Efficacy and Safety of Neoadjuvant Treatment with Bevacizumab, Liposomal Doxorubicin, Cyclophosphamide and Paclitaxel Combination in Locally/Regionally Advanced, HER2-Negative, Grade III at Premenopausal Status Breast Cancer: A Phase II Study.

BACKGROUND: In the era of personalized therapy, targeted treatment in specific patient populations is mandated. OBJECTIVE: We evaluated the efficacy and safety of neoadjuvant treatment on locally advanced breast cancer (LABC) with a monoclonal agent against vascular endothelial growth factor (VEGF), bevacizumab plus chemotherapy combination of liposomal doxorubicin, cyclophosphamide and paclitaxel (PLAC-B). METHODS: Patients enrolled were at premenopausal status and characterized by human epidermal growth factor receptor 2 (HER2)-negative, hormone-receptor positive (estrogen receptor/progesterone receptor-positive [ER/PR+]) or triple-negative (TNBC), LABC (T > 3 cm), with high-grade ductal carcinoma. Patients had to have a measurable disease and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, with adequate hematologic, renal, and hepatic function. Patients received intravenous liposomal doxorubicin 30 mg/m2, cyclophosphamide 600 mg/m2, paclitaxel 120 mg/m2, and bevacizumab 8 mg/kg on day 1 of 15-day cycles for four cycles (four administrations as neoadjuvant treatment). The primary endpoint was complete clinical (cCR) and pathologic (pCR) response rates, while secondary endpoints included safety, breast-conserving surgery (BCS) conversion rate, and disease-free survival (DFS). RESULTS: Sixty-two women were enrolled; 20 were ER/PR+ and 42 had TNBC. All underwent surgery, six received mastectomy, and 56 (90.3%) received BCS, with an equal conversion rate from initial indication for mastectomy. cCR was 25.8%. pCR in the breast and axilla occurred in 24 patients (38.7%). pCR was 42.9% for TNBC and 30% for ER/PR+. Hematologic adverse events (AEs) included neutropenia (74.2% total; 22.6% grade 3 [G3]) and febrile neutropenia (6.5% G3); non-hematologic G3 AEs included nausea (6.5%), mucositis (9.7%), and infection (3.2%), all of which were managed without negative sequelae. Over a 3-year follow-up, all patients were alive and DFS was 87.1%. CONCLUSION: PLAC-B as neoadjuvant treatment of this subpopulation with TNBC and ER/PR+ patients is effective and safe. Further studies are necessitated.

Protein and mRNA expression of notch pathway components in operable tumors of patients with laryngeal cancer.

BACKGROUND: There exist substantial evidence that laryngeal cancer represents a unique entity among squamous head and neck carcinomas. MATERIALS AND METHODS: Tumors from 289 patients with squamous cell laryngeal cancer were assessed for protein (immunohistochemistry) and mRNA (qRT-PCR) expression of Notch pathway components (Notch1 to 4 receptors and Jagged1 ligand) on tissue microarrays. RESULTS: In univariate analysis, enhanced nuclear Jagged1 expression conferred a longer disease-free survival (DFS) (p=0.013) and overall survival (OS) (p=0.004), in contrast to the unfavorable prognostic value of Notch3 for both DFS (p=0.009) and OS (p=0.024). In multivariate analysis, overexpression of either Notch or cytoplasmic Jagged1 conferred an unfavorable effect on DFS (Hazard Ratio=1.88, 95% Confidence Interval=1.03-3.43, p=0.04). CONCLUSION: Our study indicates a consistent unfavorable effect of Notch3 and cytoplasmic Jagged1 protein expression, a favorable impact of nuclear Jagged 1 localization, and a differential prognostic value of Notch2 expression according to the presence of cytoplasmic Jagged 1.

Lack of association between KRAS mutations and 18F-FDG PET/CT in Caucasian metastatic colorectal cancer patients.

BACKGROUND: Although Kirsten rat sarcoma (KRAS) gene mutational testing is essential for the optimal design of therapeutic strategies for colorectal cancer, it is not always feasible or reliable. In this retrospective study, we examined whether (18)F-Fluorodeoxyglucose positron-emission tomography/computed tomography ((18)F-FDG PET/CT) scans can serve as a surrogate examination for KRAS mutational testing. PATIENTS AND METHODS: KRAS codon 12 and 13 mutational status was tested in 44 colorectal primary tumors and was compared with the (18)F-FDG PET/CT maximum standardized uptake value (SUVmax) values of the respective metastatic lesions. Glucose transporter-1 (GLUT1) mRNA levels were also measured in colorectal primary tumors. RESULTS: No statistically significant correlation between (18)F-FDG PET/CT SUVmax values and KRAS mutation status was found (parametric t-test: p=0.4753; non-parametric Kruskal-Wallis test: p=0.51). This result cannot be attributed to the effect of differing GLUT1 mRNA levels, as shown by multivariate analysis. CONCLUSION: Our study failed to promote (18)F-FDG PET/CT uptake as a surrogate examination for KRAS mutation testing.

Prognostic significance of the Wnt pathway in squamous cell laryngeal cancer.

OBJECTIVES: We sought to determine the prognostic significance of the Wnt signaling pathway in operable squamous cell carcinoma of the larynx. MATERIALS AND METHODS: In an annotated cohort of 289 operable laryngeal cancers we evaluated the prognostic impact of E-cadherin, P-cadherin and ß-catenin protein expression with immunohistochemistry, as well as the mRNA expression of 7 key effectors of the Wnt pathway including secreted frizzled-related protein 4 (SFRP4), SNAI2 (SLUG) and WNT5A with qPCR (relative quantification [RQ]). RESULTS: Using median immunoreactive scores as a pre-defined cut-off, patients whose tumors overexpressed both cytoplasmic E-cadherin and ß-catenin experienced longer median OS as compared to those whose tumors overexpressed ß-catenin only (median OS 124 vs. 72 months, p=0.0301) and patients whose tumors overexpressed both cytoplasmic and membranous E-cadherin experienced longer DFS as compared to those whose tumors overexpressed cytoplasmic E-cadherin only (median 118 vs. 91 months, p=0.0106). Upon hierarchical clustering of SFRP4, SNAI2 and WNT5A RQ values, profiles including co-expression of all 3 genes but also profiles with under-expression of SNAI2 and WNT5A were associated with worse outcome as compared to profiles not related to the Wnt pathway. In multivariate analysis, clustering was an independent predictor for DFS (p=0.0221) and OS (p=0.0077). CONCLUSION: We identified gene expression profiles and IHC patterns associated with aberrant Wnt signaling conferring aggressive clinical behavior in operable squamous cell carcinoma of the larynx. Prospective validation of these results will determine whether targeting the Wnt pathway merits investigation in this disease.

The prognostic significance of WNT pathway in surgically-treated colorectal cancer: ß-catenin expression predicts for disease-free survival.

BACKGROUND: The wingless-type MMTV integration site family of proteins (WNT) pathway is highly involved in colorectal cancer development. The aim of this study was to explore the prognostic significance and clinicopatological correlations of this pathway in a cohort of surgically-treated patients with non-metastatic colorectal cancer in relation to the site of expression of pathway proteins. MATERIALS AND METHODS: Immunohistochemical expression of nuclear cyclin D1, membranous E-cadherin and P-cadherin, membranous and nuclear ß-catenin in the invasive front (IF), the tumor center (TC), as well as their mean, were assessed in 106 paraffin-embedded tissue samples. Adenomatous Polyposis Coli (APC), Axin-2 (AXIN2), cyclin-D1 (CCND1), Matrix Metalloproteinase-7 (MMP7), Secreted Frizzled Related Protein (SFRP) 1, 2 and 4 and WNT5A were evaluated by RT PCR. RESULTS: Membranous ß-catenin expression was statistically reduced in the IF. Cyclin-D1 was reduced in tumors arising closer to the rectum. Reduced nuclear expression of cyclin-D1 in the IF was associated with lymphatic, venous and perineural invasion. Loss of membranous ß-catenin in the TC was more common among N2 tumors. Higher SFRP4 mRNA was associated with advanced T stage. In univariate analysis, membranous expression of ß-catenin in TC and IF, and their mean, was associated with longer disease-free survival (DFS). In multivariate analysis, tumor stage and mean ß-catenin expression were prognostic for longer DFS (hazard ratio=0.33; p=0.01). ß-Catenin expression in the IF remained significant when the mean expression was not included in the multivariate analysis (hazard ratio=0.41; p=0.028). CONCLUSION: Mean membranous expression of ß-catenin, as well as that in the IF, is prognostic for longer DFS in patients with non metastatic colorectal cancer.

Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary.

BACKGROUND: Cancer of unknown or uncertain primary is a major diagnostic and clinical challenge, since identifying the tissue-of-origin of metastases is crucial for selecting optimal treatment. MicroRNAs are a family of non-coding, regulatory RNA molecules that are tissue-specific, with a great potential to be excellent biomarkers. METHODS: In this study we tested the performance of a microRNA-based assay in formalin-fixed paraffin-embedded samples from 84 CUP patients. RESULTS: The microRNA based assay agreed with the clinical diagnosis at presentation in 70% of patients; it agreed with the clinical diagnosis obtained after patient management, taking into account response and outcome data, in 89% of patients; it agreed with the final clinical diagnosis reached with supplemental immunohistochemical stains in 92% of patients, indicating a 22% improvement in agreement from diagnosis at presentation to the final clinical diagnosis. In 18 patients the assay disagreed with the presentation diagnosis and was in agreement with the final clinical diagnosis, which may have resulted in the administration of more effective chemotherapy. In three out of four discordant cases in which supplemental IHC was performed, the IHC results validated the assay's molecular diagnosis. CONCLUSIONS: This novel microRNA-based assay shows high accuracy in identifying the final clinical diagnosis in a real life CUP patient cohort and could be a useful tool to facilitate administration of optimal therapy.

Expression profiling of 21 biomolecules in locally advanced nasopharyngeal carcinomas of Caucasian patients.

BACKGROUND: Since scarce data exist on the pathogenesis of nasopharyngeal carcinoma in Caucasian patients, we attempted to elucidate the responsible molecular pathways in this patient population. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples from 107 patients, diagnosed with locally-advanced nasopharyngeal carcinoma and treated with chemotherapy or chemo-radiotherapy, were analyzed by immunohistochemistry for the expression of the following proteins: E-cadherin, P-cadherin, Fascin-1, Cyclin D1, COX-2, EGFR, VEGF-A, VEGF-C, VEGFR-2, VEGFR-3, ERCC1, p53, p63, Ki67, MAPT, phospho-p44/42MAPK, PTEN, phospho-AKT, phospho-mTOR, and phospho-GSK-3ß. EBER status was assessed by in situ hybridization. The majority of the cases were included in tissue microarray. All stains were performed and assessed centrally by two pathologists. The median follow-up time was 76.8 (42.3 - 99.2) months. RESULTS: Biomolecules expressed in >90% of cases were: p53, COX-2, P-cadherin, EBER, phospho-GSK-3ß, and Fascin-1. WHO II+III tumors were more frequently EBER & PTEN positive and VEGF-A negative. Advanced age was significantly associated with positive phospho-GSK-3ß and ERCC1 expression; male gender with positive phospho-AKT and phospho-p44/42MAPK; and worse performance status (1 or 2) with negative Ki67, ERCC1, PTEN, and phospho-mTOR expression. Earlier disease stage was closely associated with p63, MAPT, PTEN, and Cyclin D1 positivity. Univariate Cox regression analysis highlighted Cyclin D1 as a negative prognostic factor for disease-free survival (p=0.034) and EBER as a positive one for overall survival (p=0.048). In multivariate analysis, advanced age and stage, poor performance status, and positive ERCC1 emerged as predictors of worse disease-free and overall survival, as opposed to positive phospho-mTOR. Clustering analysis defined two protein-expression groups being predictive of better overall survival (p=0.043). CONCLUSIONS: Our study is the first to examine the activation and interaction of established biomolecules and signaling pathways in Caucasian NPC patients in an effort to reveal new therapeutic targets.

Global microRNA profiling in favorable prognosis subgroups of cancer of unknown primary (CUP) demonstrates no significant expression differences with metastases of matched known primary tumors.

No data exist on biologic differences between Cancer of unknown primary (CUP) and metastatic solid tumors of known primary site. We assigned a primary tissue of origin in 40 favorable CUP patients (A: serous peritoneal carcinomatosis n = 14, B: axillary adenocarcinoma n = 8, C: upper squamous cervical adenopathy n = 18) by means of a 64-microRNA assay. Subsequently, we profiled the expression of 733 microRNAs (miRs) in the CUP cases and compared results with metastases from 20 ovarian carcinomas, 10 breast adenocarcinomas, 20 squamous head neck or lung tumors. In the Peritoneal CUP versus Ovarian (Known Primary Metastases) KPM comparison, a total of 12 miR were significantly differentially expressed: higher than twofold expression difference in CUP was seen only for miR-513a-5p (3.7-fold upregulated) and miR-483-5p (2.5-fold upregulated), while miR-708 exhibited a twofold downregulation. In the Breast CUP versus Breast KPM comparison, only miR-29c that were downregulated in CUP by 2.7-fold satisfied the FDR threshold. miR-30e and miR-27b, downregulated in ovarian CUPs versus KPMs, were also non-significantly downregulated in breast CUP by 2.0- and 1.4-fold respectively. Six miRs, which belong to the 17-92 oncocluster showed a trend of upregulation in Breast CUP versus Breast KPM cases. A CUP signature remains elusive.

Expression of DNA repair and replication genes in non-small cell lung cancer (NSCLC): a role for thymidylate synthetase (TYMS).

BACKGROUND: BRCA1 (B), ERCC1 (E), RRM1 (R) and TYMS (T) mRNA expression has been extensively studied with respect to NSCLC patient outcome upon various chemotherapy agents. However, these markers have not been introduced into clinical practice yet. One of the reasons seems to be lack of a standard approach for the classification of the reported high/low mRNA expression. The aim of this study was to determine the prognostic/predictive impact of B, E, R, T in routinely-treated NSCLC patients by taking into account the expression of these genes in the normal lung parenchyma. METHODS: B, E, R, T mRNA expression was examined in 276 NSCLC samples (real-time PCR). The normal range of B, E, R, T transcript levels was first determined in matched tumor - normal pairs and then applied to the entire tumor series. Four main chemotherapy categories were examined: taxanes-without-platinum (Tax); platinum-without-taxanes (Plat); taxanes/platinum doublets (Tax/Plat); and, all-other combinations. RESULTS: In comparison to remotely located normal lung parenchyma, B, E, R, T mRNA expression was generally increased in matched tumors, as well as in the entire tumor series. Therefore, tumors were classified as expressing normal or aberrant B, E, R, T mRNA. In general, no marker was associated with overall and progression free survival (OS, PFS). Upon multivariate analysis, aberrant intratumoral TYMS predicted for shorter PFS than normal TYMS in 1st line chemo-naïve treated patients (p = 0.012). In the same setting, specific interactions were observed for aberrant TYMS with Plat and Tax/Plat (p = 0.003 and p = 0.006, respectively). Corresponding patients had longer PFS in comparison to those treated with Tax (Plat: HR = 0.234, 95% CI:0.108-0.506, Wald's p < 0.0001; Tax/Plat: HR = 0.242, 95% CI:0.131-0.447, Wald's p < 0.0001). Similar results were obtained for PFS in 1st line chemo-naïve and (neo)adjuvant pre-treated patients. Adenocarcinoma, early disease stage, and treatment with Tax/Plat doublets independently predicted for prolonged OS in patients who received only one line of treatment (adjuvant or 1st line). CONCLUSION: Classifying intratumoral B, E, R, T mRNA expression in comparison to normal lung may facilitate standardization of these parameters for prospective studies. With this approach, NSCLC patients with aberrant intratumoral TYMS expression will probably fare better with platinum-based treatments.

Topotecan and pegylated liposomal doxorubicin combination as palliative treatment in patients with pretreated advanced malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive disease with poor or modest responses to chemotherapy and dismal prognosis. In most of the cases the scope of the treatment is only palliative. In the current study, the combination of i.v. topotecan and pegylated liposomal doxorubicin (PLD) in advanced multi-treated MPM was tested. Primary objective was palliation of the symptoms, with the secondary ones being the establishment of the regimen's safety and efficacy. PATIENTS AND METHODS: Nine patients were enrolled (7 males/2 females, median age 57.5 years, ECOG performance status ≤ 2), having progressed after 2 or 3 lines of chemotherapy including pemetrexed and cisplatin. Main symptoms were dyspnea, cough, chest pain, fatigue, and anorexia. The treatment included topotecan 1.2 mg/m2 i.v. on Days 1 - 3 and PLD 40 mg/m2 on Day 4, every 28 days. The patients received 4 - 8 chemotherapy cycles (median 5.8). RESULTS: In all cases, symptoms were significantly improved after the 2nd treatment cycle. Respiratory function tests showed considerable enhancement, while cough and pain were drastically reduced. All patients had objective clinical benefit, 1 patient achieving partial response and 8 stable disease. Median time to progression and overall survival was 7 and 9 months, respectively. The chosen dose of the topotecan/ PLD combination was well-tolerated with no Grade 3/4 toxicities. Quality of life, as it was evaluated by the QLQ-C30 and QLQLC13 questionnaires, had improved scores especially the ones referring symptomatology. CONCLUSION: The current study shows a significant palliative effect of the topotecan/ PLD combination in pretreated patients with advanced MPM.

Profiling immunohistochemical expression of NOTCH1-3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary.

Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation.

Immunohistochemical study of the epithelial-mesenchymal transition phenotype in cancer of unknown primary: incidence, correlations and prognostic utility.

BACKGROUND: The epithelial to mesenchymal transition (EMT) has been associated with metastatic dissemination and poor outcome in several solid tumour types. Our aim was to study its incidence and its prognostic significance in cancer of unknown primary (CUP). PATIENTS AND METHODS: One hundred tumour samples of CUP were loaded in tissue microarrays and were studied for immunohistochemical (IHC) expression of E-cadherin, N-cadherin, vimentin, the EMT transcription factor (SNAIL) and the stem cell marker octamer-binding transcription marker 4(OCT4). An EMT phenotype was defined as low expression of E-cadherin, expression of N-cadherin with/without vimentin with concomitant expression of SNAIL, as assessed by percentage of tumour cell staining. RESULTS: Among 100 CUP cases, the histological diagnosis was adenocarcinoma in 55, squamous carcinoma in 20 and undifferentiated carcinoma in 15, with a high grade seen in 46. Therapy consisted of palliative chemotherapy, mostly platinum based. The median progression-free survival and overall survival (OS) were 7 and 12 months respectively. Distributional studies resulted in selection of IHC cut-offs for E-cadherin (negative when expressed in <60% of tumour cells), N-cadherin, vimentin (positive when expressed in ≥40% of tumour cells), SNAIL (positive when stained in ≥80% of tumour cells). An EMT phenotype was observed in 8 cases (8.1%) and was strongly associated with poor OS (median OS EMT(-)=13 months vs. median OS EMT(+)=8 months, p=0.023). When we used staining intensity (H-Score), an EMT phenotype was observed in 16 patients and carried borderline adverse prognostic utility for outcome (median OS 9 vs. 14 months, p=0.07). The presence of the EMT phenotype correlated significantly with male gender, high grade and presence of visceral metastases (χ(2) p<0.05), while EMT mediator expression was correlated to high NOTCH 2/3 expression. Other factors, prognostic for poor survival, were male gender, PS≥2, non-platinum therapy (χ(2) p<0.05). CONCLUSION: EMT is infrequently seen in tumours of CUP. However, an adverse prognostic significance for patient outcome has been identified and may warrant studies of therapeutic targeting.

Profiling clinical cancer research across the Atlantic: a review of research and its characteristics presented at ASCO and ESMO Congresses during the last decade.

INTRODUCTION: The comparison of clinical cancer research characteristics across the Atlantic and their evolution over time have not been studied to date. METHODS: We collected oral presentations on breast, lung and colorectal cancer at ASCO (n=506) and ESMO (n=239) Congresses in years 2000-2010. RESULTS: EU-originated research constituted 52% of all ASCO presentations while US-research 26.7% of ESMO Congress presentations. Industry sponsorship was reported in 24.8% of ASCO vs. 31.8% of ESMO Congress trials. ASCO-presented trials were larger with longer follow-up periods but were blinded less often. ESMO-presented trials used Event-Free Survival (EFS, 38.1%) and Surrogate (18.4%) primary endpoints and reported positive primary endpoints (65%) more often than ASCO-presented trials. Interim analysis resulted in discontinuation of a trial more often at ASCO Congress (8.3% vs. 3.2%). ASCO Congress-presented research was more often published (69.2% vs. 59.8% at ESMO) at higher impact factor journals. Strong trends over the decade were seen for more frequent industry sponsorship, blinded design, larger sample size, early interim discontinuation, use of EFS endpoints and biomarker evaluation. CONCLUSIONS: Cancer clinical research is a complex scientific activity with common global but also distinct characteristics at the two sides of the Atlantic.

Role of chemotherapy in the management of soft tissue sarcomas.

Soft tissue sarcomas are a diverse group of rare tumors that comprise 1% of all cancers. Few randomized trials of chemotherapy have been performed but there is a clear role for agents such as doxorubicin and ifosfamide in the palliation of advanced disease. There is uncertainty as to whether sequential single-agent treatment is equivalent to combination chemotherapy. For the majority of histological subtypes adjuvant chemotherapy is not of proven value, although there may be situations where it is advantageous. However, there are other subtypes, such as the Ewing's sarcoma family tumors, for which chemotherapy is an essential part of primary management and has definitely improved survival. Apart from Ewing's sarcoma family tumor and rhabdomyosarcoma, there is increasing specialization of chemotherapy according to histological subtype, such as the use of taxanes for angiosarcoma, gemcitabine and docetaxel for leiomyosarcoma, and trabectedin for leiomyosarcoma and liposarcoma, especially the myxoid/round cell variant. Nevertheless, there are serious limitations to existing treatment and novel therapies need to be developed.

Aberrant p16 promoter methylation among Greek lung cancer patients and smokers: correlation with smoking.

Genetic and environmental factors (dietary and smoking) influence lung cancer epidemiology and induce epigenetic modifications that should be assessed in individual populations. We analyzed p16 methylation among Greek non-small cell lung carcinoma patients and smokers using two-stage methylation-specific polymerase chain reaction. One hundred and fifty specimens from cancerous and adjacent non-cancerous tissue, bronchial washings and sputum from patients and 48 specimens, mostly sputum, from disease-free smokers were included. p16 methylation was very frequent in biopsies (82.85%) and bronchial washings (non-small cell lung carcinoma, 80.35%; small cell lung carcinoma, 16.66%) from patients, but also in adjacent non-cancerous tissue (45.71%). Concordance of p16 methylation and positivity by cytological examination was 51.78%. Methylation was also observed in sputum from asymptomatic cytology-negative smokers (22.5%) and chronic obstructive pulmonary disease patients (three of eight). Among disease-free individuals, methylation correlated only with heavy smoking (>50 pack-years, P<0.001) and differed among male and female disease-free smokers. In summary, p16 methylation is very frequent among non-small cell lung carcinoma patients, and correlates with heavy cigarette consumption only in disease-free smokers.

Brain metastasis in renal cell cancer responding to sunitinib.

BACKGROUND: Sunitinib (SU011248; Sutent) is a new small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases (RTKs), with established antitumor activity in renal cancer. In the current report, we describe a patient with a solitary brain metastasis from renal cell carcinoma who achieved partial response of the cerebral lesion following treatment with sunitinib. To the best of our knowledge, this is the first report of sunitinib activity in brain metastases from kidney cancer. A limited number of publications support the hypothesis that small tyrosine kinase inhibitors may cross the blood-brain barrier. Although the role of sunitinib in advanced renal carcinoma has been evaluated through prospective trials, the efficacy of the drug in patients with brain metastases has not been explored, since patients with cerebral lesions were excluded in those studies. Thus, we believe that accumulating evidence from personal experience or limited reports could be useful. Moreover, in our case, sunitinib was found to be safe, leading to considerable shrinkage of the brain metastasis without any serious adverse events or central nervous system toxicities. We consider this observation to be important, given the absence of data regarding the activity of the drug in this particular clinical setting.