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Simple Summary: The search for precision medicine applications in mesotheliomas (MM) is taking its first steps. After platinum and pemetrexed chemotherapy, the treatment for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor even if the recent introduction of immunotherapy. It is known that MM is mainly characterized by inactivanting tumor suppressor alterations and that these, along with some cellular targets or metabolic enzymes, could be potentially amenable to specific therapies The purpose of this review is to take a comprehensive excursus of the main targets and the related evidence regarding possible treatment activities intended for them. Mesothelioma (MM) is an aggressive and lethal disease with few therapeutic opportunities. Platinum-pemetrexed chemotherapy is the backbone of first-line treatment for MM. The introduction of immunotherapy (IO) has been the only novelty of the last decades, allowing an increase in survival compared to standard chemotherapy (CT). However, IO is not approved for epithelioid histology in many countries. Therefore, therapy for relapsed MM remains an unmet clinical need, and the prognosis of MM remains poor, with an average survival of only 18 months. Increasing evidence reveals MM complexity and heterogeneity, of which histological classification fails to explain. Thus, scientific focus on possibly new molecular markers or cellular targets is increasing, together with the search for target therapies directed towards them. The molecular landscape of MM is characterized by inactivating tumor suppressor alterations, the most common of which is found in CDKN2A, BAP1, MTAP, and NF2. In addition, cellular targets such as mesothelin or metabolic enzymes such as ASS1 could be potentially amenable to specific therapies. This review examines the major targets and relative attempts of therapeutic approaches to provide an overview of the potential prospects for treating this rare neoplasm. [ABSTRACT FROM AUTHOR]

Introduction: There are scarce papers about the use of fluorescence-guided surgery (FGS) in the open surgical field. This study aimed to assess the usefulness of FGS in an open setting in the pediatric population and to report our preliminary experience using the Rubina® Lens system. Methods: All patients undergoing ICG fluorescence-assisted open surgery over the period September 2022–September 2023 were enrolled. Each surgical procedure was performed using the Rubina® Lens for ICG fluorescence visualization. Results: A total of 25 patients, 14 boys and 11 girls with a median age at surgery of 5.8 years-old (range 0–15), were enrolled. Surgical indications were dermoid/epidermoid cysts of the head (n = 7), lymphangiomas of the head/neck (n = 2), thyroglossal duct cysts (n = 7), gynecomastia (n = 3), preauricular fistula (n = 2), second branchial cleft fistula (n = 1), fibrolipoma of the shoulder (n = 1) and myofibroma of the gluteal/perineal region (n = 2). In all procedures, an intralesional injection of 2.5 mg/mL ICG solution using a 30-gauge needle was administered. No adverse reactions to ICG occurred. Median operative time was 68.6 min (range 35–189). The visualization of ICG-NIRF with the Rubina® Lens was achieved in all cases. No intraoperative complications were reported. Postoperative complications occurred in 3/25 patients (12%), with gynecomastia (n = 1), thyroglossal duct cyst (n = 1) and neck lymphangioma (n = 1), who developed a fluid collection in the surgical site, requiring needle aspiration in outpatient care (Clavien–Dindo 2). Complete mass excision was confirmed with pathology reports. Conclusions: Based on this initial experience, FGS using the Rubina® Lens was very helpful in open surgery, providing enhanced visualization of anatomy and identification of margins, real-time reliability and low complication rate. It was easy to use, time saving, feasible and clinically safe. Previous experience in MIS is necessary to adopt this technology. The accuracy of the injection phase is important to avoid diffusion of the ICG into the perilesional tissue. [ABSTRACT FROM AUTHOR]

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9–2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5–20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options. [ABSTRACT FROM AUTHOR]

Tissue biopsy is essential for NSCLC diagnosis and treatment management. Over the past decades, liquid biopsy has proven to be a powerful tool in clinical oncology, isolating tumor-derived entities from the blood. Liquid biopsy permits several advantages over tissue biopsy: it is non-invasive, and it should provide a better view of tumor heterogeneity, gene alterations, and clonal evolution. Consequentially, liquid biopsy has gained attention as a cancer biomarker tool, with growing clinical applications in NSCLC. In the era of precision medicine based on molecular typing, non-invasive genotyping methods became increasingly important due to the great number of oncogene drivers and the small tissue specimen often available. In our work, we comprehensively reviewed established and emerging applications of liquid biopsy in NSCLC. We made an excursus on laboratory analysis methods and the applications of liquid biopsy either in early or metastatic NSCLC disease settings. We deeply reviewed current data and future perspectives regarding screening, minimal residual disease, micrometastasis detection, and their implication in adjuvant and neoadjuvant therapy management. Moreover, we reviewed liquid biopsy diagnostic utility in the absence of tissue biopsy and its role in monitoring treatment response and emerging resistance in metastatic NSCLC treated with target therapy and immuno-therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of advanced NSCLC patients unfit for a platinum combination is challenging and no clear evidence is available. We retrospectively collected data on advanced NSCLC not receiving a first-line platinum combination, focusing on clinical selection criteria. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 < 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (>70 years), comorbidities and poor performance status. A single agent chemotherapy was offered with the prevalence of oral metronomic vinorelbine. In the whole population, progression-free survival and overall survival ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. Limited evidence is available concerning the selection criteria and the outcomes of platinum unfit newly diagnosed advanced NSCLC patients receiving single-agent chemotherapy. We retrospectively collected data on consecutive, stage IIIB-IV, EGFR/ALK negative and PD-L1 < 50% NSCLC patients treated with first-line single agent chemotherapy. Baseline characteristics, outcome measures and toxicities were recorded, as well as criteria according to which treatment selection was made and what percentage of patients did not receive a first-line platinum-based chemotherapy. Two-hundred and twenty-one patients were included. Median age was 79 (range 56–92) years, M/F 165(74.6%)/56(25.4%), ECOG performance status (PS) 0/1/ ≥ 2 23(10.9%)/94(42.5%)/103(46.6%), with a median of two serious comorbidities. A median of 25% (range 10%-30%) of newly diagnosed NSCLC did not receive a first-line platinum combination. Clinical criteria according to which decision was made were older age (76.5%), comorbidities (72%), poor PS (55.2%) and familiar or social issues (10%). Single-agent treatment consisted of oral metronomic vinorelbine (MetV 78.6%), gemcitabine (Gem 10%), oral standard vinorelbine (Vin 8.2%) and other (O 3.2%). Median progression-free survival (PFS) and overall survival (OS) of single agent treatments ranged from 4.5 to 5 months and from 9 to 10.5 months, respectively. All grade toxicities did not differ among single agents, while grade 3–4 toxicities were less frequent with MetV. Up to 30% of newly diagnosed advanced EGFR/ALK negative and PD-L1 < 50% NSCLC patients do not receive a first-line platinum doublet. Main clinical selection criteria were older age (>70 years), comorbidities and poor PS. An oral treatment was frequently proposed with MetV being the most frequent choice according to its safety profile. [ABSTRACT FROM AUTHOR]

Background: Ovarian masses in pediatric populations are the most common abdominal masses in young girls. In neonates, the majority of masses are benign while in children and teen-agers the risk of malignancy exists. The aim of this study is to perform a 25-year experience retrospective analysis of clinical and therapeutic aspects of ovarian tumors in girls, in order to show how the development of minimally invasive technology has changed the management of this pathology. Methods: The records of patients under the age of 18 who were operated in three pediatric surgical units due to ovarian mass, in the last 25 years, were reviewed retrospectively. The study group comprised 147 patients operated between 1996 and 2021 with a diagnosis of ovarian masses. Data involved were demographical, surgical, follow-up and final diagnosis. We analyzed the type of surgical technique, intra-operative data (operative time, the use of different technologies), complications, length of stay and long-term follow-up. Based on these data, we assessed how the surgical approach to ovarian masses has changed in the last 25 years in newborns and young girls. Results: The patients ages ranged between 7 days and 15 years (median, 59 days). All the procedures were completed in laparoscopy or robotics without conversion in open surgery. One-hundred and eleven patients were neonates; they all had follicular cysts and they were all managed in laparoscopy using 1 or 3 trocars. In 80/111 patients (72%), a small part of ovarian parenchyma was saved; in 31/111 patients (28%), in which the ovarian parenchyma was not available, an ovariectomy was performed. Patients in which we saved a small part of ovary, at long term follow-up (minimum follow-up of 12 years) (29/80, 36%), developed a normal ovary at US control. Thirty-six were older patients. They had a histological diagnosis of benign (30) or malign (6) tumors. All the patients (8/36) with a pre-operative suspicion of ovarian malignancy received an ovariectomy and an adnexectomy using sealing devices. In the last 10 years in all the children, except neonates, we adopted sealing devices and, in the last 4 years, in 20 cases, we always adopted ICG fluorescence technology to check ovarian vascularization in case of torsion or to check lympho-nodes condition in case of malignancy. Conclusions: In neonatal ovarian cysts, surgical management remained unchanged and an ovarian sparing procedure is always indicated and the long-term follow-ups confirm this hypothesis. The principal innovation in this age period is the use of ICG fluorescence technology to check ovarian vascularization in case of torsion. In teenagers, the decision-making strategy is based on the tumoral markers and on the morphological aspects of the mass. Robotics cystectomy or ovariectomy now-days represents the safer and faster way to perform this. Sealing devices are essential tools for dissection and resection to avoid bleeding. ICG fluorescence technology in all ages is fundamental to check ovary vascularization after detorsion or to check lympho-node status in case of malignancy. All the suspected lesions have to be removed with an endo-bag. [ABSTRACT FROM AUTHOR]

The severe prognosis linked with a lung cancer diagnosis has changed with the discovery of oncogenic molecularly driven subgroups and the use of tailored treatment. ALK-translocated advanced lung cancer is the most interesting model, having achieved the longest overall survival. Here, we report the most important paradigmatic shifts in the prognosis and treatment for this subgroup population occurred among lung cancer. [ABSTRACT FROM AUTHOR]

The scenario of neoadjuvant and adjuvant settings in non-small cell lung cancer (NSCLC) is rapidly evolving. As already happened for the advanced disease, also early stages have entered the era of precision medicine, with molecular analysis and Programmed death-ligand 1 (PD-L1) evaluation that by now can be considered a routine assessment. New treatment options have been recently approved, with osimertinib now part of clinical practice for Epidermal Growth Factor Receptor mutated (EGFRm) patients, and immune checkpoint inhibitors (ICIs) available after FDA approval both in the adjuvant (atezolizumab) and neoadjuvant (nivolumab) setting. No mature data on overall survival benefits are available yet, though. Several clinical trials with specific-tyrosine kinase inhibitors (TKIs) and ICIs are currently ongoing, both with and without concomitant chemotherapy. As therapeutic strategies are rapidly expanding, quite a few questions remain unsettled, such as the optimal duration of adjuvant targeted therapy or the effective benefit of ICIs in early-stage EGFRm or ALK (Anaplastic Lymphoma Kinase) rearranged patients, or the possibility to individuate high-risk patients after surgical resection assessing minimal residual disease (MRD) by ctDNA evaluation. We hereby report already available literature data and summarize ongoing trials with targeted therapy and immunotherapy in early-stage NSCLC, focusing on practice-changing results and new perspectives for potentially cured patients. [ABSTRACT FROM AUTHOR]

Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications. [ABSTRACT FROM AUTHOR]

Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient's quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome. [ABSTRACT FROM AUTHOR]

Standard treatment for advanced non-small cell lung cancer (NSCLC) historically consisted of systemic cytotoxic chemotherapy until the early 2000s, when precision medicine led to a revolutionary change in the therapeutic scenario. The identification of oncogenic driver mutations in EGFR, ALK and ROS1 rearrangements identified a subset of patients who largely benefit from targeted agents. However, since the proportion of patients with druggable alterations represents a minority, the discovery of new potential driver mutations is still an urgent clinical need. We provide a comprehensive review of the emerging molecular targets in NSCLC and their applications in the advanced setting. [ABSTRACT FROM AUTHOR]

The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors. [ABSTRACT FROM AUTHOR]

Pre- event and event landslide deformations have been detected and measured for the landslide that occurred on 3 December 2013 on the south-western slope of the Montescaglioso village (Basilicata Region, southern Italy). In this paper, ground displacements have been mapped through an integrated analysis based on a series of high resolution SAR (Synthetic Aperture Radar) images acquired by the Italian constellation of satellites COSMO-SkyMed. Analysis has been performed by exploiting both phase (through multi-image SAR interferometry) and amplitude information (through speckle tracking techniques) of the satellite images. SAR Interferometry, applied to images taken before the event, revealed a general pre-event movement, in the order of a few mm/yr, in the south-western slope of the Montescaglioso village. Highest pre-event velocities, ranging between 8 and 12 mm/yr, have been recorded in the sector of the slope where the first movement of the landslide took place. Speckle tracking, applied to images acquired before and after the event, allowed the retrieval of the 3D deformation field produced by the landslide. It also showed that ground displacements produced by the landslide have a dominant SSW component, with values exceeding 10 m for large sectors of the landslide area, with local peaks of 20 m in its central and deposit areas. Two minor landslides with a dominant SSE direction, which were detected in the upper parts of the slope, likely also occurred as secondary phenomena as consequence of the SSW movement of the main Montescaglioso landslide. [ABSTRACT FROM AUTHOR]