Immunobiology of Thymic Epithelial Tumors: Implications for Immunotherapy with Immune Checkpoint Inhibitors.

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus' immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.

Lack of Hypophagia in CB1 Null Mice is Associated to Decreased Hypothalamic POMC and CART Expression.

BACKGROUND: Cumulative data indicate that the endocannabinoid system plays a major role in feeding behavior and energy balance. Genetic silencing of cannabinoid receptor type 1 (CB1) reduces body weight gain, independently of food intake. METHODS: In this work, we investigated whether the hypothalamic neuropeptide expression pattern supports the absence of the anorexigenic response observed under constitutive CB1 ablation, by using neuronal CB1 conditional null mice (CamK-CB1-KO) and whole body CB1 null mice (CB1-KO). RESULTS: Our data showed that both CB1 null models display a marked decrease in proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART) expression in the arcuate nucleus of the hypothalamus (ARC). CONCLUSIONS: This evidence suggests that a lack of hypophagia is associated with the suppression of ARC anorexigenic neuropeptides and that behavioral changes in food intake (or lack thereof) after constitutive CB1 ablation are likely mediated by impaired melanocortin and CART signaling in the hypothalamus.

Antibody drug conjugates in older patients: State of the art.

More than half of cancer cases occur in patients aged 65 years or older. The efficacy and safety of antibody drug conjugates (ADCs) in older patients remains an unclear subject as available evidence is limited. Geriatric population is underrepresented in clinical trials. Consequently, most of our knowledge regarding innovative therapeutics was studied on a younger population. In this review of published literature, we report the available information on efficacy, safety and pharmacokinetics of FDA approved ADCs for hematologic malignancies and solid tumors in the geriatric population. We explore the results of clinical trials dedicated for older individuals as well as subgroup analyses of the geriatric population in major trials evaluating these drugs. Available data suggest a similar efficacy in older adults as compared to general population. However, older patients might be prone to a higher rate of adverse events in incidence with a potential impact on quality of life. We lack data to support primary dose reductions or schedule modifications in this category of patients. No pharmacokinetic differences were reported between age groups. It is crucial to encourage the development of clinical trials dedicated to older patients with geriatric parameters (G8 score, G-CODE…) so that results can be more representative of this population outside of clinical trials.

Analysing patent landscapes in plant biotechnology and new plant breeding techniques.

This article aims to inform the reader of the importance of searching patent landscapes in plant biotechnology and the use of basic tools to perform a patent search. The recommendations for a patent search strategy are illustrated with the specific example of zinc finger nuclease technology for genetic engineering in plants. Within this scope, we provide a general introduction to searching using two online and free-access patent databases esp@cenet and PatentScope. The essential features of the two databases, and their functionality is described, together with short descriptions to enable the reader to understand patents, searching, their content, patent families, and their territorial scope. We mostly stress the value of patent searching for mining scientific, rather than legal information. Search methods through the use of keywords and patent codes are elucidated together with suggestions about how to search with or combine codes with keywords and we also comment on limitations of each method. We stress the importance of patent literature to complement more mainstream scientific literature, and the relative complexities and difficulties in searching patents compared to the latter. A parallel online resource where we describe detailed search exercises is available through reference for those intending further exploration. In essence this is aimed at a novice patent searcher who may want to examine accessory patent literature to complement knowledge gained from mainstream journal resources.

TROP-2 directed antibody-drug conjugates (ADCs): The revolution of smart drug delivery in advanced non-small cell lung cancer (NSCLC).

BACKGROUND: Antibody drug conjugates (ADCs) represent a revolutionary drug class in cancer therapy, combining the precision of targeted therapy with the cytotoxic effects of chemotherapy. Promising activity of novel ADCs, namely Trastuzumab Deruxtecan and Patritumab Deruxtecan, has been observed in hard-to treat molecular subtypes, such as HER2-positive and heavily pretreated EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). However, therapeutic advances are expected in certain subgroups of lung cancer patients, including non-oncogene-addicted NSCLC after failure of current standard of care (e.g., immunotherapy with or without chemotherapy, chemo-antiangiogenic treatment). Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface transmembrane glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family. TROP-2 represents a promising therapeutic target in refractory non-oncogene-addicted NSCLC. METHODOLOGY: We performed a systematic literature search of the clinical trials about TROP-2 directed ADCs in NSCLC referenced in the pubmed.gov database, Cochrane Library database and clinicaltrial.gov database. RESULTS: First-in-humans ADCs targeting TROP-2, namely Sacituzumab Govitecan (SN-38) and Datopotamab Deruxtecan (Dxd), yielded promising activity signals in NSCLC with a manageable safety profile. Most common grade ≥ 3 adverse events (AEs) of Sacituzumab Govitecan included neutropenia (28 %), diarrhea (7 %), nausea (7 %), fatigue (6 %), and febrile neutropenia (4 %). Nausea and stomatitis were the most common all grade AEs with Datopotamab Deruxtecan; dyspnea, amylase increase, hyperglycemia and lymphopenia were reported as grade ≥ 3 AEs in less than 12 % of patients. CONCLUSION: As more effective strategies are needed for patients with refractory non-oncogene-addicted NSCLC, the design of novel clinical trials with ADCs targeting TROP-2 is encouraged as both a monotherapy or combination strategy with existing agents (e.g., monoclonal antibodies targeting immune checkpoint inhibitors or chemotherapy).

Serological tests in gluten sensitivity (nonceliac gluten intolerance).

GOALS: To characterize the serological pattern of gluten sensitivity (GS) and to compare it with that found in celiac disease. BACKGROUND: GS has recently been identified as a new clinical entity included in the spectrum of gluten-related disorders, but it is still lacking of diagnostic markers. STUDY: Sera from 78 patients with GS and 80 patients with celiac disease were retrospectively assessed for immunoglobulin (Ig)G/IgA antigliadin antibodies (AGA), IgG deamidated gliadin peptide antibodies (DGP-AGA), IgA tissue transglutaminase antibodies (tTGA), and IgA endomysial antibodies (EmA). RESULTS: IgG AGA were positive in 56.4% of GS patients and in 81.2% of celiac patients, with high antibody titers in both groups. IgA AGA were detected in 7.7% of GS patients and in 75% of celiac patients, showing lower enzyme-linked immunosorbent assay activities in GS than those found in celiac disease. Only 1 of the 78 patients with GS was positive for IgG DGP-AGA (detected in 88.7% of patients with celiac disease). IgA tTGA and IgA EmA were negative in all GS patients, whereas their positivity in celiac patients was 98.7% and 95%, respectively. Patients with GS displayed a variegated clinical picture with intestinal and extraintestinal symptoms (abdominal pain, bloating, diarrhea, constipation, foggy mind, tiredness, eczema/skin rash, headache, joint/muscle pain, numbness of legs/arms, depression, and anemia) together with normal or mildly abnormal small intestinal mucosa. CONCLUSIONS: The serological pattern of GS is characterized by IgG AGA positivity in more than half of cases associated to IgA AGA in a few patients, but without EmA, tTGA, and DGP-AGA, which are the specific markers of celiac disease.

Monitoring tumor growth rate to predict immune checkpoint inhibitors' treatment outcome in advanced NSCLC.

INTRODUCTION: Radiological response assessment to immune checkpoint inhibitor is challenging due to atypical pattern of response and commonly used RECIST 1.1 criteria do not take into account the kinetics of tumor behavior. Our study aimed at evaluating the tumor growth rate (TGR) in addition to RECIST 1.1 criteria to assess the benefit of immune checkpoint inhibitors (ICIs). METHODS: Tumor real volume was calculated with a dedicated computed tomography (CT) software that semi-automatically assess tumor volume. Target lesions were identified according to RECIST 1.1. For each patient, we had 3 measurement of tumor volume. CT-1 was performed 8-12 weeks before ICI start, the CT at baseline for ICI was CT0, while CT + 1 was the first assessment after ICI. We calculated the percentage increase in tumor volume before (TGR1) and after immunotherapy (TGR2). Finally, we compared TGR1 and TGR2. If no progressive disease (PD), the group was disease control (DC). If PD but TGR2 < TGR1, it was called LvPD and if TGR2 ⩾ TGR1, HvPD. RESULTS: A total of 61 patients who received ICIs and 33 treated with chemotherapy (ChT) were included. In ICI group, 18 patients were HvPD, 22 LvPD, 21 DC. Median OS was 4.4 months (95% CI: 2.0-6.8, reference) for HvPD, 7.1 months (95% CI 5.4-8.8) for LvPD, p = 0.018, and 20.9 months (95% CI: 12.5-29.3) for DC, p < 0.001. In ChT group, 7 were categorized as HvPD, 17 as LvPD and 9 as DC. No difference in OS was observed in the ChT group (p = 0.786). CONCLUSION: In the presence of PD, a decrease in TGR may result in a clinical benefit in patients treated with ICI but not with chemotherapy. Monitoring TGR changes after ICIs administration can help physician in deciding to treat beyond PD.

Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib.

INTRODUCTION: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC). Some osimertinib-related interstitial lung diseases (ILDs) were shown to be transient, called transient asymptomatic pulmonary opacities (TAPO)-clinically benign pulmonary opacities that resolve despite continued osimertinib treatment-and are not associated with the clinical manifestations of typical TKI-associated ILDs. METHODS: In this multicentric study, we retrospectively analyzed 92 patients with EGFR-mutated NSCLC treated with osimertinib. Computed tomography (CT) examinations were reviewed by two radiologists and TAPO were classified according to radiologic pattern. We also analyzed associations between TAPO and patients' clinical variables and compared clinical outcomes (time to treatment failure and overall survival) for TAPO-positive and TAPO-negative groups. RESULTS: TAPO were found in 18/92 patients (19.6%), with a median follow-up of 114 weeks. Median onset time was 16 weeks (range 6-80) and median duration time 14 weeks (range 8-37). The most common radiologic pattern was focal ground-glass opacity (54.5%). We did not find any individual clinical variable significantly associated with the onset of TAPO or significant difference in clinical outcomes between TAPO-positive and TAPO-negative groups. CONCLUSIONS: TAPO are benign pulmonary findings observed in patients treated with osimertinib. TAPO variability in terms of CT features can hinder the differential diagnosis with either osimertinib-related mild ILD or tumor progression. However, because TAPO are asymptomatic, it could be reasonable to continue therapy and verify the resolution of the CT findings at follow-up in selected cases.

Mitotic catastrophe in malignant epithelial tumors: the pathologist's viewpoint.

Mitotic catastrophe is a common phenomenon occurring in tumor cells with impaired p53 function exposed to various cytotoxic and genotoxic agents. The defective p53 checkpoint causes improper segregation of chromosomes, resulting in aberrant mitosis, multiple micronuclei, multinucleate giant cells, and eventual necrosis-like death and centrosome aberration. Although various descriptions explaining mitotic catastrophe exist, there is still no generally accepted definition of this phenomenon. However, the syndrome of mitotic catastrophe may be a unifying morphological concept of particular interest to cancer research, as it integrally links cell death to checkpoints of the cell cycle. Morphological findings compatible with mitotic catastrophe may be found in pleomorphic, giant cell carcinomas--neoplasms characterized by a poor prognosis. The inclusion of mitotic catastrophe as part of the microscopic evaluation of tumors will add further insight to the pathobiology of tumor progression and in novel therapeutic designs. Finally, the possibility of assimilating mitotic catastrophe into a prognostic score is discussed.

Ultrastructural descriptions of heterotypic aggregation between eosinophils and tumor cells in human gastric carcinomas.

A histological variant of gastric adenocarcinoma, characterized by an intense tumor-associated tissue eosinophilia (TATE), has been occasionally reported in the literature. The purpose of this ultrastructural study was to determine the interactions between frequently occurring eosinophils and tumor cells in gastric carcinoma characterized by TATE. Fresh tumor tissue of 92 gastric carcinomas was processed for both light and electron microscopic examination. Intense TATE was found in 7 out of 92 (7.6%) gastric carcinomas (6 of intestinal-type and 1 of diffuse-type). Electron microscopy, selectively performed in 7 cases with intense TATE, revealed eosinophils, singly or in groups, in contact with damaged or necrotic tumor cells. Activated eosinophils showing piecemeal degranulation were also found in intimate contact with viable tumor cells, characterized by plasma membrane caveolar invaginations. The authors regard this close morphological relationship as in vivo evidence for possible cross-talk between eosinophil and viable tumor cell, a conclusion that has already been drawn from experimental studies, but until now inadequately supported by ultrastructural observations in a human tumor.

STK11/LKB1 and KEAP1 mutations in non-small cell lung cancer: Prognostic rather than predictive?

Immune checkpoint inhibitors (ICIs), either alone or combined with chemotherapy, represent the cornerstone of the treatment of advanced non-small cell lung cancer (NSCLC) without targetable gene alterations. Programmed death ligand-1 expression currently represents the only available biomarker to predict response to ICI, although its reliability is debated. However, most patients still do not derive benefit from immunotherapy, making the identification of further predictive biomarkers extremely needed. Serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) and Kelch-like ECH-associated protein 1 (KEAP1) mutations occur in 25-30% and 11-27% of advanced NSCLC, respectively. Several studies associated their presence with poor outcomes in patients treated with ICI. However, more recent evidence showed poor outcomes among NSCLC with STK11/LKB1 and/or KEAP1 mutations regardless of the treatment received. We reviewed the literature to provide a comprehensive, timely and structured overview of the role of STK11/LKB1 and KEAP1 mutations in NSCLC. Although conflicting outcomes have been reported by studies evaluating their impact in KRAS wild-type patients or regardless of KRAS mutation, the correlation between STK11/LKB1 and KEAP1 mutations and poor outcomes with ICI appears to be consistent in presence of concurrent KRAS mutations. The main limitations of most studies are represented by the inclusion of other gene mutations (e.g. TP53) together with STK11 and KEAP1 mutations as a group and by the lack of comparison arms including patients who received other treatments (e.g. chemotherapy). Studies evaluating the impact of STK11 and KEAP1 mutations on the outcomes with ICI and other therapies showed a similar effect regardless of the treatment received, suggesting a prognostic, rather than predictive, value.

Programmed Cell Death Protein-1 Inhibitors Versus Programmed Death-Ligand 1 Inhibitors in Addition to Chemotherapy for the First-Line Treatment of Advanced NSCLC: A Systematic Review and Meta-Analysis.

INTRODUCTION: The addition of programmed cell death protein-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors to first-line chemotherapy (CT) improved the outcomes of advanced NSCLC. Nonetheless, no direct comparison exists between these combination treatments. METHODS: We performed a meta-analysis of randomized clinical trials to evaluate and compare the efficacy and safety of PD-(L)1 inhibitors in combination with first-line CT for advanced NSCLC. RESULTS: A total of eight randomized clinical trials were included. The addition of a PD-(L)1 inhibitor to CT improved progression-free survival, overall survival, and objective response rate compared with CT alone. The risk of grade greater than or equal to 3 treatment-related adverse events was slightly higher with the addition of a PD-(L)1 inhibitor to CT as compared with CT alone. A subgroup analysis according to the targeted receptor (PD-1 versus PD-L1) revealed that the addition of a PD-1 inhibitor to CT led to better objective response rate (p = 0.0001), progression-free survival (p = 0.006), and overall survival (p = 0.002) compared with that of a PD-L1 inhibitor. The risk of grade greater than or equal to 3 treatment-related adverse events was significantly increased with the addition of a PD-L1 inhibitor to CT, but not with the addition of a PD-1 inhibitor. A direct comparison using the meta-regression analysis confirmed the statistical significance of all previous findings. CONCLUSIONS: On the basis of this meta-analysis, the addition of a PD-1 inhibitor to first-line CT revealed statistically significant better outcomes and less additional toxicity compared with that of a PD-L1 inhibitor, as compared with CT alone, in advanced NSCLC, regardless of PD-L1 status.

PD-1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as upfront treatment for advanced NSCLC with PD-L1 expression ≥ 50%: Selecting the best strategy.

Treatment strategies for advanced NSCLC patients without driver molecular alterations are influenced by PD-L1 expression. If PD-L1 is <50 %, the preferred upfront treatment is the association of chemotherapy and immunotherapy, while immunotherapy alone is an additional option if PD-L1 ≥ 50 %. Both treatments demonstrated their superiority over chemotherapy in this subset of NSCLC patients, with comparable efficacy outcomes but less safety concerns for immunotherapy alone. Nevertheless, a significant difference in terms of early progression-free survival rate emerges by analyzing and comparing the survival curves of the two strategies, reflecting a non-negligible loss of patients due to early disease progression at 3 and 6 months from treatment initiation with immunotherapy alone as compared to its association with chemotherapy. We deeply analyzed efficacy similarities and differences of the two approaches in advanced NSCLC with PD-L1 expression ≥50 %, trying to suggest clinical and biologic aspects to be considered when facing the treatment choice.

An Overview on Molecular Characterization of Thymic Tumors: Old and New Targets for Clinical Advances.

Thymic tumors are a group of rare mediastinal malignancies that include three different histological subtypes with completely different clinical behavior: the thymic carcinomas, the thymomas, and the rarest thymic neuroendocrine tumors. Nowadays, few therapeutic options are available for relapsed and refractory thymic tumors after a first-line platinum-based chemotherapy. In the last years, the deepening of knowledge on thymus' biological characterization has opened possibilities for new treatment options. Several clinical trials have been conducted, the majority with disappointing results mainly due to inaccurate patient selection, but recently some encouraging results have been presented. In this review, we summarize the molecular alterations observed in thymic tumors, underlying the great biological differences among the different histology, and the promising targeted therapies for the future.

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine.

Pancreatic cancer (PC) is a recalcitrant disease characterized by high incidence and poor prognosis. The extremely complex genomic landscape of PC has a deep influence on cultivating a tumor microenvironment, resulting in the promotion of tumor growth, drug resistance, and immune escape mechanisms. Despite outstanding progress in personalized medicine achieved for many types of cancer, chemotherapy still represents the mainstay of treatment for PC. Olaparib was the first agent to demonstrate a significant benefit in a biomarker-selected population, opening the doors for a personalized approach. Despite the failure of a large number of studies testing targeted agents or immunotherapy to demonstrate benefits over standard chemotherapy regimens, some interesting agents, alone or in combination with other drugs, have achieved promising results. A wide spectrum of therapeutic strategies, including immune-checkpoint inhibitors tyrosine kinase inhibitors and agents targeting metabolic pathways or the tumor microenvironment, is currently under investigation. In this review, we aim to provide a comprehensive overview of the current landscape and future directions of personalized medicine for patients affected by PC.

Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage.

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.

Deamidated gliadin peptide antibodies as a routine test for celiac disease: a prospective analysis.

GOALS: This study was designed to establish whether deamidated gliadin peptide antibodies (DGP-AGA) could improve the serologic workup for celiac disease (CD). BACKGROUND: The best serologic approach for CD screening is currently based on the combined detection of tissue transglutaminase (tTGA), endomysial (EmA), and gliadin antibodies (AGA). STUDY: One hundred forty-four consecutive patients with gastrointestinal and extraintestinal signs suggestive for CD were investigated using serologic tests, that is, IgG and IgA DGP-AGA, IgA tTGA, IgA EmA, and duodenal biopsy. RESULTS: Forty-eight out of 144 patients (33%) had CD with different severity of villous atrophy. IgA tTGA showed 93.7% sensitivity compared with 91.6% for IgA EmA, 84.3% for IgA DGP-AGA, and 82.3% for IgG DGP-AGA. Of the 3 cases negative for IgA tTGA, IgA EmA, and IgA DGP-AGA, 2 had total IgA deficiency, although both were positive for IgG DGP-AGA. IgG DGP-AGA showed a very high specificity for CD (98.9%), not only superior to IgA DGP-AGA (79.8%), but also to IgA tTGA (96.6%) and very close to IgA EmA (100%). CONCLUSIONS: Our prospective study shows that the combined search for IgA tTGA and IgG DGP-AGA provides the best diagnostic accuracy for CD, allowing the identification of all CD cases---except one---with a very high specificity. The serologic workup for CD screening could be significantly improved by the routine introduction of IgG DGP-AGA together with IgA tTGA, thus reducing the number of tests and with an obvious advantage in terms of cost-efficacy.

Evolution of cystic airspaces lung lesions on immune checkpoint inhibition in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) can be associated with pulmonary cystic airspaces (pCAs). pCAs are radiologically classified into four types based on whether the nodule or mass extrudes the wall of the pCAs. In most cases, response evaluation of these lesions by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 is challenging. Based on the observation of a case of morphological evolution of pCAs associated with NSCLC in a patient receiving immune checkpoint inhibitor (ICI), we reviewed retrospectively imaging scans of 92 consecutive advanced patients with NSCLC treated at our institution. Overall, three cases of pCAs associated with NSCLC obtained a remarkable change following ICI. Of note, these changes were not always seen in the context of a clear radiological objective response. The morphological changes observed may reflect a novel pattern of response to immunotherapy agents that clinicians should be aware of. This pattern of response, not reported before, warrants further investigation and, if confirmed, we believe that it should be considered in future version of immune RECIST.

Efficacy and safety of flash glucose monitoring in patients with type 1 and type 2 diabetes: a systematic review and meta-analysis.

INTRODUCTION: Flash glucose monitoring (FGM) is a factory-calibrated sensor-based technology for the measurement of interstitial glucose. We performed a systematic review and meta-analysis to assess its efficacy and safety in patients with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: PubMed, CENTRAL, Scopus and Web of Science were searched in July 2019. Twelve studies with a follow-up longer than 8 weeks, evaluating 2173 patients on prandial insulin, multiple daily insulin injections or continuous subcutaneous insulin infusion were included. The following data were extracted: HbA1c, time in range, time above 180 mg/dL, time below 70 mg/dL, frequency of hypoglycemic events, number of self-monitoring of blood glucose (SMBG) measurements, total daily insulin dose, patient-reported outcomes, adverse events, and discontinuation rate. A comparison with SMBG was conducted. RESULTS: FGM use was associated with a reduction in HbA1c (-0.26% (-3 mmol/mol); p=0.002) from baseline to the last available follow-up, which correlated with HbA1c levels at baseline (-0.4% (-4 mmol/mol) for each 1.0% (11 mmol/mol) of HbA1c above 7.2% (55 mmol/mol)). Also, a decrease in time below 70 mg/dL was found (-0.60 hours/day; p=0.04). Favorable findings in patient-reported outcomes and no device-related serious adverse events were reported. When compared with SMBG, FGM was characterized by no statistically different change in HbA1c (p=0.09), with lower number of SMBG measurements per day (-3.76 n/day; p<0.001) and risk of discontinuation (relative risk=0.42; p=0.001). A limited number of studies, with a heterogeneous design and usually with a short-term follow-up and without specific training, were found. CONCLUSIONS: The present review provides evidence for the use of FGM as an effective strategy for the management of diabetes.

Beyond EGFR, ALK and ROS1: Current evidence and future perspectives on newly targetable oncogenic drivers in lung adenocarcinoma.

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs.