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37 ALK FISH-positive NSCLC cases diagnosed between 2010 and 2015 in 7 Italian centres were investigated with ICH using three different anti-ALK antibodies (ALK1, 5A4 and D5F3). Staining for ALK1 and 5A4 was graded as 0+,1+,2+, and 3+, while the scoring for D5F3 was recorded as negative or positive. Proportion agreement analysis was done using Cohen's unweighted kappa (k). TS and β-actin expression levels were analysed by quantitative RT-PCR. Comparison between TS expression in ALK FISH-positive specimens and a control cohort of ALK FISH-negative ones was performed with the Mann-Whitney and Kruskal-Wallis tests.Considering 2+ and 3+ as positive, the proportion of IHC agreement was 0.1691 (95% CI 0-0.4595) for ALK1/5A4, 0.1691 (95% CI 0-0.4595) for ALK1/D5F3, and 1 for D5F3/5A4. Considering 3+ as positive, it was 0.1543 (95% CI 0-0.4665) for ALK1/ 5A4, 0.0212 (95% CI 0-0.1736) for ALK1/D5F3, and 0.2269 (95% CI 0-0.5462) for 5A4/D5F3. Median TS expression was 6.07 (1.28-14.94) and ALK-positive cases had a significant lower TS expression than ALK-negative tumoursIHC proved to be a reliable tool for the diagnosis of ALK-rearranged NSCLC. D5F3 and 5A4 clones have the highest percentage of agreement. TS levels are significantly lower in FISH-positive patients.

Introduction: In non-small cell lung cancer (NSCLC) histologic transformation upon immune checkpoint inhibitors (ICI) is rare. Case presentation: We described the case of a patient with early-stage lung adenocarcinoma who relapsed after surgery. At the time of relapse, he received chemo-radiotherapy, followed by consolidation immunotherapy. After 3 cycles the patient experienced disease hyperprogression for onset of a new lung mass, which resulted in squamous cell carcinoma. The preservation of an atypical mutation in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene in both the primary adenocarcinoma and the new squamous carcinoma suggests histological transformation, likely ICI-related. Discussion: We reviewed similar cases in literature, highlighting common patterns and substantial differences. For a deeper insight into inherent biological mechanisms, re-biopsy in case of atypical ICI response should be encouraged.

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB). Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion. Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs. Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance. Patients and methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR

Objectives: Exercise has been reported to alleviate disease as well as treatment impact in patients with lung cancer. Nevertheless, there is limited information available regarding the perception of lung cancer dedicated healthcare professionals’ and their advice on exercise. Materials and Methods: An online survey exploring healthcare professionals’ practice patterns, perceptions, barriers, and facilitators of exercise in patients with lung cancer was conducted within members of the EORTC Lung Cancer Group (LCG). Results: One hundred forty-one healthcare providers completed the survey, mainly medical and radiation oncologists. Overall, 63% of the study participants declared that they frequently assessed exercise level in their patients, and 43% of them reinforced the importance of exercise. However, only 10% referred patients to an exercise program or specialist. Although the majority of the respondents had a positive perception regarding the benefits and safety of exercise (even in patients with advanced disease and/or bone metastasis), two-thirds of clinicians reported not having adequate training about exercise counselling. Moreover, 53% reported to lack of knowledge of guidelines referring to exercise in patients with cancer. Several obstacles and facilitators to improve exercise promotion in lung cancer care were identified. Conclusion: Healthcare providers recognize the relevance and feasibility of exercise as part of cancer treatment intervention, but specific pathways to do the referral are frequently missing. Future structured and well-designed strategies and initiatives are needed to support an effective referral in order to implement exercise interventions routinely in clinical practice.

Mortality risk in COVID-19 patients is determined by several factors. The aim of our study was to adopt an integrated approach based on clinical, laboratory and chest x-ray (CXR) findings collected at the patient’s admission to Emergency Room (ER) to identify prognostic factors. Retrospective study on 346 consecutive patients admitted to the ER of two North-Western Italy hospitals between March 9 and April 10, 2020 with clinical suspicion of COVID-19 confirmed by reverse transcriptase-polymerase reaction chain test (RT-PCR), CXR performed within 24 h (analyzed with two different scores) and recorded prognosis. Clinical and laboratory data were collected. Statistical analysis on the features of 83 in-hospital dead vs 263 recovered patients was performed with univariate (uBLR), multivariate binary logistic regression (mBLR) and ROC curve analysis. uBLR identified significant differences for several variables, most of them intertwined by multiple correlations. mBLR recognized as significant independent predictors for in-hospital mortality age > 75 years, C-reactive protein (CRP) > 60 mg/L, PaO2/FiO2 ratio (P/F) 7. Among the patients with at least two predictors, the in-hospital mortality rate was 58% against 6% for others [p p

Lung cancers account for over 90% of thoracic malignancies and the rapid development of specific cytotoxic drugs and molecular therapies requires a detailed identification of the different histologies, gene drivers or immune microenvironment biomarkers. Nevertheless, the heterogeneous clonal evolution, the emergency of drug-induced resistance and the limited occurrence of genetic alterations claim the need of a deep integration of the tumor's and the patient's biological features. The aim of the present study is to generate a tecnological platform for precision medicine in order to set predictive personalized algorithms for patient diagnosis and therapy. All resectable patients having histologically confirmed stage IB-IIIA non-small cell lung cancer will be enrolled for tissue sampling. A large biobank of lung cancer samples and the corresponding healthy tissues and biological components (ie, blood, stools, etc.) with complete clinical, pathological and molecular information will be collected. The platform will include: a) digital patient data collection; b) whole NGS molecular analyses (exome, transcriptome, methylome) for tumor characterization; c) exploitation and collection of organoids from tissue patients; d) Surface Amplified Raman Spectroscopy; e) microfluidic-based technological drug screening; f) preclinical in vivo models based on patient-derived xenografts; g) generation of specific predictive algorithms taking into account all collected multiparameters. The project will lay the basis of a knowledge hub and qualified technology aimed not only at answering the medical and scientific community's questions, but also meant to be useful to individual patients by predicting the response to adjuvant and second-line drugs in case of relapse of the disease.

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Background The combination of pemetrexed and cisplatin remains the reference first-line systemic therapy for malignant pleural mesothelioma (MPM). Its activity is moderate because of tumor aggressiveness, immune-suppressive environment and resistance to chemotherapy-induced immunogenic cell death (ICD). Preliminary and limited findings suggest that MPM cells have deregulated ubiquitination and proteasome activities, although proteasome inhibitors achieved disappointing clinical results. Methods Here, we investigated the role of the E3-ubiquitin ligase SKP/Cullin/F-box (SCF) complex in cell cycle progression, endoplasmic reticulum (ER)/proteostatic stress and ICD in MPM, and the therapeutic potential of the neddylation/SCF complex inhibitor MLN4924/Pevonedistat. Results In patient-derived MPM cultures and syngenic murine models, MLN4924 and cisplatin showed anti-tumor effects, regardless of MPM histotype and BAP1 mutational status, increasing DNA damage, inducing S- and G2/M-cell cycle arrest, and apoptosis. Mechanistically, by interfering with the neddylation of cullin-1 and ubiquitin-conjugating enzyme UBE2M, MLN4924 blocks the SCF complex activity and triggers an ER stress-dependent ICD, which activated anti-MPM CD8+T-lymphocytes. The SKP2 component of SCF complex was identified as the main driver of sensitivity to MLN4924 and resistance to cisplatin. These findings were confirmed in a retrospective MPM patient series, where SKP2 high levels were associated with a worse response to platinum-based therapy and inferior survival. Conclusions We suggest that the combination of neddylation inhibitors and cisplatin could be worth of further investigation in the clinical setting for MPM unresponsive to cisplatin. We also propose SKP2 as a new stratification marker to determine the sensitivity to cisplatin and drugs interfering with ubiquitination/proteasome systems in MPM.

Although there is substantial evidence on the impact of nutritional-status deterioration on quality of life, treatment tolerance, morbidity, and mortality in people with cancer, clinical nutrition intervention trials in oncology are still limited. The rationale for deepening this topic is also justified by the availability of innovative treatment options, such as immunotherapy, which take into consideration potential modulation of the immune system by several factors. In this article, we aimed to focus on the unexplored issue of immunonutrition and its potential modulatory activity on treatment response in people receiving immunotherapy. With this perspective, we propose a clinical-trial model to explore the potential impact of immunonutrition on nutritional, functional, immunologic, safety, and efficacy parameters in people with advanced non-small cell lung cancer undergoing first-line immunotherapy-based anticancer treatment.

Contains fulltext : 215810.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

The standard front-line treatment for pleural mesothelioma (PM) is pemetrexed-based chemotherapy, whose major target is thymidylate synthase (TS). In several cancer models, miR-215 and miR-375 have been shown to target TS, while information on these miRNAs in PM are still limited although suggest their role in epithelial to mesenchymal transition. Seventy-one consecutive PM tissues (4 biphasic, 7 sarcomatoid, and 60 epithelioid types) and 16 commercial and patient-derived PM cell lines were screened for TS, miR-215, and miR-375 expression. REN and 570B cells were selected for miR-215 and miR-375 transient transfections to test TS modulation. ZEB1 protein expression in tumor samples was also tested. Moreover, genetic profile was investigated by means of BAP1 and p53 immunohistochemistry. Expression of both miR-215 and miR-375 was significantly higher in epithelioid histotype. Furthermore, inverse correlation between TS protein and both miR-215 and miR-375 expression was found. Efficiently transfected REN and 570B cell lines overexpressing miR-215 and miR-375 showed decreased TS protein levels. Epithelioid PM with a mesenchymal component highlighted by reticulin stain showed significantly higher TS and ZEB1 protein and lower miRNA expression. A better survival was recorded for BAP1 lost/TS low cases. Our data indicate that miR-215 and miR-375 are involved in TS regulation as well as in epithelial-to-mesenchymal transition in PM.

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials.

Malignant pleural mesothelioma (MPM) is a rare and orphan thoracic malignancy, with a poor prognosis as the majority of patients are diagnosed with unresectable MPM, with no significant improvements in the therapeutic strategy for over a decade. However, the recent approval of immune checkpoint inhibitors (ICI) in treatment-naive patients with unresectable MPM marks a significant step forward and hope for the treatment of this disease. In this narrative review, we discuss the biological rationale to use ICI in the treatment of MPM. We summarize the current evidence for the efficacy of ICI in MPM and discuss several unresolved challenges regarding the use of ICI in this disease, such as the best upfront immune approach in MPM (ICI versus ICI plus chemotherapy), the optimal sequential treatment strategy according to the first-line treatment, and the potential role of predictive biomarkers.

The evaluation of the homologous recombination repair (HRR) status is emerging as a predictive tumor agnostic biomarker for poly (ADP-ribose) polymerase (PARP) inhibition across different tumor types and testing for HRR-signature is currently a developing area with promising therapeutic implications. Treatment with PARP inhibitors (PARPi) either as single agent or in combination with chemotherapy have shown so far limited activity in patients with thoracic malignancies. A deeper understanding of the biological background underlying HRR-deficient tumors, along with the recent advent of new effective targeted and immunotherapeutic agents, prompted the design of a new generation of clinical trials investigating novel PARPi-combinations in patients with lung cancer as well as malignant pleural mesothelioma. In this review we briefly summarize the biological basis of the DNA damage response pathway inhibition and provide an updated and detailed overview of clinical trials testing different PARPi-combinations strategies in patients with thoracic malignancies.

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); pConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

The PACIFIC trial marked a new era in the treatment of stage III unresectable NSCLC, establishing durvalumab consolidation as new standard of care worldwide, with about 14 % increase of long-term survival and half of the patients alive at 4 years. A series of intensified immune-checkpoint inhibition regimens are currently under investigation in clinical trials in order to optimize the therapeutic benefit obtained in this population, while the identification of personalized approaches as well as the development of effective treatments in the post-durvalumab progression setting represent an actual and controversial topic for clinical lung cancer research. This review describes the current real-word treatment scenario for stage III unresectable NSCLC in Italy, and provides an updated overview of the upcoming therapeutic strategies under clinical investigation, discussing the most relevant challenges and opportunities featuring the post-PACIFIC era.

Giving the potential contribute in cancer initiation and progression, lung microbiota represents a promising topic in cancer research, although still unexplored. We performed a systematic literature search to identify clinical studies evaluating lung microbiota composition, its correlation with lung cancer patients' clinico-pathological features and prognosis. Of the identified 370 studies, 21 were eligible and included. Although studies were heterogeneous, lung cancer resulted to be enriched in peculiar microbial communities, with differences in composition and diversity according to clinico-pathological parameters. Few studies explored how lung microbiota influences cancer outcome. In light of these findings and borrowing the suggestions coming from gut microbiota, we speculate that respiratory microbiome may influence pathogenesis, progression and outcome of lung cancer. Taking advantage of the experience of chronical lung diseases, prospective studies should be designed to evaluate lung microbiota changes throughout any phase of lung cancer course, particularly with the advent of immunotherapy as pivotal treatment.

PURPOSE: COVID-19 cancer patients (C19-CP) represent a population at high risk for mortality, whose clinical characteristics are still unknown in the second SARS-CoV-2 wave. The aim of this retrospective study was to compare epidemiology and clinical presentation of C19-CP referring to the emergency department (ED) of our institution (San Luigi Gonzaga University Hospital, Orbassano, Turin, Italy), in a 3-week observation period of the first and second COVID-19 waves, starting from the introduction of the corresponding national lockdowns. METHODS: We retrieved ED admissions from March 9 to 29, 2020, for the first wave, and from October 24 to November 13, 2020, for the second wave. We collected clinical characteristics of consecutive patients with molecularly confirmed SARS-CoV-2 infection. We also considered untested or SARS-CoV-2–negative cancer patients referring to the ED in the reference time frames. RESULTS: C19-CP in the second wave exceeded those in the first wave despite the nonsignificant difference (39 of 576 v 8 of 163; P = .5). Compared with nononcological patients, C19-CP were older (median age 70 years [interquartile range 61-77] v 60 years [interquartile range 45-73]; P = .02) and presented more often with ≥ 2 comorbidities (40.4% v 24.3%; P = .02). Compared with nononcological patients, in C19-CP, respiratory failure (29 of 47 v 321 of 692; P = .049) and hospitalization (37 of 47 v 363 of 692; P = .0004) were higher, with comparable frequencies across the waves. Five of 24 and 10 of 27 hospitalized cancer patients in the first and second waves developed SARS-CoV-2 infection during hospitalization. CONCLUSION: C19-CP were a vulnerable population, irrespective of the COVID-19 waves. This highlights the need to prioritize vaccinations in oncological patients to safeguard and guarantee optimal anticancer care.

Since their discovery, relevant efforts have been made to optimize the detection approaches to EGFR mutations as well as the clinical management of EGFR-mutated NSCLC. The recent shift from single gene testing to novel comprehensive detection platforms along with the development of new generation tyrosine kinase inhibitors, targeting both common and uncommon EGFR-mutations, is leading to a progressive increase in the number of patients who may benefit from targeted approaches, with subsequent impact on their long-term survival and quality of life. However, a prompt and adequate implementation of the most recent diagnostic and treatment advances in the routine practice often remains critical to be specifically addressed. In this review we provide a complete and updated overview of the different detection platforms and therapeutic options currently available for the clinical management of advanced EGFR-positive NSCLC, summarizing scientific evidence and describing molecular testing as well as treatment practice in the real-word scenario.

Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM.A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed.We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%).Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking.

BackgroundEpithelial-to-mesenchymal transition (EMT) enhances motility, stemness and chemoresistance of carcinomas and is an important determinant of metastasis. Little is known about how various pathways coordinate to elicit EMT’s different functional aspects. Even lesser has been studied in this context in non-small cell lung cancer (NSCLC), where EMT is a key event during early tumorigenesis. Thymidylate synthase (TS), a proliferation enzyme, has been previously correlated with EMT transcription factor ZEB1 in NSCLC and is associated with resistance against anti-folate chemotherapy. In this study we establish a functional correlation between TS, EMT, chemotherapy and metastasis and identify a network that might propel the TS mediated EMT phenotype.MethodsPublished datasets were analysed to evaluate significance of TS in NSCLC fitness and prognosis. mCherry based promoter reporter assay was used to sort Calu-1 and A549 NSCLC cells in TSHIGH and TSLOW. Metastatic potential of TS knock-down was assayed in syngeneic C57BL/6 mice.ResultsLow TS levels were prognostic and predicted chemotherapy response. NSCLC cell lines with higher TS promoter activity were more mesenchymal-like. RNA-seq from these cells, and shRNA mediated TS knocked down cells, identified EMT as one of the most differentially regulated pathways. EMT transcription factors HOXC6 and HMGA2 were identified as upstream regulator of TS whereas, AXL, SPARC and FOSL1 were identified as downstream effectors. TS knock-down reduced the metastatic colonisation in vivo.ConclusionThese results establish the role of TS as a theranostic NSCLC marker integrating survival, chemo-resistance and EMT, and identifies a regulatory network that could be exploited to target EMT-driven NSCLC.

Treatment with poly ADP ribose polymerase (PARP)1/2 inhibitors represents a novel opportunity to selectively kill a subset of cancer cell types by exploiting their deficiencies in DNA repair, thus leading to synthetic lethality. Treatment of homologous recombination deficient (HRD)-tumors with PARP inhibitors generates significant levels of DNA damage, which has the potential to further increasing tumor mutational burden, promoting neoantigen release, and upregulating both interferons and programmed death ligand-1 (PD-L1) expression, suggesting a potential complementary and synergistic role with immune checkpoint inhibitors in cancer treatment. Here we present the design and rationale of a prospective, phase II, single-arm study aiming to investigate the safety and antitumor activity of the combination of niraparib and dostarlimab in patients with HRD-positive and PD-L1 ≥ 1% advanced non–small-cell lung cancer (NSCLC) and/or malignant pleural mesothelioma (MPM). Considering the prevalence of pathogenetic germline mutations in DNA repair genes, reported to be around 5% to 10% in patients with MPM and NSCLC, a total of 700 to 1000 cases will be screened to identify 70 patients who are HRD-positive/PD-L1 ≥ 1% (N = 35 NSCLC; N = 35 MPM) to be included. Patients will receive the combination of niraparib orally once daily and dostarlimab intravenously. The primary endpoint is progression-free survival. Secondary endpoints are objective response, duration of response, overall survival, and safety. The results of this study will provide evidence on the safety and antitumor activity of niraparib and dostarlimab combination in patients with advanced, HRD-positive and PD-L1 ≥ 1% NSCLC and/or MPM.

Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naive NSCLC and a PD-L1 expression of ≥ 50%. One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2–49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9–9.5; 599 events) and 17.2 months (95% CI 15.3–22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p

Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β-catenin/c-myc axis that also increased IL-8 and IL-1β production. IL-8 and IL-1β-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1β secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3β/β-catenin and IL-8/IL-1β signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.

5-Fluorouracil- and leucovorin-based chemotherapy regimens are the backbone of colorectal cancer treatment. The addition of oxaliplatin, irinotecan and monoclonal antibodies to this backbone has largely improved clinical outcomes, but has also led to new questions, with conflicting data frequently reported in studies. Thymidine phosphorylase (TP) is a nucleoside-metabolizing enzyme involved in 5-fluorouracil pharmacokinetics, as well as inflammatory responses, neoangiogenesis and apoptosis. TP expression is regulated by hypoxia, inflammatory cytokines and antitumoral agents. We hypothesize that TP could be the unforeseen driver in the conflicting data observed with different regimens commonly used in colorectal cancer treatment. Greater comprehension of the role of this enzyme in tumor progression and pyrimidine metabolism may lead to more accurate, patient-tailored therapy.

Antiandrogen withdrawal syndrome is an unpredictable event diagnosed in patients with hormone-sensitive prostate cancer treated with combined androgen blockade therapy. It is defined by prostate-specific antigen value reduction, occasionally associated with a radiological response, that occurs 4–6 weeks after first-generation antiandrogen therapy discontinuation. New-generation hormonal therapies, such as enzalutamide and abiraterone acetate, improved the overall survival in patients with metastatic castration-resistant prostate cancer, and recent trials have also shown the efficacy of abiraterone in hormone-sensitive disease. In the last few years, several case reports and retrospective studies suggested that the withdrawal syndrome may also occur with these new drugs. This review summarizes literature data and hypothesis about the biological rationale underlying the syndrome and its potential clinical relevance, focusing mainly on new-generation hormonal therapies. Severalin vitrostudies suggest that androgen receptor gain-of-function mutations are involved in this syndrome, shifting the antiandrogen activity from antagonist to agonist. Several different drug-specific point mutations have been reported. The association of the withdrawal syndrome for enzalutamide and abiraterone needs confirmation by additional investigations. However, new-generation hormonal therapies being increasingly used in all stages of disease, more patients may experience the syndrome when stopping the treatment at the time of disease progression, although the clinical relevance of this phenomenon in the management of metastatic castration-resistant prostate cancer remains to be defined.

We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease's recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients.

Objectives We previously reported that quality of life (QoL) is not included among trial endpoints and QoL results are underreported in a significant proportion of phase III oncology trials. Here we describe QoL adoption, reporting and methodology of QoL analysis in lung cancer trials. Materials and methods We selected all primary publications of lung cancer phase III trials assessing anticancer drugs published between 2012 and 2018 by 11 major journals. Results 122 publications were included. In 39 (32.0%) publications, QoL was not listed among endpoints: in 10/17 (58.8%) early stage/locally advanced NSCLC, in 15/54 (27.8%) first-line of advanced NSCLC; in 10/41 (24.4%) second and further lines of advanced NSCLC, in 4/10 (40.0%) SCLC. Proportion of trials not including QoL was similar over time: 32.9% publications in 2012–2015 vs. 30.6% in 2016–2018. Out of 83 trials including QoL among endpoints, QoL results were absent in 36 primary publications (43.4%). Proportion of trials without QoL results in primary publication increased over time (30.6% 2012–2015 vs. 61.8% 2016–2018, p = 0.005). Overall, QoL data were not available in 75/122 (61.5%) primary publications, due to the absent endpoint or unpublished results. QoL data were lacking in 48/68 (70.6%) publications of trials with overall survival as primary endpoint, 27/54 (50.0%) with other primary endpoints and 28/54 (51.9%) publications with a positive result. For trials including QoL among endpoints but lacking QoL results in primary publication, probability of secondary publication was 6.3%, 30.1% and 49.8% after 1, 2 and 3 years respectively, without evidence of improvement comparing 2012–2015 vs. 2016–2018. Conclusion QoL is not assessed or published in many phase III lung cancer trials, a setting where QoL value should be highly considered, due to high symptom burden and generally limited life expectancy. Timely inclusion of results in primary publications is worsening in recent years.

Introduction A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. Methods We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients’ outcome. Results The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule–positive (CD4+) programmed death 1–positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3–positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3–positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival. Conclusions A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients’ outcome.

Graphical abstract, Highlights • Survey to evaluate outpatient management and therapeutic decisions for NSCLC patients. • Delay of lung cancer diagnosis and a dramatic decrease of patients’ accrual within clinical trials. • Major changes in the treatment management of elderly population. • Major changes in the selection of second line treatments. • Telemedicine as a valid support to facilitate patient-healthcare interactions., This study investigated the clinical management of non small cell lung cancer (NSCLC) patients during the first wave of coronavirus disease 2019 (COVID-19) outbreak in Italy. A 29-questions survey was sent to 95 Italian thoracic oncologists, with 77% of them declaring significant changes in the outpatients management and treatment. The results of this survey pointed out a significant delay of lung cancer diagnosis along with a relevant reduction of patients’ accrual within clinical trials, while telemedicine emerged as a valid support for patient-healthcare interactions. Therapeutic indications followed the guidelines for adjuvant chemotherapy and concurrent chemo-radiation. Clinical indications to first-line therapies were largely confirmed, while major changes regarded the selection of second line treatment options as well as the management of elderly population. This work may represent a valid source of information to improve the clinical management of NSCLC patients during second wave of COVID-19 pandemic.

This report summarizes the clinical features and the indications for treating HCV infection in immunocompromised and transplanted patients in the Direct Acting Antiviral drugs era.

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

The research leading to these results received funding from the Obra Social “la Caixa” (to ME), the Cellex Foundation (to ME), the European Union's Horizon 2020 research and innovation programme under grant agreement No 727264 Epipharm (to ME), the 2015 Endowment fund for Research into Respiratory Health (“Fonds de Dotation Recherche en Santé Respiratoire”; to MD), the “Fondation ARC pour la recherche sur le cancer - Aide individuelle” (to MD), the Spanish Association Against Cancer (to VD), the Pla Estratègic de Recerca i Innovació en Salut (to SM), the Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (PI16/01821 to LMM and PI15/02223, to IG-B), RETTICS grant (RD12/0036/0040 to IG-B), Fundación Merck Salud (to IG-B), Departamento de Salud, Gobierno de Navarra (074-2017, to IGB), the European Commission MSCA IMMUNOMARK-799818 (to IBara), the China Scholarship Council and Karolinska Institutet Fonder (to QX), and the Health and Science Departments of the Generalitat de Catalunya (to ME). We thank IGTP–HUGTP Biobank (PT13/0010/0009) University Hospital Ramon y Cajal-IRYCIS Biobank (PT13/0010/0002), members of the Spanish National Biobanks Network of the Instituto de Salud Carlos III, Andalusia Public Health System Biobank, the Biological Resource Center of the Hospices Civils de Lyon (Tissu-tumorothèque Est), and the Tumor Bank Network of Catalonia for their help with the collection of samples., Duruisseaux, M., Martínez-Cardús, A., Calleja-Cervantes, M.E., Moran, S., Castro de Moura, M. , Davalos, V., Piñeyro, D., Sanchez-Cespedes, M., Girard, N., Brevet, M.,Giroux-Leprieur, E., Dumenil, C. Pradotto, M., Bironzo, P., Capelletto, E., Novello, S., Cortot, A. , Copin, M.-C., Karachaliou, N.,Gonzalez-Cao, M. ,Peralta, S., Montuenga, L.M.,Gil-Bazo, I. ,Baraibar, I.,Lozano, M.D., Varela, M. ,Ruffinelli, J.C.,Palmero, R., Nadal, E.,Moran, T., Perez, L., Ramos, I., Xiao, Q.,Fernandez, A.F., Fraga, M.F.,Gut, M., Gut, I. ,Teixidó, C. , Vilariño, N., Prat, A., Reguart, N., Benito, A.,Garrido, P., Barragan, I., Emile, J.-F., Rosell, R., Brambilla, E., Esteller, M.

Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma.In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients.From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines.The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori.

The administration of pemetrexed requires routine supplementation with vitamin B12 and folate, even if blood concentrations are normal, in order to mitigate its hematologic toxicity. Emerging data suggest that such premedication can be initiated less than 1 week before starting chemotherapy. The current available data on later administration of vitamin B12 in patients with thoracic tumors are placed into a general context, and the possible role of such strategy in the era of immunooncology is discussed.

Immune checkpoint inhibitors have emerged as an effective treatment for several tumor types and their use in clinical practice is expected to further increase in the immediate future. Although these agents are well tolerated, they are associated with a peculiar spectrum of toxicity, which is immune mediated and may potentially affect every organ. However, immune-related adverse events are mostly reversible if promptly diagnosed and adequately treated. Therefore, it is crucial that medical oncologists know how to diagnose and treat immune-related adverse events. This review focuses on the pathogenesis, clinical manifestations and management of immune-related toxicity of anti-CTLA-4 and anti-PD-1 antibodies.

Over the last 10 years, the systemic treatment of advanced non-small-cell lung cancer has progressively moved away from the 'one-size-fits-all' approach to histological subtyping. Currently, there is a progressive implementation of targeted therapies based on specific molecular characteristics such as the EGF receptor sensitizing mutations and the anaplastic lymphoma kinase rearrangements. Despite the availability of effective agents against these abnormalities, acquired resistance is still a major issue. A new generation of tyrosine kinase inhibitors for EGF receptor and anaplastic lymphoma kinase targeting acquired resistance mechanisms have been recently investigated. Several promising tyrosine kinase inhibitors that hit other targets are also in clinical development, including: rat sarcoma gene/MEK, BRAF1, PIK3A, c-mesenchymal-epithelial transition, c-ros oncogene 1, rearranged during transfection, human EGFR 2, FGFR, VEGFR, PDGFR and discoidin death receptor 2. Furthermore, new advances in immunology have been achieved through the discovery of vaccines and immune checkpoint pathways such as the cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1 and its ligands.

The immune surveillance system is complex and regulated by different actors. Programmed death protein-ligand 1 (PD-L1), the only approved biomarker in clinical practice, has proven to be imperfect in selecting patients to immune checkpoint inhibitors treatment. Therefore, new biomarkers, and new therapeutic targets, are needed to maximise the efficacy of immunotherapy. V-domain Ig Suppressor of T-cell Activation (VISTA) is a programmed death protein-1 (PD-1) homolog expressed on T cells and on antigen-presenting cells, which regulates processes of activation and repression of the immune system with not yet completely clarified mechanisms. Its blockage has demonstrated in vitro and in vivo antitumour activity. The clinical research of VISTA antagonists is ongoing. Particularly, CA-170, an orally delivered dual inhibitor of VISTA and PD-L1, has shown to have clinical efficacy in phase I and II clinical trials in different advanced solid tumour types. Further data are needed to define whether this drug class can become a new therapeutic option for patients with VISTA expressing cancers.

PURPOSE The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). MATERIALS AND METHODS A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R2). RESULTS Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R2=0.539, p < 0.001) and poor correlation (R=0.169, R2=0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. CONCLUSION Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

In recent years, in castration resistant prostate cancer (CRPC), several new drugs have been approved that prolong overall survival, including enzalutamide and abiraterone, two new-generation hormonal therapies. Despite the demonstrated benefit of these agents, not all patients with CRPC are responsive to treatment, the gain in median progression-free survival with these therapies compared to standard of care is, rather disappointingly, still less than six months and the appearance of acquired resistance is almost universal. Approximately one third of patients treated with abiraterone and 25% of those treated with enzalutamide show primary resistance to these agents. Even if the mechanisms of resistance to these agents are not fully defined, many hypotheses are emerging, including systemic and intratumoral androgen biosynthesis up-regulation, androgen receptor (AR) gene mutations and amplifications, alteration of pathways involved in cross-talk with AR signaling, glucocorticoid receptor overexpression, neuroendocrine differentiation, immune system deregulation and others. The aim of this paper is to review currently available data about mechanisms of resistance to abiraterone and enzalutamide, and to discuss how these mechanisms could be potentially overcome through novel therapeutic agents.

Chemotherapy is currently the standard of care for non-oncogene-driven advanced non-small cell lung cancer (NSCLC). Due to improvements in chemotherapeutic choices and supportive care, patients currently typically undergo multiple lines of chemotherapy as their disease progresses. Although treatments have improved over recent years, limited benefits are seen, especially in patients receiving later-line chemotherapy, as response rates can be low, response duration short and survival poor. Furthermore, only a small percentage of patients derive benefit from later-line therapy, with most experiencing deteriorating quality of life and significant toxicities. More recently, molecular targeted therapies have provided improvements in outcomes. However, these treatments only offer a clear benefit in subsets of tumours harbouring the appropriate genomic alteration (mutation, amplification, translocation). Most of the genomic abnormalities susceptible to therapeutic intervention are detected in adenocarcinoma, mainly in never smokers, while alterations in the genome of other histological subtypes are known but specific agents targeting these alterations have yet to be developed. Thus, the therapeutic management of these subtypes represents an ongoing challenge. Recent advances in immunotherapy have highlighted the potential of immuno-oncology based treatments for NSCLC, offering the potential to provide durable responses and outcomes regardless of histology or mutation status. This review discusses the current unmet medical needs in NSCLC, the limits of current first-line and later-line chemotherapy and targeted agents, and the emergence of new therapeutic strategies.

Background Abiraterone strongly inhibits androgen synthesis but may lead to an increase in mineralocorticoid hormones that may impair its long term tolerability in patients with prostate cancer. How to implement available therapies in the management and prevention of these potential side effects is a matter of current clinical research. Methods The acute and long term consequences of mineralocorticoid excess and the effects of available treatments have been reviewed. Prospective studies in which abiraterone was employed were identified to assess the frequency and severity of the mineralocorticoid excess syndrome and the efficacy of ameliorating therapeutic approaches. Results Glucocorticoids to inhibit the ACTH increase that drives mineralocorticoid synthesis and mineralocorticoid receptor (MR) antagonists can be used in the management of the abiraterone-induced mineralocorticoid excess syndrome. Phase I and II trials of abiraterone without additional therapies revealed that mineralocorticoid excess symptoms occur in the majority of patients. Eplerenone, a specific MR antagonist, seems to be effective but it does not control the mineralocorticoid excess. Glucorticoid supplementation to control ACTH drive is therefore needed. In several randomized trials the addition of prednisone (10 mg daily) to abiraterone was not able to prevent mineralocorticoid excess syndrome in many cases and thus cannot be considered the gold standard. Conclusion At present, the best conceivable treatment for managing the abiraterone-induced mineralocorticoid excess consists of the administration of glucocorticoid replacement at the lowest effective dose ± MR antagonists and salt deprivation. The drug doses should be modulated by monitoring blood pressure, fluid retention and potassium levels during therapy.

Aims and background Multimodal therapy is a keystone of care in advanced esophageal cancer. Although neoadjuvant chemoradiotherapy is known to provide a survival advantage in selected cases, reliable prognostic and response predictive factors remain elusive. We report the outcome in a series of esophageal cancer patients treated at our center and the results of a retrospective analysis of epidermal growth factor receptor (EGFR) expression and EGFR/HER2 gene copy numbers taken as possible prognostic and predictive factors. Methods and study design Between 2001 and 2009, a total of 40 consecutive patients (34 men and 6 women; median age, 59 years) were treated for esophageal cancer. Treatment: cisplatin, 80 mg/m2 day 1, and 5-fluorouracil, 800 mg/m2/24 h on days 1–5, every 21 days, concomitant with 3D-conformal radiotherapy (54–59.4 in 30–33 fractions) for three up to four cycles. Surgery was performed in eligible patients 6–8 weeks after chemoradiation. EGFR expression and EGFR/HER2 amplification and gene copy number were studied by immunohistochemical analysis and fluorescence in situ hybridization, respectively. Results Acceptable toxicity following chemoradiation was recorded, with G3–G4 hematological toxicity in 20% of patients and G3–G4 dysphagia in less than 10%; 14 (35%) patients achieved complete response and 19 (48%) partial response; 18 underwent surgery after chemoradiation, of which 8 (20%) achieved pathologic complete response. The median survival was 29 months (95% CI, 25.7–32.1): 42 months for the resected and 20 for the unresected patients. EGFR and HER2 analysis in 28 patients showed that 89% had immunohistochemical EGFR expression, with 5 cases of EGFR and 10 of HER2 gene gain without a significant difference in response rate and survival in these patient subgroups. Conclusions Our results suggest a better outcome in patients who underwent surgery after chemoradiation. A larger sample size is necessary to clarify the role of EGFR and HER2 gene gain in predict response and survival.

The nucleotide excision repair pathway is crucial for cellular DNA integrity and the ERCC1 helicase is also potentially involved in resistance to platinum-based chemotherapy, and high levels of ERCC1 mRNA in tumours have been associated with cisplatin resistance in different human cancers. The aim of this work was to investigate the correlation between DNA repair gene expression levels in tumour tissue, normal tissue and peripheral blood samples from patients with two common human cancers, non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (HNSCC), to test if blood gene expression could be a proxy for tumour tissue gene expression to predict response to platinum-based chemotherapy. Using RT-qPCR we determined ERCC1, ERCC2, ERCC4, XPA, XPC, XRCC1, XRCC3, APEX, OGG1, MGMT mRNA levels in fresh NSCLC, normal lung and HNSCC tissue, as well as blood, from NSCLC and HNSCC patients who were treated surgically. Target gene expression in NSCLC and HNSCC tissue was higher than in blood. A statistically significant correlation (p