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Background: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Materials and methods: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. Results: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7). Conclusions: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

Promoting blood donation requires understanding and identifying the factors that motivate donations so that strategies for retaining and increasing loyalty can be developed. Transfusion literacy can be improved through school-based teaching and information about giving and solidarity to promote the development of future donors. For the purpose of aligning any strategies and motivational dynamics that promote adherence to informed donation and loyalty among students in the municipality of Coimbra. This study was undertaken to assess the perception of secondary school teachers regarding the students' knowledge of blood donation. A survey was conducted among teachers from seven public schools in Coimbra with regard to the 3rd and Secondary cycles. Based on the data, people give blood for a feeling of personal satisfaction and peer influence, as well as for the satisfaction of helping others. Blood donation should be made a focal point of relevance and interest in the school community, by implementing programs, projects, and dissemination actions targeting this target group. We are extremely glad and most enthusiastic to be invited to share our study through what's happening with the readers globally., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs)., Methods: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion., Results: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85)., Conclusion: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs., (© 2023. The Author(s).)

Aim: In renal cell carcinoma (RCC), tumor heterogeneity generated challenges to biomarker development and therapeutic management, often becoming responsible for primary and acquired drug resistance. This study aimed to assess the inter-tumoral, intra-tumoral, and intra-lesional heterogeneity of known druggable targets in metastatic RCC (mRCC)., Methods: The RIVELATOR study was a monocenter retrospective analysis of biological samples from 25 cases of primary RCC and their paired pulmonary metastases. The biomarkers analyzed included MET, mTOR, PD-1/PD-L1 pathways and the immune context., Results: High multi-level heterogeneity was demonstrated. MET was the most reliable biomarker, with the lowest intratumor heterogeneity: the positive mutual correlation between MET expression in primary tumors and their metastases had a significantly proportional intensity ( P = 0.038). The intratumor heterogeneity grade was significantly higher for the mTOR pathway proteins. Combined immunophenotypical expression patterns and their correlations with the immune context were uncovered [i.e., mTOR expression in the metastases positively correlated with PD-L1 expression in tumor-infiltrating lymphocytes (TILs), P = 0.019; MET expression was related to PD-1 expression on TILs ( P = 0.041, ρ = 0.41) and peritumoral lymphocytes (RILs; P = 0.013, ρ = 0.49)], suggesting the possibility of predicting drug response or resistance to tyrosine kinase, mTOR, or immune checkpoint inhibitors., Conclusions: In mRCC, multiple and multi-level assays of potentially predictive biomarkers are needed for their reliable translation into clinical practice. The easy-to-use immunohistochemical method of the present study allowed the identification of different combined expression patterns, providing cues for planning the management of systemic treatment combinations and sequences in an mRCC patient population. The quantitative heterogeneity of the investigated biomarkers suggests that multiple intralesional assays are needed to consider the assessment reliable for clinical considerations., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2023.)

Background: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients., Materials and Methods: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status., Results: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7)., Conclusions: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Burnout is a stress-induced occupational related syndrome, characterized by Emotional Exhaustion (EE), feeling of depersonalization (DP) and low sense of professional accomplishment (PA). The aim of this study is to analyse the effectiveness of interventions in decreasing health professionals Burnout as well as work and life-style risk factors.  Methods: A survey in Medical Oncology Department in the University Hospital of Parma was conducted using the validated Maslach Burnout Inventory (MBI) and two additional questionnaires exploring lifestyle and work factors. An 8-months intervention involved fortnight meetings by facilitators, incorporated elements of reflection, shared experiences and managing emotions. Six months after the end of the intervention a second survey was performed among the participants using MBI and the same questionnaires mentioned above.  Results: EE resulted the most problematic score in Day Hospital: after the 8-month intervention we described a significant decreasing in EE score especially for Day Hospital operators (from 16.7 to 10.9) and a considerable reduction in DP score. In the Oncology Ward a correlation between lack of collaboration among different health categories and DE score was detected; in the Day Hospital the absence of solid working teams was related to higher EE scores.  Conclusion: The Oncology professional health care personnel are at the greatest risk of Burnout. Our study in Oncology Department shows that specific intervention should be used to prevent and reduce Burnout. Effective personal health care strategies should be incorporated into routine oncology care to prevent and treat Burnout.

Objectives: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients., Materials and Methods: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed., Results: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71)., Conclusions: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aim: Evaluating the incidence and course of COVID-19 in cancer patients treated with immunotherapy. Patients & methods: We reported the influenza-like illness events with diagnosis of COVID-19 within the patient cohort enrolled in the prospective observational multicenter INVIDIa-2 study in the single center of Parma. Results: Among 53 patients, eight experienced influenza-like illness during the influenza season 2019/2020, and three of them had diagnosis of COVID-19. They were males, elderly, with cardiovascular disease. Radiological features of COVID-19 pneumonitis were found in all of three cases, although the pharyngeal swab resulted positive in only two. Two of these three patients died due to respiratory failure. Conclusion: Cancer patients are at high risk of severe events from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Background: Pembrolizumab is the first-line standard of care for advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumour proportion score (TPS) ≥ 50%. Eastern Cooperative Oncology Group performance status (PS) 2 patients may receive pembrolizumab, despite the absence of sustaining evidence., Patients and Methods: GOIRC-2018-01 is a multicentre, retrospective, observational study. PS 2 NSCLC patients with a PD-L1 TPS ≥50% receiving first-line pembrolizumab from June 2017 to December 2018 at 21 Italian institutions were included. Clinical-pathological characteristics were correlated with disease response and survival outcomes; adverse events were recorded. The primary objective was 6-months progression-free rate (6-months PFR)., Results: One hundred fifty-three patients (median age 70 years) were enrolled. At a median follow-up of 18.2 months, median progression-free survival (PFS) and overall survival (OS) were 2.4 (95% confidence interval, 95% CI, 1.6-2.5) and 3.0 months (95% CI 2.4-3.5), respectively. 6-months PFR was 27% (95% CI 21-35%). Patients with a PS 2 determined by comorbidities (n = 41) had significantly better outcomes compared with disease burden-induced PS 2 (n = 112). Indeed, 6-months PFR was 49% versus 19%, median PFS 5.6 versus 1.8 months and OS 11.8 versus 2.8 months, respectively. Additional potential prognostic factors (radiotherapy, antibiotics, steroids received before pembrolizumab) correlated with clinical outcomes. The determinant of PS 2 resulted the only factor independently impacting on both PFS and OS. No toxicity issues emerged., Conclusions: Outcomes of PS 2 NSCLC patients with PD-L1 TPS ≥50% receiving first-line pembrolizumab were globally dismal but strongly dependent on the reason conditioning the poor PS itself., Competing Interests: Conflict of interest statement F.F. declares he has attended editorial activities sponsored by Roche and BMS. F.P. declares having attended advisory boards and having performed consultant activities from MSD. C.P. declares honoraria and travel accommodation from BMS; travel accommodation from MSD: advisory board and travel accommodation from Roche; speaker's bureau from Eli Lilly. S.P. received honoraria or speakers’ fee from AstraZeneca, BMS, Boehringer Ingelheim, MSD, Roche and Istituto Gentili. V.S. declares speakers’ fees and advisory boards from MSD. A.D.C. declares speakers’ fees from MSD. A.A. declares advisory board and research grants from BMS; advisory board from MSD; speakers' fees from Eli Lilly; advisory boards from Boehringer Ingelheim; speakers’ fees from Pfizer; research grants from Celgene. A.B. declares advisor and speaker services for Takeda, Boehringer Ingelheim, Novartis, Pfizer, MSD, travel grants from Jansen, Roche, MSD, BMS. M.C.G. declares personal financial interests with the following organizations: AstraZeneca, MSD International GmbH, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, Inivata, MedImmune, Novartis, Pfizer, Roche and Takeda. S.N. declares speaker bureau/advisory boards for AstraZeneca, Boehringer Ingelheim, MSD, Pfizer, Bayer, Takeda, Abbvie, Eli Lilly, Roche, BMS. E.B. declares consulting, scientific advisory board, speaker's fees from Roche, MSD, AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis; research funding from AstraZeneca and Roche. A.R. declares advisory boards and honoraria as speaker's bureau from MSD, Eli Lilly, AstraZeneca, Roche, Boehringer Ingelheim. M.D.M. received honoraria and had roles as consultant or advisor for AstraZeneca, Eli Lilly, BMS, MSD and Janssen. M.T. declares advisory boards and speakers’ fees from AstraZeneca, Pfizer, Eli Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre; research grants from AstraZeneca and Boehringer Ingelheim. All other authors declare they have no conflict of interest to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Three biochars were produced using sawdust from waste biomass, via a simple pyrolysis thermal conversion at 450, 650, and 850 °C (BC450, BC650, and BC850), without any activation process. These materials, together with vegetal and mineral commercial activated carbons (VAC and MAC), were characterized for their elemental composition, Brunauer-Emmett-Teller surface area, t-plot microporosity and Barrett-Joyner-Halenda mesoporosity. Moreover, iodine, phenol and methylene blue porosity indexes were measured. The materials were also evaluated for their pH of the point of zero charge, as well as near-surface chemical composition and surface functionality by means of X-ray photoelectron and Fourier-transform infrared spectroscopy. Ash content, water-extractable metals and polycyclic aromatic hydrocarbons (PAHs) were also determined. BC650 showed a much higher surface area (319 m 2  g -1 ) compared to BC450 (102 m 2  g -1 ), as well as an increase in aromatization and the residual presence of functional polar groups. BC850 exhibited a loss of polar and aromatic groups, with the dominance of graphitic carbon and the highest value of surface area (419 m 2  g -1 ). Biochars comply with the EN 12915-1/2009 limits for metal and PAH release in water treatment. Biochars and MAC were tested using Langmuir and Freundlich isotherms for the sorption in real effluent wastewater of a mixture of 14 branched ethoxylated 4-t-octyl and 4-nonylphenols, as well as 4-t-octyl and 4-nonylphenol, the latter representing persistent, endocrine disrupting contaminants, widespread in the effluents from wastewater treatment plants and listed as priority/priority hazardous substances in the Directive 2013/39/EU. Biochars showed a lower sorption efficiency compared to MAC. The best performance was found for BC650 towards the alkylphenols (9-13 times less efficient than the MAC). Considering the lower market price of biochar compared to MAC (estimated as at least 16 times less expensive by a small market survey), the former can be considered more competitive than the latter., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Several reports attest the feasibility and the favorable outcomes of kinase inhibitors administration through feeding tubes or Percutaneous Endoscopic Gastrostomies (PEG), mainly in Non-Small Cell Lung Cancer (NSCLC) patients exposed to first-generation compounds. Here we present the case of an ALK-positive NSCLC patient who achieved cerebral and extra-cranial disease response with ceritinib (a novel ALK inhibitor) administered through a Nasogastric Tube (NGT). We moreover provide a review gathering clinical successes obtained with targeted agents intake through NGT or PEG., Case Presentation: A 53-year-old never-smoker woman was diagnosed with ALK-rearranged stage IV lung adenocarcinoma. After a brilliant response to crizotinib and several lines of systemic therapy, NGT positioning intended for ceritinib administration was required, given the development of a pleuro-esophageal fistula. Enteral drug administration allowed a significant reduction of hepatic and cerebral disease localizations., Literature Review and Discussion: The majority of kinase inhibitors administration through NGT or PEG accounts for EGFR-mutated (seven) or ALK-positive (seven, including our report) NSCLC patients. Five additional cases concerning different malignancies were described. Enteral drug administration was mostly required by disease-related respiratory impairment, requiring mechanical ventilation in the emergency setting. In our case, the cerebral and extra-cranial response obtained with enteral ceritinib intake suggests the proposition of novel inhibitors in these circumstances may take place after first-generation compounds failure or even upfront. Indeed, their grater potency and activity against brain metastases point out the role of their enteral administration in the first-line setting too, when a rapid systemic and intra-cerebral disease response is required., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes (EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and -beta, HER2 and c-MET) and the expression of ALK and PD-L1., Patients and Methods: One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected. Immunohistochemical expression of ALK (clone D5F3) and PD-L1 (clone E1L3N), molecular analysis of EGFR (exons 18-21), c-KIT (exons 9,11,13,14,17), KRAS (exon 2), BRAF (exon 15), PDGFR-alpha (exon 12) and -beta (exons 12, 14, 18), HER-2 (exons 19 and 20) and c-MET (exons 14, 17, 18, 19) mutations were performed. Immuno-molecular results were then statistically matched with clinico-pathologic characteristics., Results: Patients were male in 54% of cases, with a median age of 61 years (range 19-83) and affected mainly by thymoma (78%) in stage II (45%). At molecular analysis, there were 4 c-KIT mutations (occurring in exon 11 V559A, L576P, Y553N and exon 17 D820E) in thymic carcinomas (typeC), but not in other tumor types (p=0.003). No mutations were detected in other genes and none case was ALK positive. Twenty-nine (26%) cases were PD-L1 positive (65% of thymic carcinomas and 18% of thymomas). High PD-L1 expression was statistically associated with WHO classification stage type C (p<0.001) and Masaoka stage III-IV disease (p=0.007). In univariate analysis, WHO classification type C, advanced Masaoka stage and absence of myasthenia, but not PD-L1 expressions were correlated with worse survival; at multivariate analysis, only WHO type C confirmed its negative prognostic role., Conclusion: A subset of TETs as thymic carcinomas can harbor c-KIT mutations and elevated PD-L1 expression that could represent targets of potential therapeutic use., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim of the Work: BRCA1/2 mutation carriers diagnosed with breast cancer have a strong life-time risk of developing contralateral breast cancer (CBC). We performed a population-based study with the aim of estimating the proportion of CBC associated with BRCA1/BRCA2 mutations, and the contribution of germline mutations to both molecular and clinical features of these tumors., Methods: Fifty-five women with invasive CBC consecutively seen at the at the Genetic Oncology Service of the University Hospital of Parma from 2000 to 2011 were subjected to BRCA1/2 testing. Fifty-five case-matched, unilateral breast cancer (UBC)  patients (pts), which tested negative for BRCA1/2 mutations, were selected as control group., Results: BRCA mutations were detected in 13 (24%) of 55 CBC pts. Women with BRCA1 mutations, and to a lesser extent BRCA2 mutations, were significantly more likely to present with high histologic grade, negative hormone receptor status and high proliferation rate in both first and second primary breast cancers than BRCA-negative, CBC tumors. A diagnosis of triple-negative breast cancer (TNBC) was significantly more frequent in women with BRCA mutations in comparison with BRCA-negative, UBC controls. There were no survival differences between BRCA-positive and non-BRCA tumors., Conclusions: Results of the present study indicate that both first primary and second primary breast cancers in BRCA carriers are qualitatively distinct from BRCA negative CBC, and from sporadic UBC controls. These findings highlight relevant clinical considerations about the potential value of BRCA testing in women with CBC as well as therapeutic, preventive, and surveillance implications for patients carrying a mutation.

Objectives: Pemetrexed has been approved for the treatment of advanced non-small cell lung cancer (NSCLC) non-squamous histology, both as first- and second-line therapy. Pemetrexed is an antimetabolite drug, that inhibits enzymes involved in nucleotides bio-synthesis arresting cancer cells cycle. The aim of this study was the evaluation of the impact of pemetrexed on erythrocyte mean corpuscular volume (MCV) change and its possible correlation with disease control rate (DCR), progression free (PFS) and overall survival (OS) in NSCLC patients., Materials and Methods: A retrospective collection of clinical and laboratory data (including basal MCV and maximum MCV occurred during therapy) in advanced NSCLC patients treated with pemetrexed at seven Italian centers was performed. Nonparametric tests, univariate and multivariate analysis were used to assess correlation between variables and to identify predictors of outcomes., Results: 191 patients were enrolled: median age 62, 60% male, 61% performance status (PS) 0, 91% stage IV, 88% adenocarcinoma histotype, 25% never smoker, 62% received pemetrexed as first-line. Mean MCV significantly increased from basal (89fL) to during treatment (94fL), with mean ΔMCV=4fL. The median time from therapy start to maximum MCV was 2.2 months. Median PFS was 7 [CI95% 6-8] and 3 [CI95% 2-4] months [P=0.0016], and median survival was 17 [CI95% 12-23] and 10 [CI95% 8-12] months [P=0.02], in patients with ΔMCV>5fL (n=80) and ΔMCV≤5fL (n=111), respectively. Multivariate analysis identified age ≥62, PS 0, adenocarcinoma histology and ΔMCV>5fL as independent predictors of longer PFS. A ΔMCV>5fL significantly correlates with DCR., Conclusion: Pemetrexed induces macrocytosis. ΔMCV>5fL on pemetrexed therapy correlated with better DCR, PFS and OS. These results deserve further validation in prospective studies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-α (IFN-α) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-α or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were secondary endpoints. ClinicalTrials.gov registration number was NCT00502034. 303/310 randomized patients (156 in the immunotherapy arm and 154 in the observation group) were evaluable at the intention-to-treat analyses. The 2 arms were well balanced. At a median follow-up of 52 months (range, 12-151 mo), RFS, and OS were similar, with an estimated hazard ratio (HR) of 0.84 [95% confidence interval (CI), 0.54-1.31; P=0.44] and of 1.07 (95% CI, 0.64-1.79; P=0.79), respectively in the 2 groups. Unplanned, subgroup analysis showed a positive effect of the treatment for patients with age 60 years and younger, pN0, tumor grades 1-2, and pT3a stage. Among patients with the combined presence of ≥ 2 of these factors, immunotherapy had a positive effect on RFS (HR=0.44; 95% CI, 0.24-0.82; P ≤ 0.01), whereas patients with <2 factors in the treatment arm exhibited a significant poorer OS (HR=2.27; 95% CI, 1.03-5.03 P=0.037). Toxicity of immunotherapy was mild and limited to World Health Organization grade 1-2 in most cases. Adjuvant immunotherapy with IL-2+IFN-α showed no RFS or OS improvement in RCC patients who underwent radical surgery. The results of subset analysis here presented are only hypothesis generating.

The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib.

Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab.

Aim: To evaluate the activity, safety and long-term survival of patients after preoperative oxaliplatin and 5-fluorouracil chemoradiation therapy in locally advanced rectal cancer (LARC)., Patients and Methods: Patients with resectable, T3-4 and/or nodal involvement rectal adenocarcinoma were treated with oxaliplatin 60 mg/m(2) weekly and 5-fluorouracil 200 mg/m(2)/d infused continuously for five days, over a period of five weeks, and radiotherapy (45 Gy/25 fractions). The primary end-point was pathological complete response (ypCR). Safety, overall survival (OS) and relapse-free survival (RFS) were secondary end-points., Results: Sixty-six patients were treated. Grade 1-2 diarrhea was the most common adverse event. The ypCR rate was 16.7% (95% confidence interval=7.7-25.7%). After a median follow-up of 73.5 months, 23 patients (34.8%) had experienced relapse. Five-year actuarial RFS and OS rates were 64% and 73%, respectively. Five-year actuarial RFS was 91.7% in the ypCR group versus 57.8% in non-ypCR cases., Conclusion: Long-term local control and survival after this very well-tolerated regimen appear encouraging.

Purpose: To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS)., Results: From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039)., Conclusion: Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

Aims and background. The incidence of asymptomatic pulmonary embolism in cancer patients is unknown and strictly related to the imaging used for tumor assessment. Recent findings suggest a similar clinical outcome of asymptomatic pulmonary embolism events compared to symptomatic events with a significant impact on survival. The aim of the present study was to determine the prevalence of asymptomatic pulmonary embolism in a population of lung cancer outpatients and to investigate its clinical features. Methods. Outpatients with a diagnosis of lung carcinoma undergoing chemotherapy were selected from October 2006 to June 2009. Disease and patient characteristics, risk factors and treatment modalities were collected. All the computed tomography images performed for each patient during the study period were retrospectively reviewed to identify pulmonary embolism. Results. A total of 141 consecutive patients were included and 657 computed tomography scans were completely reviewed (from two to six consecutive scans for each patient). Asymptomatic pulmonary embolism in the study population had a prevalence of 14.9% (21 patients). Most of the events occurred in patients with adenocarcinoma, advanced stage and poor performance status, during the early phases of first-line chemotherapy or at the same time of the cancer diagnosis. Compared with the symptomatic pulmonary embolism events (5 patients), asymptomatic events occurred earlier (time from cancer diagnosis to pulmonary embolism of 3.5 [95% CI, 2.0-4.9] versus 12.1 months [95% CI, 6.3-17.9; P = 0.02]) and had a better prognosis (survival from PE of 7.5 [95% CI, 3.4-11.6] versus 1.9 months [95% CI, 0-3.9; P = 0.04]). Conclusions. Our findings indicate an underestimation of embolic events among lung cancer outpatients due to their frequent asymptomatic natur. Such a high prevalence suggests the importance to pay more attention to pulmonary embolism prevention in this population.

Background: Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma., Methods: The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours., Results: Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis., Conclusion: The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.

This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD.

A number of different clinical characteristics and molecular markers related to epidermal growth factor receptor (EGFR) activation have been reported to singly correlate with therapeutic activity of EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). This study was designed to evaluate the predictive value on gefitinib outcomes of a comprehensive panel of molecular parameters in advanced NSCLC patients. EGFR and K-ras mutations were detected by direct sequencing on tumor DNA from paraffin embedded samples. EGFR and HER2 gene copy number was assessed by FISH. EGFR protein expression was quantified by immunohistochemistry. EGFR gene intron 1 polymorphism was assessed on genomic DNA isolated from venous whole blood samples. Ninety-one patients were prospectively enrolled and the overall gefitinib response rate was 18.7% (2 complete and 15 partial responses). Sex (p=0.005), non-smoking status (p=0.010), skin toxicity (p=0.020), EGFR gene mutations (p<0.001) and EGFR FISH positivity (p=0.016) were found to be associated with gefitinib response. K-ras mutation was detected in only seven non-responder patients. The median overall survival was of 10 months. Only non-smoking status and EGFR intron 1 polymorphism showed a statistically significant correlation with survival (p=0.031 and 0.044, respectively). In conclusion, we have confirmed the role of EGFR gene mutation as predictor of response to EGFR TKIs. Moreover, EGFR gene copy number and, potentially, also EGFR intron 1 polymorphism could aid in better prediction of EGFR TKI responsiveness in advanced NSCLC.

Background: Loss of phosphatase and tensin homologue deleted in chromosome 10 (PTEN) function in advanced colorectal cancer (CRC) may represent one of the resistance mechanisms to cetuximab by interfering with the epidermal growth factor receptor signal transduction pathway., Methods: PTEN expression tested by indirect immunofluorescence was evaluated both on primary (n=43) and on metastatic (n=24) sites in CRC patients treated with cetuximab., Results: The loss of PTEN expression tested on metastatic sites was negatively associated with response (100% progressive disease (PD) in PTEN-negative cases vs 30% PD in PTEN-positive cases; P<0.05), PFS (0.8 vs 8.2 months; P<0.001) and OS (2.9 vs 14.2 months; P<0.001)., Conclusion: A potential role of PTEN in the anti-tumour activity of cetuximab could be hypothesised.

The presence in the serum of specific autoantibodies, such as antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), and antiextractable nuclear antigens (anti-ENA), is one of the diagnostic criteria for autoimmune rheumatic disease, and the requests for these tests in the last few years have grown remarkably. A guideline for reducing clinically inappropriate requests in autoantibody testing (ANA, anti-dsDNA, anti-ENA) has been applied in the Parma Hospital since 2007. The results for the period January-December 2007 were compared to those of the previous period January-December 2006, and a significant reduction in the number of anti-dsDNA (23.9%) and anti-ENA (20.7%) was found. The aim of this study was to assess the applicability of a similar guideline in a wide area (Parma, Modena, Piacenza, Reggio-Emilia) with reference to the diagnosis of autoimmune rheumatic disease. This project, supported by a regional grant for innovative research projects, was started in January 2008 and consists of three different steps: (1) a study group of clinicians and laboratory physicians to evaluate the diagnostic criteria, the analytical procedures, and the number of tests performed in different hospitals; (2) developing common guidelines for autoantibody testing that takes into account the different clinical needs with the aim of improving efficiency and clinical effectiveness of diagnosis and monitoring; and (3) assessing compliance with the guidelines in the different hospitals that are evaluating the second-level test (anti-dsDNA, anti-ENA) decrease. We think that the validation of guidelines for the laboratory diagnosis of autoimmune rheumatic disease can represent a tool for improving patients' outcomes and economic efficiency.

The role of Wnt pathway in digestive endocrine tumours is debated. The aim of this work is to investigate key players in Wnt pathway by a multimodal approach. Sixty cases (49 well-differentiated and 11 poorly differentiated) were investigated for methylation of adenomatous polyposis coli (APC) and E-cadherin promoters, the loss of heterozygosity (LOH) at APC locus and beta-catenin and E-cadherin expression by immunohistochemistry. Tumours showing altered beta-catenin localization were tested for beta-catenin and APC mutations. APC promoter methylation was restricted to gastroduodenal tumours (21 out of 59, 36%), prevalent in poorly differentiated carcinomas (P=0.042) and correlating with aggressive features (high histology grade, P<0.02; tumour death, P=0.026; high fractional allelic loss, P=0.002, in turn correlating with short survival, P=0.017). LOH at APC locus was found in 14 out of 53 cases (26%, 10 gastroduodenal and 4 colorectal), prevalent in poorly differentiated carcinomas (P=0.002) and correlating with histology grade (P=0.012). beta-catenin abnormal expression was found in 41 out of 54 cases (76%), with nuclear staining correlating with APC alteration (P=0.047) and short survival (P=0.006). APC, but not beta-catenin, gene mutations were found (7 out of 35 tumours), 4 of which in the midgut. E-cadherin promoter methylation was rarely detected (2 out of 52 cases), with cytoplasmic expression in 18 out of 43 cases (42%), not correlating with any clinico-pathological feature. In conclusion, Wnt pathway alterations, as represented by abnormal beta-catenin localization, are common events in digestive endocrine tumours, but only nuclear expression correlates with tumour aggressiveness. Though with different alteration mechanisms according to anatomical site, APC plays a major role in Wnt pathway activation and in determining the high chromosomal instability observed in aggressive endocrine carcinomas.

Introduction: Epidermal growth factor receptor (EGFR) gene intron 1 contains a polymorphic single sequence dinucleotide repeat (CA)n whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)n polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC)., Methods: Blood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron 1 gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron 1 polymorphism was also studied., Results: EGFR intron 1 polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)16 and with a (CA)else genotype, respectively; p = 0.044). Patients with a (CA)16 genotype had a longer survival compared with those with a (CA)else genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)16 allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)16 allele (p = 0.003)., Conclusions: This study supports a potential role of EGFR intron 1 polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC.

Purpose: The anti-HER-2/neu monoclonal antibody trastuzumab has been shown to engage both activatory (fragment C receptor [Fc gamma R]IIIa; Fc gamma RIIa) and inhibitory (Fc gamma RIIb) antibody receptors and Fc gamma R polymorphisms have been identified that may affect the antibody-dependent cell-mediated cytotoxicity (ADCC) of natural-killer cells/monocytes. In this study, we tested whether Fc gamma R polymorphisms are associated with clinical outcome of patients with breast cancer who received trastuzumab., Patients and Methods: Fifty-four consecutive patients with HER-2/neu-amplified breast cancer receiving trastuzumab plus taxane for metastatic disease were evaluated for genotype for the Fc gamma RIIIa-158 valine(V)/phenylalanine(F), Fc gamma RIIa-131 histidine(H)/arginine(R), and Fc gamma RIIb-232 isoleucine(I)/threonine(T) polymorphisms. Trastuzumab-mediated ADCC of patients' peripheral blood mononuclear cells (PBMCs) was measured by chromium-51 release using a HER-2/neu-expressing human breast cancer cell line as a target. Controls comprised thirty-four patients treated with taxane alone., Results: Our population was in Hardy-Weinberg equilibrium except for the Fc gamma RIIb polymorphism. The Fc gamma RIIIa-158 V/V genotype was significantly correlated with objective response rate (ORR) and progression-free survival (PFS). Also, there was trend significance in ORR and PFS for the Fc gamma RIIa-131 H/H genotype. The combination of the two favorable genotypes (VV and/or H/H) was independently associated with better ORR and PFS compared with the other combinations. The ADCC analysis showed that V/V and/or H/H PBMCs had a significantly higher trastuzumab-mediated cytotoxicity than PBMCs harboring different genotypes., Conclusion: These data support for the first time the hypothesis that Fc gamma R-mediated ADCC plays an important role in the clinical effect of trastuzumab. Prospective studies are needed to confirm the role of Fc gamma R polymorphisms in predicting clinical outcome of patients with breast cancer treated with trastuzumab-based therapy.

Background: Complete surgical resection of gastric cancer is potentially curative, but long-term survival is poor., Methods: Patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV (T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m(2), on days 1 and 5], epirubicin [30 mg/m(2), days 1 and 5], L-leucovorin [100 mg/m(2), days 1-4], and 5-fluorouracil [300 mg/m(2), days 1-4] in a hospital setting. Frequencies and severity of adverse events were determined. Overall survival (OS) and disease-free survival (DFS) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model. All statistical tests were two-sided., Results: From January 1995 through September 2000, 258 patients were randomly assigned to chemotherapy (n = 130) or surgery alone (n = 128). Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26)., Conclusions: Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.

We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P=0.002) and in N0 tumours (P=0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR+micR; P=0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P=0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P=0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT.

Aims and Background: To demonstrate the efficacy of 13-cis-retinoic acid (RA) or Interferon alpha-2a (IFN alpha-2a) with Tamoxifen (TAM) in the treatment of advanced breast cancer., Methods: Ninety-nine postmenopausal patients with advanced breast cancer, and a positive or unknown estrogen (ER) or progesterone (PgR) receptor status, were randomised to receive TAM 20 mg/m2/day orally (arm A), or TAM plus RA 1 mg/kg/day orally (arm B), or TAM plus IFN alpha-2a 3 MU thrice a week intramuscular (arm C). The three treatment groups were well balanced in terms of the main prognostic factors., Results: Response was evaluable in 32 of the patients in arm A, 32 in arm B, and 30 in arm C. Intention-to-treat analysis showed no significant difference of response rate in the three arms (44% vs 38% vs 42%). After an eight years median follow-up, there was no significant between-group difference in median overall survival: 47.4 vs 38.2 vs 45.1 months. Side effects were negligible in arm A, but cutaneous (39%) and mucosal (62%) toxicities were frequent in arm B, and flu-like syndrome and/or myalgia (46%) in arm C., Conclusions: The administration of RA or IFN alpha-2a does not add anything to the therapeutic effects of TAM.

Purpose: To evaluate the role of pretreatment and posttreatment expression in buccal mucosa cells of signal transduction proteins activated by epidermal growth factor receptor, including phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated mitogen-activated protein kinase (p-MAPK), and phosphorylated AKT (p-AKT), in predicting gefitinib activity in advanced non-small cell lung cancer patients. Expression of the same proteins was also assessed on corresponding tissue samples for comparison. Moreover, EGFR gene mutations and copy number were analyzed., Experimental Design: Protein expression was evaluated by standard immunocytochemistry in buccal smears, obtained by scraping immediately before and after 2 weeks of gefitinib treatment, and in the available archival tumor specimens. EGFR gene mutations were evaluated by direct sequencing and gene copy number was determined by fluorescence in situ hybridization. Data were correlated with gefitinib toxicity and objective response., Results: Fifty-eight patients with pretreated advanced non-small cell lung cancer were enrolled and nine of these patients (15%) showed an objective response to gefitinib (including two complete responses). Toxicity (P = 0.025) and baseline p-AKT expression in buccal mucosa cells (P = 0.061) showed a potential predictive role. On the contrary, the probability of achieving an objective response was not affected by pretreatment expression of EGFR, p-EGFR, and p-MAPK, either in buccal mucosa or in tumor tissue. Responders showed a nonstatistically significant trend toward a more pronounced reduction in the expression of p-EGFR, p-MAPK, and p-AKT after gefitinib treatment. Among responders, five of six (83%) tumors showed EGFR gene mutation, whereas none of the tumors from patients with stable or progressive disease did (P < 0.001)., Conclusions: Epithelial cells obtained from buccal mucosa may be used to assess the pharmacodynamic effect of EGFR-targeted agents, and pretreatment p-AKT expression may be a possible predictive biomarker of in vivo gefitinib activity.