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Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. Results: PD-1 positive (+) was significantly associated with current smoking status ( P =0.02) and with the presence of KRAS mutations ( P =0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology ( P =0.005) and with presence of EGFR mutations ( P =0.001). In patients treated with EGFR tyrosine kinase inhibitors ( N =95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P =0.01) time to progression (TTP: P <0.0001) and survival (OS: P =0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative ( P =0.01). Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Background Lung NET, classified in typical carcinoids (TC) and atypical carcinoids (AC), are highly heterogeneous in their biology and prognosis. The histological subtype and TNM stage are well-established prognostic factors for lung NET. In a previous work by our group, we demonstrated a significant impact of laterality on lung NET survival outcomes. Materials and methods We developed a nomogram that integrates relevant prognostic factors to predict lung NET outcomes. By adding the scores for each of the variables included in the model, it was possible to obtain a prognostic score (Rachel score). Wilcoxon non-parametric statistical test was applied among parameters and Harrell’s concordance index was used to measure the models’ predictive power. To test the discriminatory power and the predictive accuracy of the model, we calculated Gonen and Heller concordance index. Time-dependent ROC curves and their area under the curve (AUC) were used to evaluate the models’ predictive performance. Results By applying Rachel score, we were able to identify three prognostic groups (specifically, high, medium and low risk). These three groups were associate to well-defined ranges of points according to the obtained nomogram (I: 0–90, II: 91–130; III: > 130 points), providing a useful tool for prognostic stratification. The overall survival (OS) and progression free survival (PFS) Kaplan–Meier curves confirmed significant differences ( p < 0.0001) among the three groups identified by Rachel score. Conclusions A prognostic nomogram was developed, incorporating variables with significant impact on lung NET survival. The nomogram showed a satisfactory and stable ability to predict OS and PFS in this population, confirming the heterogeneity beyond the histopathological diagnosis of TC vs AC.

Plants produce and release in the surrounding soil, the so-called rhizosphere, a vast variety of secondary metabolites. Among them, flavonoids are the most studied, mainly for their role in the establishment of rhizobium–legume symbiosis; on the other hand, some studies highlight that they are also important in the plant strategies to acquire nutrients from the soil, for example, by acting on its chemistry. The scope of this review is to give a quick overview on the types and amounts of plant-released flavonoids in order to focus on their effects on soil activities that in turn can influence nutrient availability and so plant mineral nutrition; emphasis is given to the different nutrient cycles, soil enzyme, and soil bacteria activities, and their influence on soil macrofauna and roots of other plants. Finally, the possible outcome of the climate change on these processes is discussed.

Background: In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease. Methods: We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab. Results: Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R: HER2 /CEP17⩾2) in all neoplastic cells ( HER2 -all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones ( HER2- FISH+*), and 35% of patients had no or slight HER2 gain ( HER2 -FISH−). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P =0.0006), progression-free survival (PFS; P <0.0001) and overall survival (OS; P <0.0001). Patients with HER2- all-A profile experienced the worst outcome, patients with HER2- FISH− profile showed an intermediate behaviour and patients with HER2- FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively). Conclusion: HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.

Small-cell lung cancer (SCLC) is the most aggressive lung cancer, mostly diagnosed at advanced stage, and with few therapeutic options for patients failing the first-line treatment. Antibody-based therapies, such as antibody-drug conjugates and T-cell engagers, are emerging as a promising option in the treatment of various solid tumors, including SCLC. T-cell engagers are molecules able to trigger the T-cell-mediated tumor cell death binding, at the same time, a T-cell and a tumor cell target. Tarlatamab is a DLL3-directed bi-specific T-cell engager (BiTE) whose efficacy was evaluated in a Phase 2 study. Antibody-drug conjugates (ADC) consist of a tumor-directed monoclonal antibody conjugated to a cytotoxic payload able to selectively kill tumor cells through different mechanisms. Ifinatamab-deruxtecan is an anti-B7-H3 ADC showing efficacy in pretreated SCLC patients in a phase 2 clinical trial. Sacituzumab govitecan is a Trop-2-directed ADC already used in other tumor types and evaluated in SCLC in the phase 2 TROPiCS-03 trial, with positive results. Bispecific antibodies targeting VEGF and PD-(L)1 showed antitumor activity in phase 1 and 2 clinical trials. Other antibody-based agents are currently at an earlier phase of their clinical development and showed a promising activity. Novel antibody-based agents could potentially acquire a prominent role in the treatment of SCLC, a field with few therapeutic options. Direct comparisons with the current standard of care still lack, however Phase 3 trials are currently ongoing.

This joint report from the Italian Society of Orthopaedics and Traumatology (SIOT) and the Italian Society of Periodontology and Implantology (SIdP) aims for a consensus around the scientific rationale and clinical strategy for the management of osteoporotic patients affected by periodontitis who are undergoing anti-resorptive (AR) therapy to manage the risk of the occurrence of a medication-related osteonecrosis of the jaws (MRONJ). Osteoporosis and periodontitis are chronic diseases with a high prevalence in aging patients, and they share some of the same pathogenetic mechanisms based upon inflammation. Available evidence shows the relationship among osteoporosis, AR agents, periodontitis and implant therapy in relation to the incidence of MRONJ. Uncontrolled periodontitis may lead to tooth loss and to the need to replace teeth with dental implants. Tooth extraction and surgical dental procedures are recognized as the main risk factors for developing MRONJ in individuals taking AR therapy for osteometabolic conditions. Although the incidence of MRONJ in osteometabolic patients taking AR therapy may be as low as 0.9%, the increasing prevalence of osteoporosis and the high prevalence of periodontitis suggest that this potential complication should not be overlooked. Good clinical practice (GCP) guidelines are proposed that aim at a more integrated approach (prescriber, dentist, periodontist and dental hygienist) in the management of periodontitis patients undergoing AR therapy for osteometabolic disorders to reduce the risk of MRONJ. Dental professional and prescribers should educate patients regarding the potential risk associated with the long-term use of AR therapy and oral health behavior.HighlightsAR drugs such as bisphosphonates (BPs), denosumab (DNB) and romosozumab (RMB) are very effective in the treatment of osteoporosis and in the prevention of fragility bone fractures.Periodontitis is a widespread infective inflammatory disease that is the major cause of tooth loss, and it is strongly connected with other systemic diseases, including osteoporosis.MRONJ is a serious and rare complication associated with the use of AR drugs in osteoporotic patients. The reported incidence is rather low and ranges between 0.01 and 0.9%, but may be higher in the presence of comorbidities.Periodontitis and MRONJ share some risk factors, such as diabetes, smoking, steroids, cardiovascular diseases and rheumatoid arthritis.The risk of developing MRONJ in a case of successfully treated periodontitis is much lower than the risk of fragility fracture in a high-risk person such as one with a previous fracture.Oral and periodontal conditions should be assessed before starting an AR therapy, and local intra-oral inflammation should be brought under control. Periodontal therapy is effective at reducing the risk of teeth extraction and therefore the need for major bone reconstructive intervention and implant placement.Control of periodontal inflammation should be achieved and maintained over time in osteoporosis-affected patients treated with AR.Peri-implant diseases rather than dental implant placement may be considered a trigger for MRONJ; for this reason, periodontitis and peri-implant inflammatory disease control and the inclusion of patients in a supportive periodontal program are critical.AR therapy should not be discontinued or deferred by the dentist unless done in accordance with the prescriber.The suspension of BP therapy is not recommended on a routine basis, as BP binds to the skeletal sites and continue to be released for months or years after treatment, with a long tail effect on bone metabolism.DNB administration should not be withdrawn because the rebound effect may increase the risk of bone fractures. A therapeutic window in which to perform dento-alveolar surgical procedures is suggested.It is advisable to calibrate the timing of dental extraction and surgical procedures between the dentist and prescribers according to the oral condition, the general health condition, and the time and type of AR drugs used.A more integrated approach between prescriber, dentist, periodontist and dental hygienist should be encouraged, particularly in the management of periodontitis-affected patients who are taking AR drugs for osteometabolic disorders.Prescribers and dentists must educate patients regarding the potential risk associated with long-term use of AR therapy.

Background: To investigate whether copy number gain of MET or hepatocyte growth factor ( HGF ) affect trastuzumab sensitivity in HER2-positive metastatic breast cancer (MBC). Methods: We analysed 130 HER2-positive MBC treated with trastuzumab-based therapy. MET and HGF gene copy numbers (GCN) were assessed by fluorescence in situ hybridisation (FISH) in primary breast cancer samples. Receiver operating characteristic analysis was applied to find the best cutoff point for both MET and HGF GCN. Results: MET FISH-positive cases ( N =36, mean ⩾3.72) had a significantly higher trastuzumab failure rate (44.4% vs 16.0%; P =0.001) and a significantly shorter time to progression (5.7 vs 9.9 months; HR 1.74; P =0.006) than MET FISH-negative cases ( N =94, mean <3.72). Hepatocyte growth factor GCN was evaluated in 84 cases (64.6%). Receiver operating characteristic analysis identified 33 HGF FISH-positive patients (mean HGF GCN ⩾3.01). HGF FISH-positive status was significantly associated with higher risk of failure (30.3% vs 7.8%; P =0.007) as compared with HGF FISH-negative cases ( N =51, mean <3.01). MET and HGF FISH-positive status was highly correlated ( P <0.001) and combination of both biomarkers did not increase predictive value of either considered separately. Conclusion: High GCNs of MET and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive MBC.

Background In Western countries, ovarian cancer (OC) still represents the leading cause of gynecological cancer-related deaths, despite the remarkable gains in therapeutical options. Novel biomarkers of early diagnosis, prognosis definition and prediction of treatment outcomes are of pivotal importance. Prior studies have shown the potentials of micro-ribonucleic acids (miRNAs) as biomarkers for OC and other cancers. Methods We focused on the prognostic and/or predictive potential of miRNAs in OC by conducting a comprehensive array profiling of miRNA expression levels in ovarian tissue samples from 17 non-neoplastic controls, and 60 tumor samples from OC patients treated at the Regina Elena National Cancer Institute (IRE). A set of 54 miRNAs with differential expression in tumor versus normal samples (T/N-deregulated) was identified in the IRE cohort and validated against data from the Cancer Genoma Atlas (TCGA) related to 563 OC patients and 8 non-neoplastic controls. The prognostic/predictive role of the selected 54 biomarkers was tested in reference to survival endpoints and platinum resistance (P-res). Results In the IRE cohort, downregulation of the 2 miRNA-signature including miR-99a-5p and miR-320a held a negative prognostic relevance, while upregulation of miR-224-5p was predictive of less favorable event free survival (EFS) and P-res. Data from the TCGA showed that downregulation of 5 miRNAs, i.e., miR-150, miR-30d, miR-342, miR-424, and miR-502, was associated with more favorable EFS and overall survival outcomes, while miR-200a upregulation was predictive of P-res. The 9 miRNAs globally identified were all included into a single biologic signature, which was tested in enrichment analysis using predicted/validated miRNA target genes, followed by network representation of the miRNA-mRNA interactions . Conclusions Specific dysregulated microRNA sets in tumor tissue showed predictive/prognostic value in OC, and resulted in a promising biological signature for this disease.

To evaluate the change over time of vision-related quality of life (QoL) and glaucoma symptoms in a population of newly-diagnosed primary open angle glaucoma (POAG) patients. Multicenter, prospective study. Consecutive newly-diagnosed POAG patients were enrolled and followed-up for one year. Follow-up visits were scheduled at 6 and 12 months from baseline. At each visit, vision-related QoL and glaucoma-related symptoms were assessed by the means of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and the Glaucoma Symptom Scale (GSS), respectively. Trends over time for NEI-VFQ-25 and GSS scores were evaluated with longitudinal linear mixed models. One-hundred seventy-eight patients were included in the analysis. At baseline, early to moderate glaucoma stages were associated with higher scores for most GSS and NEI-VFQ-25 items, while lower best-corrected visual acuity was associated with lower scores for 4 of the 12 NEI-VFQ-25 items. During the follow-up, all the GSS scores, the NEI-VFQ-25 total score, and 7 of the 12 NEI-VFQ-25 scores significantly improved (p < 0.05). In multivariate model, higher increases of most GSS and NEI-VFQ-25 scores were modeled in patients with low scores at baseline. Vision-related QoL and glaucoma-related symptom perception significantly improved during the one-year follow-up in this population of newly diagnosed POAG patients.

The different types of organogenic (roots and adventitious shoots) and callus formation responses of leaves from 30-day-old proliferating shoots of different Fragaria spp. genotypes were studied in response to MS medium supplemented with 4.54 microM 1-phenyl-3-(1,2,3-thiadiazol-5-yl) urea (thidiazuron; TDZ) alone and in combination with 0.98 microM indole-3-butyric acid (IBA), 0.84 microM 3-benzo[b]selenienyl acetic acid (BSAA) or 0.90 microM 2,4-dichlorophenoxy acetic acid (2,4-D). The study included: nine octoploid Fragaria x ananassa cultivars and breeding selections; two octoploid breeding selections from F. virginiana glauca inter-species crosses; two diploid F. vesca cultivars; and one diploid clone of F. nubicola Lindl. TDZ plus IBA promoted the highest shoot regeneration efficiencies from leaves of nearly all of the genotypes, while the TDZ/BSAA and TDZ/2,4-D combinations promoted high regeneration efficiencies for only some of the genotypes (Alpina W.O., Sveva, AN 91.371.53, Onda, Paros and FO93.143.5). For the more efficient regenerating genotypes, IBA induced the highest frequency of regenerating leaves, while BSAA induced the highest number of regenerated shoots from leaves and more callus production for most of the genotypes.