Smoking Prevalence, Knowledge and Perceptions on Tobacco Control Among Healthcare Professionals: A Survey in an Italian Cancer Center.

Smoking is recognized as the major cause of lung cancer. Healthcare professionals play an important role in lung cancer prevention policies, as they act as a source of guidance for patients and advocates. The following survey evaluated prevalence, knowledge, and attitudes toward tobacco smoking among a sample of workers in "IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, an Italian cancer hospital. An anonymous questionnaire was completed by 104 healthcare professionals to collect personal and occupational data about smoking status, knowledge about the harms of smoking, current legislation in place, Second-Hand Smoke (SHS) awareness, and, for ex-smokers, the reasons for quitting. Among participants, 17.8% were current smokers, 26.2% former smokers, and 56% never smoked. Only 40% acknowledged that the smoking ban is generally respected, and 63.2% reported that they smoke during working hours. Most of the participants perceived tobacco control policy as an efficient way to protect public health. Currently, the implementation of Italian anti-smoking legislation has so far improved neither smoking cessation rates nor the will to quit smoking completely. Our experience highlights that to date the anti-smoking strategies have limited efficacy even in a cancer center; in fact, there is still a large prevalence of smokers among hospital personnel. Therefore, it is strongly suggested that interventions be shared with all healthcare workers, specifically aimed at developing a culture of health promotion.

Enzalutamide in patients with castration-resistant prostate cancer: retrospective, multicenter, real life study.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is the final stage of pCa history and represents a clinically relevant phenotype with an elevated burden of mortality. The aim of the present study was to evaluate the efficacy and safety of enzalutamide in a "real-life" setting in mCRPC patients. METHODS: Data about all mCRPC patients treated with enzalutamide from September 2017 to September 2018 were collected. Demographics, comorbidities, clinical parameters, outcomes, toxicity, overall survival and progression free survival were analyzed. RESULTS: Overall, 158 patients were enrolled. Mean age was 75.8 (±8.7) years with a baseline median PSA of 16.5 (IQR 7.4-47.8) ng/mL. The median follow-up lasted 7.7 (IQR 4-14.1) months. Of all the 10.1% of patients reported grade 3-4 adverse events. 43.7% of patients experienced a progression. Overall, the 6 and 12 months PFS rates were 69.5% (95% CI: 61.7-78.3%) and the 45.6% (95% CI: 36.5-57.1%); a median baseline PSA>16 ng/mL (HR:2.0, 95% CI: 1.2-3.3, P<0.005), the use of opioid (HR: 3.1, 95% CI: 1.9-5.0, P<0.001), a previous treatment (abiraterone, docetaxel or abiraterone + docetaxel) were significantly associated with higher rates of cancer progression. Conversely, a brief pain questionnaire of 0-1 (HR: 0.4, 95% CI: 0.2-0.7, P<0.001), a 12 weeks 50% PSA reduction (HR: 0.4, 95% CI: 0.2-0.8, P<0.006) and a longer time to mCRPC (HR: 0.4, 95% CI: 0.3-0.7, P<0.002) were related to lower cancer progression rates. CONCLUSIONS: Our data shows an effective and safe profile of enzalutamide in a "real world" perspective in patients with mcRPC.

Impact of tobacco control interventions on smoking initiation, cessation, and prevalence: a systematic review.

This article investigates the effects of tobacco control policies on smoking initiation, cessation and prevalence by examining the papers published in the last 5 years. Twenty-one articles have been selected by two authors and sorted by four types of tobacco control: tobacco prices, anti-smoking campaigns for young people, mass media intervention and public smoking bans. Price/tax increase has deterrent effect on smoking initiation but does not promote smoking cessation; intervention on young people could reduce the smoking initiation if carried out at an early age and if acted on social skills and with peer-led approach, as opposed to restraining measures which hare generally easily circumvented by young people. The mass media campaigns showed positive effect on attempts to quit among smokers if carried forward over time and by involving multiple communication channels (TV, internet, radio). The bans in public have little effect on smoking cessation but could improve the overall well-being of non-smokers. Heterogeneous results have been described by different studies probably because of different research methodologies, cultural aspects and the really effective implementation of the rules for each country. In conclusion, comprehensive tobacco control interventions to reduce smoking prevalence and modify the smoking behavior are recommended. Moreover, the use of e-cigarettes and heat-not-burn (HnB) products, as possible helping tool for smoke cessation, currently remains controversial.

EPSILoN: A Prognostic Score Using Clinical and Blood Biomarkers in Advanced Non-Small-cell Lung Cancer Treated With Immunotherapy.

BACKGROUND: Second-line immunotherapy (IO) has shown an overall survival benefit. However, only 18% to 20% of patients with advanced non-small-cell lung cancer (aNSCLC) will respond, with a median progression-free survival (PFS) of 2 to 4 months. Thus, biomarkers to select those patients most likely to benefit from IO are greatly needed. PATIENTS AND METHODS: We conducted a retrospective analysis of 154 patients with aNSCLC who had received anti-programmed cell death 1 therapy as second line or further treatment. We assessed the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts at baseline (T0) and the second (T1) and third (T2) cycles. The neutrophil/lymphocyte ratio (NLR), derived-NLR (dNLR), lymphocyte/monocyte ratio (LMR), and their percentage of change at T1 and T2 compared with T0 were evaluated. The clinical characteristics and lactate dehydrogenase (LDH) level were also considered. Univariate and multivariate analyses were performed. Significant biomarkers for PFS on multivariate analysis were combined in a prognostic score. RESULTS: For overall survival, the negative prognostic biomarkers were Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, NLR at T0, and dNLR at T1; the LMR at T0, T1, and T2 was identified as a positive prognostic biomarker. For PFS, the negative prognostic biomarkers were ECOG PS 2, liver metastases, NLR at T0, dNLR at T1 and T2, and ≥ 30% increase of NLR from T0 to T1; the positive prognostic biomarkers were heavy smoking, LDH, and LMR at T2. The ≥ 30% increase of LMR from T0 to T1 and T0 to T2 correlated with the overall response rate. A prognostic score (EPSILoN score; smoking, ECOG PS, liver metastases, LDH, NLR) identified 3 prognostic groups (median PFS, 10.2, 4.9, and 1.7 months, respectively; P < .001). CONCLUSIONS: The EPSILoN score combines 5 baseline clinical and blood biomarkers and can help to identify patients with aNSCLC who will most likely benefit from second-line IO. Further studies are warranted.

DiM: Prognostic Score for Second- or Further-line Immunotherapy in Advanced Non-Small-Cell Lung Cancer: An External Validation.

BACKGROUND: Other than the programmed cell death ligand 1 (PD-L1) value, oncologists have only the clinical characteristics of patients with advanced non-small-cell lung cancer (aNSCLC) to determine candidates for immunotherapy. A clinical prognostic score composed of the Eastern Cooperative Oncology Group performance status, sex, histologic type, stage, platinum-based first-line therapy, and response to first-line therapy has categorized 3 prognostic groups for patients undergoing second-line chemotherapy. We sought to validate the same score for patients with aNSCLC treated with second- or further-line immunotherapy. MATERIALS AND METHODS: We collected data from 2 Italian centers. A score was generated to divide patients into 3 prognostic groups: best, score < 5; intermediate, score 5 to 9; and worst, score > 9. Overall survival (OS) and progression-free survival (PFS) were the endpoints. RESULTS: A total of 347 patients were included for analysis. Their median age was 66 years (range, 30-88 years), most were aged < 70 years (67.5%), 70.7% were men, 79.5% were smokers, and 74.6% had had adenocarcinoma. The Eastern Cooperative Oncology Group performance status was 0 for 23%, 1 for 54.5%, and 2 for 22.5%. Of the 347 patients, 28% were in the best prognosis, 51% in the intermediate, and 21% in the worst prognosis group, respectively. The median OS was 18.0 months for the best, 8.5 months for the intermediate (hazard ratio [HR] vs. best, 1.83; 95% confidence interval [CI], 1.35-2.47; P < .001) and 2.6 months for worst (HR vs. best, 5.77; 95% CI, 3.99-8.33; P < .001) group. The median PFS was 3.4 months for the best, 3.7 months for the intermediate (HR vs. best, 1.35; 95% CI, 1.03-1.77; P = .032), and 1.9 months for the worst (HR vs. best, 2.51; 95% CI, 1.80-3.50; P < .001) group. CONCLUSIONS: The prognostic score was able to predict the outcomes of patients with aNSCLC who had received immunotherapy. The worst category showed a dismal life expectancy and probably would not benefit from active systemic therapy. Thus, for these patients, best supportive care could be the best choice.

KRAS-Driven Lung Adenocarcinoma and B Cell Infiltration: Novel Insights for Immunotherapy.

Non-small-cell lung cancer, histologically classified into adenocarcinoma (AD) and squamous cell carcinoma, is one of the most deadly malignancies worldwide. Lung AD (LUAD) could benefit of a plethora of target therapies and, in the last few years, also of immunotherapies. Here we focused on a real-life cohort of LUAD and The Cancer Genome Atlas (TCGA)-LUAD dataset aiming to gain insights into the immune contexture of such a malignancy. We explored the mutational status of 41 genes and the expression of 94 genes, related to immune-checkpoint, inflammation, and stromal microenvironment. Surprisingly, we found that our cohort has a very low mutational burden if we consider our panel as its surrogate. Regarding gene expression data, we identified 31 genes significantly deregulated in tumor tissues compared with a pool of normal samples. Unsupervised hierarchical clustering of the deregulated genes is able to identify two clusters of tumor samples, differently enriched in alterations in actionable genes. In particular, we identified a cluster enriched in patients carrying KRAS alterations. In silico deconvolution, that is the inferring of tumor microenvironment composition by gene expression data, through TIMER algorithm has been performed to explore immune microenvironment. Estimation performed on our gene expression matrix showed that B cell infiltration is lower in the KRAS-mutated enriched cluster, as in the TCGA-LUAD dataset. Such a finding has been validated in situ through immunohistochemistry in an independent cohort. Moreover, cases in LUAD-TCGA with low B cell infiltration have a significantly worse overall survival than those with higher levels. In the real-life cohort we observed that cases belonging to cluster enriched in KRAS-mutated patients have a poor outcome. LUAD driven by KRAS mutation represents an unmet clinical need, being refractory to pharmacological inhibition. Our results link KRAS mutations to B cell infiltration. Thus, the present findings could be helpful in a better definition of immunotherapeutic approaches for KRAS mutated patients.

Neoadjuvant vs. Adjuvant Chemotherapy in Muscle Invasive Bladder Cancer (MIBC): Analysis From the RISC Database.

Background: MIBC is an aggressive disease, with 5-year survival rates ranging from 36 to 48% for p T3/p T4/p N+tumors. Perioperative treatment can improve overall survival, with more robust evidence in favor of neoadjuvant chemotherapy. Few randomized studies have compared neoadjuvant and adjuvant therapy in bladder cancer. Consequently, it has been difficult to establish the benefit of adjuvant chemotherapy (AC) in MIBC. Methods: Data from patients with muscle invasive bladder cancer (>pT2) collected from 2005 to 2012 within the RISC data base (Retrospective International Study of Cancers of the Urothelial Tract) were evaluated. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) between NC and AC generated using the Kaplan-Meier method were compared for MIBC by log-rank test. All patients in this analysis received either NC or AC. Results: A total of 656 patients with MIBC (325 treated with AC and 331 with NC) were analyzed. The median DFS was 34.6 months (95% CI:25.3-43.9) for NC vs. 24.9 months (95% CI: 19.4-30.5) with AC, with a reduction in the risk of disease progression of 21% in favor of NC (HR: 0.78, 95% CI: 0.63-0.96, P = 0.02). There were no significant differences in terms of CSS (HR: 1.06, 95% CI: 0.79-1.43, P: 0.70), and OS (HR: 1.08, 95% CI: 0.83-1.39, P = 0.57). Conclusions: This study demonstrates superiority in DFS for NC compared to AC. The positive prognostic impact of complete pathological response to NC was confirmed.

Safety and Efficacy of Cabozantinib in Metastatic Renal-Cell Carcinoma: Real-World Data From an Italian Managed Access Program.

BACKGROUND: The randomized phase 3 METEOR study confirmed a survival benefit of cabozantinib over everolimus in patients with metastatic renal-cell carcinoma (mRCC) with disease that progressed after treatment with at least one previous antiangiogenic inhibitor. The aim of this analysis was to evaluate the safety and activity of cabozantinib in an unselected population. METHODS: Data were collected across 24 Italian centers. Cabozantinib therapy was initiated at physician request between September and December 2016. Patients with mRCC with disease that progressed after one or more prior systemic treatment were evaluated. Cabozantinib 60 mg was administered orally once daily. Doses were reduced to 40 mg or 20 mg in patients experiencing grade 3 or intolerable grade 2 adverse events (AEs). RESULTS: Data from 96 patients were evaluated. Cabozantinib was administered as second-line therapy in 28 patients (29%) and as third-line therapy in 18 patients (19%), while the remaining 50 patients (52%) received cabozantinib in further treatment lines. Sixty-six patients began therapy with the full dose of 60 mg. Because of poor performance status, 29 patients began therapy with a reduced dose of 40 mg and 1 patient with 20 mg. At the time of our analysis, grade 3/4 AEs were observed in 35 patients (36%). Only 5 patients discontinued treatment as a result of AEs. Partial response was observed in 35 patients (36%), whereas 33 (34%) had stable disease and 28 (30%) progressive disease. Median progression-free survival was 8.0 months. CONCLUSION: Cabozantinib showed acceptable tolerability and activity in a large unselected population treated according to everyday clinical practice.

Systemic chemotherapy in muscle invasive and metastatic bladder cancer: present and future.

Bladder cancer is the most frequent among the urothelial tumors, and it is responsible for about 2% of all cancer mortality worldwide. The mainstay of chemotherapy treatment, both for muscle-invasive and metastatic disease, is cisplatin-based regimens. In recent years, ground-breaking results have been achieved with immunotherapy, which have led to important breakthroughs in the bladder cancer treatment scenario, with the approval of several new agents. New insights derive from a greater characterization of the tumor genome, which could lead to developing new therapies, more personalized, in the near future.

Evaluation of the efficacy of cisplatin-etoposide and the role of thoracic radiotherapy and prophylactic cranial irradiation in LCNEC.

In small-cell lung cancer (SCLC), the role of chemotherapy and radiotherapy is well established. Large-cell neuroendocrine carcinoma (LCNEC) shares several clinicopathological features with SCLC, but its optimal therapy is not defined. We evaluated clinical response and survival outcomes of advanced LCNEC treated in first-line therapy compared with SCLC. 72 patients with stage III-IV LCNEC (n=28) and extensive-stage SCLC (ES-SCLC) (n=44) received cisplatin-etoposide with/without thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). Comparing LCNEC with SCLC, we observed similar response rates (64.2% versus 59.1%), disease control rates (82.1% versus 88.6%), progression-free survival (mPFS) (7.4 versus 6.1 months) and overall survival (mOS) (10.4 versus 10.9 months). TRT and PCI in both histologies showed a benefit in mOS (34 versus 7.8 months and 34 versus 8.6 months, both p=0.0001). LCNEC patients receiving TRT showed an improvement in mPFS and mOS (12.5 versus 5 months, p=0.02 and 28.3 versus 5 months, p=0.004), similarly to ES-SCLC. PCI in LCNEC showed an increase in mPFS (20.5 versus 6.4 months, p=0.09) and mOS (33.4 versus 8.6 months, p=0.05), as in ES-SCLC. Advanced LCNEC treated with SCLC first-line therapy has a similar clinical response and survival outcomes to ES-SCLC.

Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab.

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.

Regulatory T cells with multiple suppressive and potentially pro-tumor activities accumulate in human colorectal cancer.

Tregs can contribute to tumor progression by suppressing antitumor immunity. Exceptionally, in human colorectal cancer (CRC), Tregs are thought to exert beneficial roles in controlling pro-tumor chronic inflammation. The goal of our study was to characterize CRC-infiltrating Tregs at multiple levels, by phenotypical, molecular and functional evaluation of Tregs from the tumor site, compared to non-tumoral mucosa and peripheral blood of CRC patients. The frequency of Tregs was higher in mucosa than in blood, and further significantly increased in tumor. Ex vivo, those Tregs suppressed the proliferation of tumor-infiltrating CD8(+) and CD4(+) T cells. A differential compartmentalization was detected between Helios(high) and Helios(low) Treg subsets (thymus-derived versus peripherally induced): while Helios(low) Tregs were enriched in both sites, only Helios(high) Tregs accumulated significantly and specifically in tumors, displayed a highly demethylated TSDR region and contained high proportions of cells expressing CD39 and OX40, markers of activation and suppression. Besides the suppression of T cells, Tregs may contribute to CRC progression also through releasing IL-17, or differentiating into Tfr cells that potentially antagonize a protective Tfh response, events that were both detected in tumor-associated Tregs. Overall, our data indicate that Treg accumulation may contribute through multiple mechanisms to CRC establishment and progression.

Merkel cell carcinoma of the retroperitoneum with no identifiable primary site.

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.