmed, even though the volunteer did not consume meldonium. The European directive and the method that was validated and cited by the anti-doping agency identified meldonium on at least four specific ions, whereas the anti-doping analysis used only three ions. This discrepancy compromises the specificity of meldonium identification. CONCLUSIONS: To enhance the analytical methodology, two strategic interventions are suggested: adjusting the meldonium cut-off value and expanding the analysis to include meldonium metabolites. By addressing these avenues, the precision of meldonium detection and doping verdicts can be improved. In conclusion, this study challenges the anti-doping agency's verdict and prompts a reevaluation of meldonium detection methodologies in anti-doping measures.