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Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type—which includes most patients—is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m2 every 21 days or 35 mg/m2 on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910. We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8–10·9) with docetaxel versus 5·4 months (4·5–6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53–1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4–3·8) with docetaxel versus 2·4 months (2·1–2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53–0·95; p=0·02). The most common grade 3–4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%]). Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours. Agenzia Italiana del Farmaco.

We conducted a large, multicenter, retrospective survey aimed to explore the impact of tumor bone involvement in Non-Small Cell Lung Cancer.Data on clinical-pathology, skeletal outcomes and bone-directed therapies for 661 deceased patients with evidence of bone metastasis were collected and statistically analyzed. Bone metastases were evident at diagnosis in 57.5% of patients. In the remaining cases median time to bone metastases appearance was 9 months. Biphosphonates were administered in 59.6% of patients. Skeletal-related events were experienced by 57.7% of patients; the most common was the need for radiotherapy. Median time to first skeletal-related event was 6 months. Median survival after bone metastases diagnosis was 9.5 months and after the first skeletal-related event was 7 months. We created a score based on four factors used to predict the overall survival from the diagnosis of bone metastases: age >65 years, non-adenocarcinoma histology, ECOG Performance Status >2, concomitant presence of visceral metastases at the bone metastases diagnosis. The presence of more than two of these factors is associated with a worse prognosis.This study demonstrates that patients affected by Non-Small Cell Lung Cancer with bone metastases represent a heterogeneous population in terms of risk of skeletal events and survival.

Indigenous schools are spaces for the convergence of different worldviews and to demonstrate how the creativity of each ethnic group challenges exogenous and established concepts and methodologies. The present article examines main trends and pending gaps related to indigenous education in Brazil between the years 2007 and 2019. Issues such as the characterisation of indigenous schools, teachers and students are analysed, with a focus on the evolution of the number of students enrolled, infrastructure, language and pedagogic approaches. The analysis is focused on the states of Mato Grosso do Sul, which has a large indigenous population and an economy based on export-oriented agribusiness, and Sao Paulo, the main economic, demographic and political centre of Brazil with a much smaller indigenous population. The results demonstrate concrete improvements, especially the expansion of the number of schools and the student population. A growing number of schools are now dedicated to serve indigenous populations and make use of specific teaching material (although this material is of uneven quality). However, many problems remain unresolved, as in the case of threats to funding and uncertain administrative support from public authorities, a situation that has been aggravated in recent years with the growing adoption of elitist, anti-indigenous government policies.

Here, we developed an unbiased, functional target-discovery platform to identify immunogenic proteins from primary non-small cell lung cancer (NSCLC) cells that had been induced to apoptosis by cisplatin (CDDP) treatment in vitro, as compared with their live counterparts. Among the multitude of proteins identified, some of them were represented as fragmented proteins in apoptotic tumor cells, and acted as non-mutated neoantigens (NM-neoAgs). Indeed, only the fragmented proteins elicited effective multi-specific CD4 + and CD8 + T cell responses, upon a chemotherapy protocol including CDDP. Importantly, these responses further increased upon anti-PD-1 therapy, and correlated with patients’ survival and decreased PD-1 expression. Cross-presentation assays showed that NM-neoAgs were unveiled in apoptotic tumor cells as the result of caspase-dependent proteolytic activity of cellular proteins. Our study demonstrates that apoptotic tumor cells generate a repertoire of immunogenic NM-neoAgs that could be potentially used for developing effective T cell-based immunotherapy across multiple cancer patients. Grimaldi and Cammarata et al. develop a proteomics-based, target discovery platform to identify immunogenic proteins specific to apoptotic tumor cells. This study highlights the importance of protein modifications in apoptotic tumor cells as a mechanism of generating immunogenic neoantigens that can be targeted for T cell-based immunotherapy.

Background The combination of a neurokinin-1 receptor antagonist, dexamethasone, and a 5-HT 3 receptor antagonist is currently the standard antiemetic treatment in patients receiving cisplatin-based high emetogenic chemotherapy (HEC). The aim of this study was to evaluate the efficacy of a combination of palonosetron, a unique second-generation 5-HT 3 receptor antagonist, aprepitant, the only approved neurokinin-1 receptor antagonist, and dexamethasone as antiemetic prophylaxis in patients receiving HEC (cisplatin ≥50 mg/mq). Methods Chemotherapy-naïve adult patients, receiving cisplatin-based HEC, were treated with palonosetron 0.25 mg/i.v., dexamethasone 20 mg/i.v., and aprepitant 125 mg/p.o., 1-h before chemotherapy. Aprepitant 80 mg/p.o. and dexamethasone 4 mg p.o. were administered on days 2–3. Primary end point was complete response (CR; no vomiting and no use of rescue medication), during the overall study period (0–120 h). Secondary end points were complete control (CR and no more than mild nausea), emesis-free rate, and nausea-free rate during the acute (0–24 h), delayed (24–120 h), and overall (0-120 h) periods. Safety was also evaluated. Results A total of 222 patients were included in the study. Median age was 62 years, 76.6% were male and 23.4% female, and most common tumors were lung (66.7%) and head and neck (15.8%); 70.3% of patients achieved CR during the overall study period. Complete control, emesis-free rate, and nausea-free rate were 70.3%, 92.8%, and 59.9%, respectively, during the overall phase. The most commonly reported side effects were constipation (39% of patients) and headache (5%). Conclusions This study shows that palonosetron in combination with aprepitant and dexamethasone is effective to prevent chemotherapy-induced nausea and vomiting in patients treated with cisplatin-based HEC.

Controversial results on the predictive value of programmed death ligand 1 (PD-L1) status in lung tumor tissue for response to immune checkpoint inhibitors do not allow for any conclusive consideration. Liquid biopsy might allow real-time sampling of patients for PD-L1 through the course of the disease. Twenty-four stage IV NSCLC patients included in the Expanded Access Program with Nivolumab were enrolled. Circulating tumor cells (CTCs) were analyzed by CellSearch with anti-human B7-H1/PD-L1 PE-conjugated antibody. PD-L1 expressing CTCs were assessed at baseline, at 3 and 6 months after starting therapy, and correlated with outcome. At baseline and at 3 months of treatment, the presence of CTCs and the expression of PD-L1 on their surface were found associated to poor patients outcome. Nevertheless, the high frequency of PD-L1 expressing CTCs hampered to discriminate the role of PD-L1 in defining prognosis. Conversely although CTCs were found in all patients 6 months after treatment, at this time patients could be dichotomized into two groups based PD-L1 expression on CTCs. Patients with PD-L1 negative CTCs all obtained a clinical benefit, while patients with PD-L1 (+) CTCs all experienced progressive disease. This suggests that the persistence of PD-L1(+) CTCs might mirror a mechanism of therapy escape.

Bevacizumab plus chemotherapy prolongs progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC). Although there is strong evidence to suggest that the mutational status of the K-ras oncogene has a role as a predictive factor for activity in patients treated with cetuximab and panitumumab, few data have been obtained in patients treated with bevacizumab. We conducted an additional retrospective analysis to investigate the prognostic value of K-ras mutation relative to mCRC first-line treatment with bevacizumab. A total of 108 patients were retrospectively reviewed. K-ras status was assessed in the overall population by sequencing. Statistical association for PFS and OS was analyzed using the Kaplan-Meier method, and the prognostic role of K-ras was determined using the logrank test. Median PFS was 10 months both for patients with wild-type (WT) K-ras and mutated (MT) K-ras (hazard ratio [HR] 0.94, P=0.75); neither difference in median OS was significant (27 months WT K-ras versus 26 months MT K-ras, HR 0.92; P=0.70). A further analysis was carried out in the two groups according to metastatic sites. No statistically significant difference in terms of PFS and OS was demonstrated between WT K-ras and MT K-ras with liver metastases only and in those with extrahepatic disease. Although further study is required, our results seem to confirm that K-ras mutation does not have a prognostic role in mCRC patients receiving first-line treatment with bevacizumab.

Purpose Non-small cell lung cancer (NSCLC) is a condition with significant clinical burden for patients and relevant economic impact. Limited evidence exists on the management costs of NSCLC patients, especially in the late phases of the disease. The main objective of this analysis was to evaluate the economic impact of clinical management of NSCLC patients in the Italian population. Methods This evaluation was an economic analysis of the observational and multicentre study LIFE, which described the therapeutic approach in routine clinical practice for NSCLC patients, progressing after first-line treatment. This study evaluated resource consumption in different Italian hospitals, including specialist visits, hospitalizations, accesses to first aid, pharmacological treatment, laboratory tests and palliative care. The National Healthcare Service perspective was adopted. Results In this study, N  = 191 patients enrolled in the LIFE study were included. Patients were aged 64.2 years and were predominantly males (66%). In the different line of treatments, monthly costs of patients ranged between €1471 (first line) and €1788 (third line). The overall healthcare cost over the average period of observation (16.4 months) was €25,859 per patient. Overall, oncology therapy was the cost driver, although the composition of medical costs changed across the different lines of treatment, with costs for concomitant medication and palliative care being predominant in late phase of the disease. Conclusions The economic burden of NSCLC is extremely high during the overall period of treatment, and a significant level of care is required in each stage of the disease.

Merkel cell carcinoma (MCC) is an extremely rare primary neuroendocrine neoplasm of the skin that shows aggressive behavior and a poor prognosis. We report a case of a 67-year-old male with a Merkel cell carcinoma which initially presented itself as a large retroperitoneal mass. Pathological and immunohistochemical analysis revealed tissue consistent with neuroendocrine carcinoma. Despite complete medical workup, no other primary MCC could be detected. While being an atypical presentation, the tumor mass showed an excellent response to the combination of chemotherapy followed by radiotherapy.

Objective Evaluate the performance of a robotic system for CT-guided lung biopsy in comparison to the conventional manual technique. Materials and methods One hundred patients referred for CT-guided lung biopsy were randomly assigned to group A (robot-assisted procedure) or group B (conventional procedure). Size, distance from entry point and position in lung of target lesions were evaluated to assess homogeneity differences between the two groups. Procedure duration, dose length product (DLP), precision of needle positioning, diagnostic performance of the biopsy and rate of complications were evaluated to assess the clinical performance of the robotic system as compared to the conventional technique. Results All biopsies were successfully performed. The size ( p  = 0.41), distance from entry point ( p  = 0.86) and position in lung ( p  = 0.32) of target lesions were similar in both groups ( p  = 0.05). Procedure duration and radiation dose were significantly reduced in group A as compared to group B ( p  = 0.001). Precision of needle positioning, diagnostic performance of the biopsy and rate of complications were similar in both groups ( p  = 0.05). Conclusion Robot-assisted CT-guided lung biopsy can be performed safely and with high diagnostic accuracy, reducing procedure duration and radiation dose in comparison to the conventional manual technique. Key Points • CT-guided biopsy is the main procedure to obtain diagnosis in lung tumours . • The robotic device facilitates percutaneous needle placement under CT guidance . • Robot-assisted CT-guided lung biopsy reduces procedure duration and radiation dose .