A preliminary investigation of circulating extracellular vesicles and biomarker discovery associated with treatment response in head and neck squamous cell carcinoma.

BACKGROUND: There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay. METHODS: In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array. RESULTS: Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients. CONCLUSION: This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.

Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.

BACKGROUND: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. METHODS: In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. FINDINGS: Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. INTERPRETATION: Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING: Boehringer Ingelheim.

High expression of MLANA in the plasma of patients with head and neck squamous cell carcinoma as a predictor of tumor progression.

BACKGROUND: There is a paucity of plasma-based biomarkers that predict outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Here, we evaluate the prognostic potential of plasma Melanoma-Antigen Recognized by T-cells 1 (MLANA) in this setting. METHODS: MLANA expression in HNSCC lines were evaluated by reverse transcription polymerase chain reaction, whereas plasma levels were quantified using ELISA in 48 patients with locally advanced HNSCC undergoing a phase 2 trial with CRT. RESULTS: MLANA is expressed at variable levels in a panel of HNSCC lines. In plasma, levels were elevated in patients with tumor relapse compared to those without (P < .004); 73.9% of the patients expressing high plasma MLANA levels progressed with recurrent disease (P = .020). Multivariate analysis showed that plasma MLANA levels and tumor resectability were independent prognostic factors for progression free survival. CONCLUSION: Plasma MLANA expression appears to be an effective noninvasive biomarker for outcomes in patients treated with CRT, and could potentially guide therapeutic decisions in this context.

The role of single-nucleotide polymorphism (SNPs) in toxicity of induction chemotherapy based on cisplatin and paclitaxel in patients with advanced head and neck cancer.

BACKGROUND: Induction chemotherapy in locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients is potentially associated to serious adverse events. Biomarkers associated with toxicity could tailor its indication. This study evaluated the association between single-nucleotide polymorphisms (SNPs) in metabolic genes and toxicity to induction chemotherapy. METHODS: 59 LAHNSCC phase II clinical trial patients (NCT00959387) were assessed regarding 47 metabolic genes (366 SNPs). Toxicities were graded (CTCAE 3.0) and statistical analysis was performed. RESULTS: The SNPs rs8187710 (ABCC2) and rs1801131 (MTHFR) were associated to increased risk of gastrointestinal toxicity, whereas the SNPs rs3788007 (ABCG1) and rs4148943 (CHST3) were associated to decreased risk. Two other SNPs, rs2301159 (SLC10A2) and rs2470890 (CYP1A2), were associated with increased risk of hematological toxicity. Nevertheless, these SNPs did not remain significant after adjusting for multiple comparisons. CONCLUSIONS: This study could not demonstrate relationship between SNPs and toxicity to induction chemotherapy in LAHNSCC patients. The small number of patients may have affected the results.

Mutational profile of Brazilian lung adenocarcinoma unveils association of EGFR mutations with high Asian ancestry and independent prognostic role of KRAS mutations.

Lung cancer is the deadliest cancer worldwide. The mutational frequency of EGFR and KRAS genes in lung adenocarcinoma varies worldwide per ethnicity and smoking. The impact of EGFR and KRAS mutations in Brazilian lung cancer remains poorly explored. Thus, we investigated the frequency of EGFR and KRAS mutations in a large Brazilian series of lung adenocarcinoma together with patients' genetic ancestry, clinicopathological and sociodemographic characteristics. The mutational frequency of EGFR was 22.7% and KRAS was 20.4%. The average ancestry proportions were 73.1% for EUR, 13.1% for AFR, 6.5% for AME and 7.3% for ASN. EGFR mutations were independently associated with never-smokers, high-Asian ancestry, and better performance status. KRAS mutations were independently associated with tobacco exposure and non-Asian ancestry. EGFR-exon 20 mutations were associated with worse outcome. The Cox regression model indicated a worse outcome for patients whose were older at diagnosis (>61 y), solid histological subtype, loss of weight (>10%), worse performance status (≥2), and presence of KRAS mutations and EGFR mutational status in TKi non-treated patients. In conclusion, we assessed the clinicopathological and ethnic impact of EGFR and KRAS mutations in the largest series reported of Brazilian lung adenocarcinomas. These findings can support future clinical strategies for Brazilian lung cancer patients.

Afatinib as second-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: Subgroup analyses of treatment adherence, safety and mode of afatinib administration in the LUX-Head and Neck 1 trial.

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). METHODS: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). RESULTS: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). CONCLUSION: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.

Afatinib vs Placebo as Adjuvant Therapy After Chemoradiotherapy in Squamous Cell Carcinoma of the Head and Neck: A Randomized Clinical Trial.

IMPORTANCE: Locoregionally advanced head and neck squamous cell cancer (HNSCC) is treated curatively; however, risk of recurrence remains high among some patients. The ERBB family blocker afatinib has shown efficacy in recurrent or metastatic HNSCC. OBJECTIVE: To assess whether afatinib therapy after definitive chemoradiotherapy (CRT) improves disease-free survival (DFS) in patients with HNSCC. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 3, double-blind randomized clinical trial (LUX-Head & Neck 2) studied 617 patients from November 2, 2011, to July 4, 2016. Patients who had complete response after CRT, comprising radiotherapy with cisplatin or carboplatin, with or without resection of residual disease, for locoregionally advanced high- or intermediate-risk HNSCC of the oral cavity, hypopharynx, larynx, or oropharynx were included in the study. Data analysis was of the intention-to-treat population. INTERVENTIONS: Patients were randomized (2:1) to treatment with afatinib (40 mg/d) or placebo, stratified by nodal status (N0-2a or N2b-3) and Eastern Cooperative Oncology Group performance status (0 or 1). Treatment continued for 18 months or until disease recurrence, unacceptable adverse events, or patient withdrawal. MAIN OUTCOMES AND MEASURES: The primary end point was DFS, defined as time from the date of randomization to the date of tumor recurrence or secondary primary tumor or death from any cause. Secondary end points were DFS at 2 years, overall survival (defined as time from the date of randomization to death), and health-related quality of life. RESULTS: A total of 617 patients were studied (mean [SD] age, 58 [8.4] years; 528 male [85.6%]). Recruitment was stopped after a preplanned interim futility analysis on July 4, 2016, on recommendation from an independent data monitoring committee. Treatment was discontinued. Median DFS was 43.4 months (95% CI, 37.4 months to not estimable) in the afatinib group and not estimable (95% CI, 40.1 months to not estimable) in the placebo group (hazard ratio, 1.13; 95% CI, 0.81-1.57; stratified log-rank test P = .48). The most common grade 3 and 4 drug-related adverse effects were acneiform rash (61 [14.8%] of 411 patients in the afatinib group vs 1 [0.5%] of 206 patients in the placebo group), stomatitis (55 [13.4%] in the afatinib group vs 1 [0.5%] in the placebo group), and diarrhea (32 [7.8%] in the afatinib group vs 1 [0.5%] in the placebo group). CONCLUSIONS AND RELEVANCE: This study's findings indicate that treatment with afatinib after CRT did not improve DFS and was associated with more adverse events than placebo in patients with primary, unresected, clinically high- to intermediate-risk HNSCC. The use of adjuvant afatinib after CRT is not recommended. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01345669.

Is Lipidomic the Answer to the Search of a Biomarker for Organ Preservation Protocol in Head and Neck Squamous Cell Carcinoma?

In the last decade organ preservation protocols based on chemoradiotherapy (CRT) has been showing the possibility of preserving function without jeopardizing survival for locally advanced head and neck squamous cell carcinoma (HNSCC). Still, only a percentage of the patients will benefit from this approach and, to date, no biomarkers are known to correctly predict these patients. More recently, modern mass spectrometry method has been used to determine metabolic profiles, and lipidomics, in particular, emerged as a new field of study in oncology and other diseases. This study aimed to analyze the lipid profile on saliva from patients undergoing to a prospective, single center, open-label, non-randomized phase II trial for organ preservation on HNSCC. The lipid analysis was performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Multivariate statistical analyses based on principal component analysis and orthogonal partial least square-discriminant analysis were applied to MALDI-TOF-MS data to visualize differences between the lipid profiles and identify potential biomarkers. The results assisted on distinguishing complete responders from non-responders to the treatment protocol. In conclusion, we demonstrated that a group of lipids is differentially abundant in saliva from HNSCC patients submitted to an organ preservation protocol, being able to differentiate responders from non-responders. These results suggest the potential use of lipid biomarkers to identify patients who may benefit from this treatment. Also, we showed that saliva testing might be routinely used in clinical practice, for being a non-invasive alternative to blood testing, besides inexpensive and easy to obtain.

AKT can modulate the in vitro response of HNSCC cells to irreversible EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of head and neck squamous cell carcinoma (HNSCC) tumors. Cetuximab is the first targeted (anti-EGFR) therapy approved for the treatment of HNSCC patients. However, its efficacy is limited due to primary and secondary resistance, and there is no predict biomarkers of response. New generation of EGFR inhibitors with pan HER targeting and irreversible action, such as afatinib and allitinib, represents a significant therapeutic promise. In this study, we intend to compare the potential cytotoxicity of two anti-EGFR inhibitors (afatinib and allitinib) with cetuximab and to identify potential predictive biomarkers of response in a panel of HNSCC cell lines. The mutational analysis in the eight HNSCC cell lines revealed an EGFR mutation (p.H773Y) and gene amplification in the HN13 cells. According to the growth inhibition score (GI), allitinib was the most cytotoxic drug, followed by afatinib and finally cetuximab. The higher AKT phosphorylation level was associated with resistance to anti-EGFR agents. Therefore, we further performed drug combinations with anti-AKT agent (MK2206) and AKT1 gene editing, which demonstrated afatinib and allitinib sensitivity restored. Additionally, in silico analysis of TCGA database showed that AKT1 overexpression was present in 14.7% (41/279) of HNSCC cases, and was associated with perineural invasion in advanced stage. In conclusion, allitinib presented a greater cytotoxic profile when compared to afatinib and cetuximab. AKT pathway constitutes a predictive marker of allitinib response and combination with AKT inhibitors could restore response and increase treatment success.

MiR-21 as prognostic biomarker in head and neck squamous cell carcinoma patients undergoing an organ preservation protocol.

Despite progress in the treatment of head and neck squamous cell carcinoma (HNSCC) in recent decades, including new surgical techniques, radiotherapy advances and chemotherapy schedules, the prognosis for the affected patients has not improved at the same pace, and still, most HNSCC patients are diagnosed in advanced stages. To increase their survival, the development of better screening methods for early detection is required and appropriate tailored therapeutic interventions are desired. The aim of the present study was to evaluate miRNAs as prognostic biomarkers in patients undergoing organ preservation protocol for locally advanced HNSCC. For this purpose, we assessed the global miRNA expression profile of 15 HNSCC patients ('screening set') to identify miRNAs differentially expressed in responders and non-responders to therapy. Four miRNAs differentially expressed in HNSCC samples from the 'screening set' were validated in a different cohort of patients (47 samples - 'validation set'). The results from the 'validation set' showed that the higher expression of one of these miRNAs, miR-21, was negatively associated with the treatment response to the organ preservation protocol (p=0.029). A multivariate analysis showed that, in a model adjusted for age, tumor site, p16 immunoexpression and tumor resectability, high expression of miR-21 remained an independent predictor of poor response to the organ preservation protocol (OR=5.69; 95%CI 1.27-25.58; p=0.023), together with clinical stage IV (OR=5.05; 95%CI 1.22-20.88; p=0.025). Furthermore, considering the entire cohort, patients with high expression of miR-21 had worse survival. A multivariate Cox regression analysis also showed miR-21 (HR=2.05; 95%CI 1.05-4.02; p=0.036) and clinical stage IV (HR=3.17; 95%CI 1.49-6.77; p=0.003) as independent prognostic factors (model adjusted for age, tumor site, tumor resectability, and sets 'screening' or 'validation').In conclusion, the results of this study suggest that the evaluation of miR-21 expression could be an important tool for treatment planning and a prognosis predictior for HNSCC patients undergoing organ preservation protocols.

Evaluation of PD-L1 Expression in Tumor Tissue of Patients with Lung Carcinoma and Correlation with Clinical and Demographic Data.

Lung cancer is the leading world cause of cancer-related death, in both genders, and smoking is the main etiological factor. The discovery of immune checkpoints corroborates the hypothesis that ligands presented in tumors modulate the mechanisms of carcinogenesis and the immune activity of tumor microenvironment. Among the most studied coregulatory molecules, PD-1 (programmed cell death 1) and its ligand PD-L1 (programmed cell death 1 ligand 1) are noteworthy. The present study aims to enhance the understanding of the tumor microenvironment of lung cancer patients who underwent surgery, by means of analysis of PD-L1 expression in tumor cells and in intratumoral immune cells (IICs). It was found that PD-L1 expression was more frequent in tumor cells than in IICs. Collective analysis by Tissue Microarray Assay (TMA) for PD-L1 expression in tumor cells and IICs did not reproduce the findings for separate individual analysis of tumor tissues. Patients with past history of smoking were more likely to express PD-L1 in tumor cells than those who never smoked. Patients with past history of smoking were less likely to have PD-L1 positive IICs compared to those who had never smoked. The immunohistochemical expression of PD-L1 in tumor cells and IICs did not correlate with survival.

Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that activates downstream signaling pathways, including the Ras-MEK-Erk and PI3K-AKT pathways, leading to cell proliferation, resistance to apoptosis, angiogenesis and the ability to metastasize. EGFR overexpression is a significant finding in cancer, particularly in head and neck cancer, where it is also associated with a poor prognosis. In recent years, several molecules have been designed to inhibit EGFR activation. Among the many available anti-EGFR drugs, only cetuximab was approved for the treatment of head and neck cancers. However, no predictive biomarkers of cetuximab response are currently known. In the present review, we provide an updated assessment of EGFR biology and its clinical impact in head and neck cancers. A special emphasis is placed on novel patents of EGFR-inhibitors that are anticipated to diversify the anti-EGFR therapies available to treat head and neck cancers. In particular, we outline a new class of irreversible multi-target inhibitors (e.g. afatinib, icotinib, CUDC-101), which may significantly contribute to new head and neck cancer therapies.

Cytotoxicity of allitinib, an irreversible anti-EGFR agent, in a large panel of human cancer-derived cell lines: KRAS mutation status as a predictive biomarker.

BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the HER family of growth factors that activates several intracellular signaling pathways promoting proliferation and survival. EGFR over-expression is frequently associated with gene mutation or amplification, thereby constituting a major target for molecular therapies. Recently, a new generation of EGFR inhibitors has been developed with pan-HER properties and irreversible actions. Allitinib® (AST1306) is an orally active, highly selective irreversible inhibitor of the HER family of receptor tyrosine kinases with promising efficacies. In the present study we aimed to investigate the cytotoxicity of allitinib in a large panel of human cancer-derived cell lines and to correlate its efficacy to the mutational status of the EGFR, KRAS, BRAF, PI3KCA and PTEN genes. In addition, we aimed to evaluate the functional role of KRAS mutations in the response to this new inhibitor. RESULTS: In total 76 different cancer-derived cell lines, representing 11 distinct histological types, were analyzed and classified into three groups: highly sensitive (HS), moderately sensitive (MS) and resistant (R). We found that 28 (36.8 %) cancer-derived cell lines exhibited a HS phenotype, 19 (25.0 %) a MS phenotype and 29 (38.1 %) a R phenotype. Allitinib showed a stronger cytotoxicity in head and neck, esophageal, melanoma and lung cancer-derived cell lines. We found that KRAS mutations were significantly associated with the R phenotype. To substantiate these results, an allitinib-sensitive lung cancer-derived cell line (H292) was transfected with plasmids carrying the two most common activating KRAS mutations (p.G12D and p.G12S). We found that both mutations reverted the allitinib-sensitive phenotype in these cells. CONCLUSIONS: The current study represents the largest in vitro assessment of allitinib cytotoxicity performed to date. Through this study, we identified cancer types that could potentially benefit from this drug. Additionally, our findings suggest that prevalent KRAS mutations constitute potential predictive biomarkers for allitinib response.

Efficacy and safety of a cisplatin and paclitaxel induction regimen followed by chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma.

BACKGROUND: The purpose of this phase II trial was to evaluate the tolerability, safety, and efficacy of a non-5-fluorouracil (5-FU)-based induction chemotherapy followed by chemoradiotherapy (CRT) for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Sixty patients with stage III to IV HNSCC were treated with induction paclitaxel and cisplatin (TP; paclitaxel 175 mg/m(2) and cisplatin 80 mg/m(2) , 3 cycles) followed by CRT (cisplatin 100 mg/m(2) ; D1, 22, and 43 of radiotherapy). RESULTS: Fifty-six patients (93.3%) completed 3 cycles of induction TP (no treatment-related deaths), 52 (86.7%) completed definitive CRT per protocol (adverse event [AE] grade ≥2 in 53.3%). The overall response rate after induction TP was 82.5% for patients with resectable disease and 55.5% for unresectable disease (p = .023), and complete response (CR) rate after CRT was 70.0% for patients with resectable disease and 30.0% for unresectable disease (p = .005). CONCLUSION: Induction TP followed by cisplatin based-CRT was well-tolerated, safe, and had high overall response rate in selected patients with locally advanced HNSCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E970-E980, 2016.

Overexpression of the ITGAV gene is associated with progression and spread of colorectal cancer.

BACKGROUND/AIM: The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. We evaluated the relationship between the expression of SPARC, ITGAV, THBS1 and VCAM-1 genes of extracellular matrix in the progression and dissemination of colorectal cancer (CRC). PATIENTS AND METHODS: Adult patients (N=114) underwent resection of CRC. Gene expression in CRC was determined by quantitative real-time polymerase chain reaction (PCR). Protein expression was analyzed by immunohistochemistry (IHC). Correlation with pathway-related molecules (p53, Bcl-2, Ki-67, EGFR and VEGF) was assessed. RESULTS: Tumors with perineural invasion showed overexpression (p=0.028) of the ITGAV gene with regard to cancers without perineural invasion and validation of the result through IHC expression of the corresponding proteins, was significant for the expression of ITGAV protein (p=0.001). CONCLUSION: The overexpression of ITGAV gene was associated with higher progression and spread of CRC via perineural invasion.

Performance of a modified MASCC index score for identifying low-risk febrile neutropenic cancer patients.

GOALS OF WORK: This is a prospective and observational study comparing the efficacy of risk-assessment models in patients with neutropenic fever in a reference treatment center. The meaning of the complex infection was evaluated. MATERIALS AND METHODS: Patients were recruited throughout a 9-month period. Inclusion criteria were histologic diagnosis of malignancy, neutropenic febrile secondary to chemotherapy and/or radiotherapy (absolute neutrophil count of <500/microl and axillary temperature > or = 38 degrees C), and > or = 18 years of age. MAIN RESULTS: Fifty-three febrile neutropenic patients were included. Twenty one of them were classified as low risk by the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the MASCC risk-index scores were, respectively 87.9, 85.0, 90.6, 80.9, and 86.8%. None of the low-risk patients died, but four patients classified as low risk by the MASCC model developed serious medical complications during febrile neutropenic episodes. When we subtracted patients with complex infections from the group of patients with the MASCC risk-index score of > or = 21, we got 15 patients that were classified as low risk by a proposed adjustment by complex infection (PACI) model. None of them developed serious medical complications. The sensitivity, specificity, PPV, NPV, and the accuracy of this new model were, respectively, 100, 75.0, 86.8, 100, and 90.6%. CONCLUSION: The MASCC risk-index score had high sensitivity and specificity to predict the absence of complications, but the PACI model was better than MASCC for predicting the absence of complications in this febrile neutropenic patients.