Search

Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy.Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling.Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS.Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

Airway examination techniques are procedures that can potentially transmit infectious diseases to both patients and healthcare professionals who perform them, by various mechanisms. The pandemic situation due to the COVID-19 disease has practically halted most of the activity of the clinics and laboratories of pulmonary and nasal function, with clear recommendations in this regard. Being already in the early stages after the peak of the pandemic, we still do not know for sure what its consequences will be in the short or long term, since there are important gaps in the knowledge of aspects as fundamental as the transmission mechanisms of the virus, its pathophysiology and immune response or its diagnosis. In this review we will examine the different examination techniques available on the assessment of patients suffering from respiratory allergy, asthma and associated diseases, int the postpandemic momentum, highlighting their possible advantages and disadvantages. For this reason, we wanted to focus on exploring the entire upper and lower airways, from the perspective of the safety of both the healthcare professionals and patients and their specific characteristics. And at the same time we will approach the analysis of the intrinsic value that these interventions provide from the point of view of both diagnosis and management of these patients. The changing situation of this disease may cause some modifications of the assertions presented in this review in the future.While this guidance seeks to ensure a consistent wide approach, some differences in operational details may be applied due to local regulations.

Purpose: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including alpha-fetoprotein and/or beta-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. Materials and Methods: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. Results: The elevated prechemotherapy tumor markers were alpha-fetoprotein in 48% of cases, beta-human chorionic gonadotropin in 14%, and alpha-fetoprotein and beta-human chorionic gonadotropin in 38%. Median alpha-fetoprotein and beta-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. Conclusions: Stage IS testicular cancer is more commonly associated with elevated alpha-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

Data regarding management of frail patients with pancreatic ductal adenocarcinoma practice is currently very scarce. Randomized clinical trials usually exclude these subgroup of patients and the majority of the publications only consider chronological age and ECOG performance status for their classification. Therefore, the current available data do not reflect daily clinical practice. Only data from a phase two study (FRAGANCE study), designed to select a tolerable dose-schedule of nab-placitaxel + gemcitabine (Phase one) and to evaluate the efficacy of the selected regimen (Phase two) in patients with ECOG-2 and previously untreated advanced PDAC, are currently available. Management of these particular patients is exceedingly complex and requires collaboration of multidisciplinary teams and intensive support treatment. This article reviews the literature available regarding the management of the so-called frail patients and provide guidance for chemotherapy as well as supportive care treatments.

Farmers constitute a large professional group worldwide. In developed countries farms tend to become larger, with a concentration of farm operations. Animal farming has been associated with negative respiratory effects such as work-related asthma and rhinitis. However, being born and raised or working on a farm reduces the risk of atopic asthma and rhinitis later in life. A risk of chronic bronchitis and bronchial obstruction/COPD has been reported in confinement buildings and livestock farmers. This position paper reviews the literature linking exposure information to intensive animal farming and the risk of work-related respiratory diseases and focuses on prevention. Animal farming is associated with exposure to organic dust containing allergens and microbial matter including alive microorganisms and viruses, endotoxins and other factors like irritant gases such as ammonia and disinfectants. These exposures have been identified as specific agents/risk factors of asthma, rhinitis, chronic bronchitis, COPD and reduced FEV1. Published studies on dust and endotoxin exposure in livestock farmers do not show a downward trend in exposure over the last 30 years, suggesting that the workforce in these industries is still overexposed and at risk of developing respiratory disease. In cases of occupational asthma and rhinitis, avoidance of further exposure to causal agents is recommended, but it may not be obtainable in agriculture, mainly due to socio-economic considerations. Hence, there is an urgent need for focus on farming exposure in order to protect farmers and others at work in these and related industries from developing respiratory diseases and allergy.

BACKGROUND Allergic diseases are highly prevalent in industrialized populations. In Spain, children suspected of having an allergic disease are usually referred by their primary care pediatrician to an allergy unit at a general hospital or a children's hospital. We report data from a subanalysis of the pediatric population in Alergologica 2015. METHODS Data were collected from pediatric patients (age, ≤14 years) consulting an allergist for the first time in 2014 and the first quarter of 2015 in order to determine variations compared with data reported in Alergologica 2005. RESULTS Alergologica 2015 included fewer pediatric patients than Alergologica 2005. The study population comprised 481 patients aged ≤14 years from more than 200 centers throughout Spain. Males accounted for 56.5%. Rhinoconjunctivitis was the main reason for consulting an allergist (53.8% vs 46.3% in 2005), followed by asthma (30.2% vs 34.6%), and food allergy (20.0% vs 14.5%). CONCLUSIONS The findings of Alergologica 2015 show a notable increased frequency of allergic rhinitis, drug allergy, and food allergy. The frequency of other allergic conditions remained unchanged, except for asthma, whose frequency decreased, as in adult patients.

Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 × 10-23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 × 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT.

Background: Chronic spontaneous urticaria (CSU) is a frequent clinical entity that often presents a diagnostic and therapeutic challenge. Objective: To explore the degree of agreement that exists among the experts caring for patients with CSU diagnosis, evaluation, and management. Methods: An online survey was conducted to explore the opinions of experts in CSU, address controversial issues, and provide recommendations regarding its definition, natural history, diagnosis, and treatment. A modified Delphi method was used for the consensus. Results: The questionnaire was answered by 68 experts (dermatologists, allergologists, and primary care physicians). A consensus was reached on 54 of the 65 items posed (96.4%). The experts concluded that CSU is a difficult-to-control disease of unpredictable evolution. Diagnostic testsshould be limited and based on clinical history and should not be indiscriminate. Autoinflammatory syndromes and urticarial vasculitis must be ruled out in the differential diagnosis. A cutaneous biopsy is only recommended when wheals last more than 24h, to rule out urticarial vasculitis. The use of specific scales to assess the severity of the disease and the quality of life is recommended. In patients with severe and resistant CSU, second -generation H1 -antihistamines could be used at doses up to four times the standard dose before giving second-line treatments. Omalizumab is a safe and effective treatment for CSU that is refractory to H1 -antihistamines treatment. In general, diagnosis and treatment recommendations given for adults could be extrapolated to children. Conclusions: This work offers consensus recommendations that may be useful in the management of CSU. (C) 2016 SEICAP. Published by Elsevier Espana, S.L.U. All rights reserved.

This is a post hoc analysis of biomarkers from a large cohort of patients with chemo-naive metastatic colorectal cancer. Both high baseline circulating tumor cell count and RAS mutated were associated with clinical or pathologic features classically associated with poor prognosis. Selection of high- and low-risk populations may help to individualize approaches in the future. Background: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naive metastatic CRC population. Patients and Methods: A total of 1202 patients from the Spanish VISNU-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNU-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients. Results: Interestingly, 41% of the population studied presented >= 3 bCTC count. bCTC count >= 3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels. Conclusions: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naive metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors. (C) 2020 Elsevier Inc. All rights reserved.

Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, it represents the sixth cause of cancer death. In Western countries, the incidence is decreasing slightly, with an increase in gastroesophageal junction adenocarcinoma (GEJA), a different entity that we separate specifically in the guideline. Molecular biology advances have been done recently, but do not yet lead to the choice in treatment approach except in advanced disease with overexpression of HER2. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors and preliminary immune therapy resulting in advanced disease are the main treatment innovations in the GC/GEJA treatment. We describe the different evidences and recommendations following the statements of the American College of Physicians.

Introduction: In colorectal cancer, anti-VEGF agents have demonstrated a survival benefit when combined with chemotherapy. However, development of resistance is very common. One of the mechanisms i...

Summary Background Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. Methods This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov , NCT02301143 , and EudraCT, 2014-001408-23 and is complete. Findings Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3–10·1); median progression-free survival was 10·9 months (90% CI 9·3–11·6), and median overall survival was 18·8 months (90% CI 15·0–24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3–83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6–41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. Interpretation The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Funding Celgene.

Neuroendocrine pancreatic tumors (PanNETs) are graded on the basis of their proliferative activity. Cytological samples are commonly the only samples available, but the determination of Ki-67 in cytology and its reliability as a measure of tumor mitotic activity is not well settled. We have retrospectively reviewed all the cases of FNA under EUS control of PanNETs in a 10-year period (2006-2016) in the Hospital Clínico San Carlos (Madrid). We identified 10 PanNET cases with histological correlation. Median age was 49.4 years and the patients were mainly women. PanNETs were located more frequently in the tail of the pancreas, with a median size of 33.8 mm. None of our cases was a grade 3 tumor. The seven grade 1 tumors confirmed in histology had consistent Ki-67 in cytology. In three cases (30 %), there were discrepancies between the Ki-67 index measured in cytology and histology, and the differences ranged from 2 to 15 %; all these cases were grade 2 tumors in histology and were graded as grade 1 tumors in FNA material. Our results are consistent with previous studies which showed understaging when tumor grade was assessed in cytological samples, mainly in G2 tumors. Previous literature has shown that Ki-67 assessment in EUS-FNA samples is a useful tool to rule out G3 tumors, but can be problematic for distinguishing G1 and G2 tumors.

Background Providing adjuvant chemotherapy in locally advanced rectal cancer after neoadjuvant chemoradiation is currently a matter of debate. Recommendations from clinical guidelines range from offering no treatment to oxaliplatin-based combinations. We present a risk-adapted approach based on the response to initial chemoradiation as the strongest prognostic factor for disease-free survival (DFS). Patients and Methods One hundred one patients were treated at a single institution with preoperative long-course radiotherapy plus concurrent fluoropyrimidines. Patients with disease downstaged to pT0-2N0 received adjuvant fluoropyrimidines alone, while the remaining received an oxaliplatin-based combination. The primary study end point was 5-year DFS. Results Overall, the disease of 54 patients was downstaged to pT0-2N0 (53.5%), while that of 47 patients was staged as pT3-4 or N+ (46.5%) after surgery. In the intention-to-treat analysis, 5-year DFS for patients in the good-prognosis group (downstaging to pT0-2 N0) and for those with poor prognosis (pT3-4 or N+) were 79.4% and 66.3%, respectively (hazard ratio, 0.489; P = .043). Downstaging and pN+ were independent prognostic factors for DFS. Conclusion A risk-adapted adjuvant therapy strategy based on pathologic stage after neoadjuvant chemoradiation is feasible and achieves high rates of 5-year DFS. Patients with good prognostic factors can be treated with adjuvant fluoropyrimidines alone, thus permitting the avoidance of oxaliplatin-derived toxicities.

Pancreatic neuroendocrine tumors (pNETs) are usually well-to-moderately differentiated neuroendocrine tumors (NETs) that most often metastasize to the liver and lymph nodes with other locations being uncommon. We present a case of intradural pNET metastasis and conduct a review of the literature. Forty-five cases, including the case presently reported, of spinal cord compression due to well-differentiated NETs were found: carcinoid (80%), pNET (13.3%), and NETs of unknown primary (6.7%). Seventy-eight percent of cases consisted of extradural compressions from vertebral bone metastases, whereas there were only 5 cases of intradural extramedullary spinal cord compression. Most cases were managed with surgery and/or radiotherapy with a good clinical outcome in the majority. We report the first case of a pNET intradural extramedullary metastasis and conduct the largest review to date of an infrequent complication of well-differentiated NETs such as malignant spinal cord compression. Aggressive local treatment is warranted in most cases because it usually achieves neurologic improvement and symptomatic relief in patients who may still have a long life expectancy.

Colorectal cancer (CRC) is the second cause of cancer death in Spain, the objective of this guide published by the Spanish Society of Medical Oncology is to develop a consensus for the diagnosis and management of metastatic disease. The optimal treatment strategy for patients with metastatic CRC should be discussed in a multidisciplinary expert team to select the most appropriate treatment, and integrate systemic treatment and other options such as surgery and ablative techniques depending on the characteristics of the tumour, the patient and the location of the disease and metastases.

Photodynamic therapy (PDT) eradicates tumors by the local activation of a photosensitizer with near-infrared light. One of the aspects hampering the clinical use of PDT is the poor selectivity of the photosensitizer. To improve this, we have recently introduced a new approach for targeted PDT by conjugating photosensitizers to nanobodies. Diverse G protein-coupled receptors (GPCRs) show aberrant overexpression in tumors and are therefore interesting targets in cancer therapy. Here we show that GPCR-targeting nanobodies can be used in targeted PDT. We have developed a nanobody binding the extracellular side of the viral GPCR US28, which is detected in tumors like glioblastoma. The nanobody was site-directionally conjugated to the water-soluble photosensitizer IRDye700DX. This nanobody-photosensitizer conjugate selectively killed US28-expressing glioblastoma cells both in 2D and 3D cultures upon illumination with near-infrared light. This is the first example employing a GPCR as target for nanobody-directed PDT. With the emerging role of GPCRs in cancer, this data provides a new angle for exploiting this large family of receptors for targeted therapies.

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

The aim of the present study was to develop folic acid (FA) conjugates which can deliver the kinase inhibitor dactolisib to the kidneys via folate receptor-mediated uptake in tubular epithelial cells. Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) and is considered an attractive agent for treatment of polycystic kidney disease. The ethylenediamine platinum(II) linker, herein called Lx, was employed to couple dactolisib via coordination chemistry to thiol-containing FA-spacer adducts to yield FA-Lx-dactolisib conjugates. The dye lissamine was coupled via similar linker chemistry to folate to yield fluorescent FA-Lx-lissamine conjugates. Three different spacers (PEG(5)-Cys, PEG(27)-Cys or an Asp-Arg-Asp-Asp-Cys peptide spacer) were used to compare the influence of hydrophilicity and charged groups in the spacer on interaction with target cells and in vivo organ distribution of the final conjugates. The purity and identity of the final products were confirmed by UPLC and LC-MS analysis, respectively. FA-Lx-dactolisib conjugates were stable in serum and culture medium, while dactolisib was released from the conjugates in the presence of glutathione. All three type of conjugates were internalized efficiently by HK-2 cells and uptake could be blocked by an excess of folic acid in the medium, demonstrating FR mediated uptake. FA-Lx-dactolisib conjugates showed nanomolar inhibition of the PI3K pathway (Akt phosphorylation) and mTOR pathway (S6 phosphorylation) in cultured kidney epithelial cells (HK-2 cells). After intraperitoneal administration, all three types conjugates accumulated extensively in kidneys of iKsp-Pkd1(del) mice with polycystic kidney disease. In conclusion, folate conjugates were successfully prepared by platinum(II) coordination chemistry and accumulated in a target-specific manner in kidney cells and polycystic kidneys. The folate conjugate of dactolisib thus may have potential for targeted therapy of polycystic kidney disease.

Mutational analysis of RAS is required for anti-epidermal growth factor receptor (EGFR) treatment for patients with metastatic colorectal cancer (mCRC). However, most patients with KRAS wild-type tumors still do not respond. Other molecules downstream of the EGFR may also play a role in resistance to EGFR therapies. Our objective was to investigate the clinical importance of biomarkers in relation to response, progression-free survival, and overall survival in patients with mCRC receiving first-line treatment with anti-EGFR therapy plus chemotherapy. We studied the EGFR pathway [EGFR, NRAS, BRAF, PIK3CA, phosphatase and tensin homolog (PTEN), amphiregulin (AREG), and epiregulin (EREG)] in 105 patients with mCRC KRAS codon 12 wild type. We analysed objective response, progression-free survival, and overall survival in molecularly defined subgroups of the patients receiving anti-EGFR therapy plus chemotherapy as first-line treatment. We found a significant association between RAS wild-type, BRAF wild-type, EREG, and AREG overexpression and response to anti-EGFR therapy (p = 0.003, p = 0.015, p = 0.05, and p = 0.009, respectively). Progression-free survival and overall survival were lower in patients with RAS (p = 0.36 and p ≤ 0.001, respectively) or BRAF (p = 0.003 and p = 0.002, respectively) mutant tumors. Patients with EREG and AREG messenger RNA (mRNA) expression had longer survival than those with low-expression tumors; progression-free survival and overall survival were significant for AREG (p = 0.001 and p = 0.05, respectively). Patients with EGFR amplification tumors responded better to treatment and had better survival rates, although this was not significant. PIK3CA and PTEN were not associated with either response or survival. The multivariate logistic regression model for response showed only BRAF as a significant predictor after adjustment for the other covariates (p = 0.04, odds ratio 8.3, 95 % confidence interval 0.81–86.0). RAS, BRAF, AREG, and EREG predict for efficacy of first-line anti-EGFR therapy in patients with mCRC.

Background The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. Methods This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. Results A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8–14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09–139.2; P = 0.042 and HR: 6.9; 95% CI 0.96–49.9; P = 0.055, respectively]. Conclusions Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). Clinical trial number NCT01280201.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members.

Background: This multicentre, randomised, and phase II study evaluated mFOL-FOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316). Patients and methods: Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months. Results: One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2: 1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]< 0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade >= III AEs: 70%/68%). The most common grade >= III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade >= III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%). Conclusion(s): This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients. (C) 2018 Elsevier Ltd. All rights reserved.

Introduction: Neuroendocrine tumors (NETs) occur more often in lungs, gastrointestinal tract, or pancreas. Data about terminology and grading of NETs in rare locations are scarce and variable, and they have been reported mainly as case reports. Materials and Methods: We here describe our experience with NETs in unusual locations. We have reviewed all NETs diagnosed in our institution and summarized their clinicopathological features. We have also reviewed the literature and discussed the main characteristics of NETs in each site. Results: Two hundred and forty-three primary NETs were diagnosed. About 55.2% of patients were men and the mean age was 62 years. About 90.7% of NETs were located in lungs, gastrointestinal tract, or pancreas, and 50.8% of them were low-grade tumors. We identified 13 NETs in rare locations: breast, ovary, endometrium, vulva, uterine cervix, extrahepatic biliary tract, kidney, sinonasal tract, and thymus. Three additional tumors were diagnosed by the senior author in other institution. Patients were asymptomatic or presented with nonspecific symptoms. All NETs were treated with surgery and 31% of patients received adjuvant therapy. There were 10 Grade 3 (62.5%), 2 Grade 2 (12.5%), and 4 Grade 1 (25%) tumors. Mean follow-up was 72 months. About 60% of G3 tumors recurred or progressed. G2 tumors were located in breast, and both patients are stable. About 50% of G1 tumors recurred or progressed (both renal NETs). Conclusions: NETs in rare locations are heterogeneous, and their behavior does not seem to correlate absolutely with tumor grade. More studies are needed to clarify the role of proliferation rate in these tumors.

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Summary Aim To assess the evolution of occupational asthma (OA) depending on whether the patient avoids or continues with exposure to the offending agent. Methods Study in patients diagnosed with OA using a specific inhalation challenge. Patients underwent the following examinations on the same day: clinical interview, physical examination, forced spirometry, methacholine test and determination of total IgE. Clinical improvement, deterioration or no change were defined according to the changes seen on the GINA severity scale at the time of diagnosis. Results Of the 73 patients finally included, 55 had totally ended exposure and 18 continued to be exposed at work. Clinical improvement was observed in 47% of those who had terminated exposure and in 22% of those who remained exposed; clinical deterioration was observed in 14% and 17% respectively ( p = 0.805). Logistical regression analysis, including the type of agent and the persistence or avoidance of exposure among the variables, did not show any predictive factors of clinical evolution. Similarly, the changes in FEV 1 and in bronchial hyperresponsiveness were not associated with the avoidance or continuation of exposure to the causative agent. Conclusions Avoiding exposure to the causative agent in patients with OA does not seem to improve prognosis in this disease. Despite these findings, there is insufficient evidence to recommend a change in current management guidelines.

Background Despite improvements in diagnosis and aggressive chemotherapy treatment, a proportion of young patients are still dying from germ cell cancer (GCC). We aim to identify additional prognostic factors that help to select patients that might benefit from new treatment strategies. Anaemia is prognostic in several tumours. Thus, our objective was to address the prognostic significance of anaemia in disseminated testicular GCC. Methods A multicentre, observational, retrospective study of patients with disseminated testicular GCC receiving first-line platinum-containing chemotherapy between 2000-2014, pooled from the Spanish Germ-Cell Cancer Group registry and another 3 tertiary hospitals. All patients with haemoglobin level available at diagnosis were selected for the analysis. We used the Cox-proportional hazard model to identify prognostic factors. Results 665 consecutive patients from 18 centres were included for analysis. The patient distribution according to the International Germ Cell Cancer Collaboration Group (IGCCCG) classification was: 427, 125 and 113 patients for good, intermediate and poor risk categories, respectively. Hb Conclusions In our series, Hb Legal entity responsible for the study The Spanish Germ Cell Cancer Group (SGCCG). Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

3549 Background: The outcome for mCRC has changed since the introduction of new chemotherapy schedules and targeted therapies, however new predictive biomarkers are needed. bCTCs and BRAF / PIK3CA mutations have been studied as a potential predictive biomarkers. The primary endpoint was progression-free survival (PFS) in pts WT KRAS and 1) and mutation status of BRAF and/or PIK3CA (WT vs MUT) and randomized to group A (FOLFIRI+Bev) or group B (FOLFIRI+Cet). Results: 240 pts (196 WT and 44 MUT: 6 BRAF, 12 PIK3CA and 6 BRAF + PIK3CA) were included. General characteristics per mutation status (WT vs MUT): Mean age (59 vs 61 years), gender (Male/Female 68/32 vs 70/30%), ECOG 0/1 (57/43 vs 66/34%), primary tumor unresected (48 vs 64%), RAS MUT in 12 pts (11 and 1 pts, respectively), previous chemotherapy (12 vs 9%). Overall response rate (ORR) was 52 and 41% in the WT and MUT groups, respectively. PFS and overall survival (OS) are presented in the table. Conclusions: In the low risk mCRC pts according to bCTCs, BRAF and/or PIK3CA MUT have a negative impact in OS and a trend to worse PFS in the ITT population. The impact of treatment is under evaluation and will be provided during the meeting. Clinical trial information: 2012-000840-90. [Table: see text]

e15151 Background: RAS mutations predict a lack of response to anti-EGFR therapies in metastatic colorectal cancer (mCRC). BEAMing technology is useful for detecting hot-spot mutations in ctDNA in mCRC. Analysis of these mutations in DNA from Circulating Tumor Cells (CTC) may increase the predictive value in mCRC patients (pts). Our aim was to explore the feasibility of studying RAS status using BEAMing in DNA from CTC. Methods: First, spiking experiments (SE) using wild-type (WT) and KRAS-mutated (MUT) cell lines were performed to establish the limit of detection (LOD) for RAS analysis with BEAMing. Second, SE were performed with CTC collected by CellCelector (removes non-CTC background achieving 100% purity of CTC). Finally, BEAMing was used for RAS analysis in ctDNA and in DNA from CTC isolated either with IsoFlux or with CellCelector in 9 mCRC pts with confirmed RAS mutation in primary tumor. Total DNA from CTC was preamplified using RepliG. Results: In SE, 10 and 5 KRAS MUT-cells using different backgrounds of WT-cells (10-0.2% MUT-cells) were detected using BEAMing. However, 3 and 1 MUT-cells (0.009-0%) were not detected. In SE of CTCs collected with CellCelector, BEAMing detected KRAS mutations with 50, 20, 10, 6, 4, 2 and 1 cell (MAF: 23.8%±3.8). A mutation (codon 13) was detected in CTC from one patient positive in tissue and ctDNA (CellCelector; 15 CTCs; MAF: 11.4%). Discordant results were found in 8 patients when CTCs were isolated using Isoflux (min: 0, max: 9 CTCs). CTC from another patient were possibly mutated but WT in ctDNA. Conclusions: This pilot study indicates that RAS mutations can be detected in CTCs using BEAMing. Reducing the non-CTC cellular background may be needed in cases with low CTC number. Molecular information provided by CTC and ctDNA may prove complementary and useful for taking therapeutic decisions in mCRC. These results merit confirmation in larger, prospective studies.

3507 Background: FOLFOXIRI+BEV has demonstrated a survival benefit compared with FOLFIRI plus BEV (TRIBE Lancet Oncol 2015) in first-line mCRC. Nevertheless, due to its safety profile, this schedule is not recommended for all pts. In addition, we have showed that the detection of ≥3 bCTCs is a poor prognostic factor for survival (MACRO The Oncologist 2012). The VISNU-1 trial compares FOLFOX + BEV vs FOLFOXIRI + BEV in pts with mCRC and ≥3 bCTCs. Progression-free survival (PFS) is the primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Methods: This is an open, multicentric, randomized phase III trial. Patients with mCRC younger than 70 years, ECOG 0-1 were randomized to FOLFOX+BEV (arm A) or FOLFOXIRI+BEV (arm B), stratified per KRAS mutation (mutated vs WT) and number of involved organs (1 vs >1). Results: 349 pts were included in the ITT population; 177 in group A and 172 in group B. Characteristics of the pts, molecular profiling and safety analysis have been previously presented at ASCO 2018 and showed that this schedule had an acceptable toxicity profile. Efficacy analysis in the ITT population is shown in the table. Conclusions: In this population with very bad prognosis, our study met its primary endpoint. Pts who received FOLFOXIRI + Bev benefit for a statistically significative PFS and ORR. OS showed a trend of benefit in the experimental arm. According to these results, FOLFOXIRI-Bev could be considered an adequate treatment option for pts with mCRC and ≥3 bCTCs. Clinical trial information: 2012-000846-37. [Table: see text]

Cetuximab is a chimeric monoclonal antibody targeting the EGFR, which has proven effective in patients with metastatic colorectal cancer (mCRC), wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS).The aim of this manuscript is to discuss the current impact of cetuximab in the most important scenarios of mCRC. We review the currently available data regarding the role of other biomarkers, such as the mutational status of neuroblastoma RAS viral (v-ras) oncogene homolog in identifying patients who could benefit most from anti-EGFR. In addition, a review is included of the most relevant clinical trials that have assessed the effectiveness of cetuximab in the management of patients with potentially resectable metastatic disease and in the first-line treatment of wild-type KRAS mCRC, as well as the impact of this anti-EGFR agent on patient quality of life.Cetuximab has had a progressive clinical development from the earliest to the later stages of the evolution of mCRC and has been consolidated as a therapeutic option for all scenarios of unresectable disease. Patient selection by analysis of KRAS mutations has been a fundamental event to increase efficiency, being a dynamic process that continues in assessment. There are few comparative data with other biological agents in combination with chemotherapy, although data from a recent study are promising.

Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment.In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102.Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [1%]), gastrointestinal perforation (seven [2%] vs three [1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group.Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers.F Hoffmann-La Roche.

Circulating tumor cells (CTC) have shown to be prognostic in advanced colorectal cancer (advCRC), but their value for predicting response to treatment or as a source of molecular data is debated. We compared CellSearch® (Janssen Diagnostics, LLC) and IsoFluxTM (Fluxion Biosciences Inc, South San Francisco, CA) systems for the enumeration of CTC in patients with newly diagnosed advCRC (group 1; n=34). Using castPCRTM we studied KRAS status in CTC isolated with IsoFluxTM and compared it with that of the primary tumor in patients from group 1 and in KRAS wild-type (KRASWT) patients with progressive disease (group 2; n=22). Median number of CTC detected with CellSearch® (groups 1 and 2) was 1 (range: 0-78) and with IsoFluxTM (group 1) was 8 (range: 0-419), showing a modest correlation (r=0.345, P=0.036), which improved if lung metastases (r=0.805, P=0.016) or if lung and liver metastases were present (r=0.812, P=0.05). A Bland-Altman plot showed that the higher the number of CTC detected the larger the difference between both methods in favor of IsoFluxTM. After a median follow-up since CTC collection of 16 months (range: 1-30) CellSearch®≥ 3 CTC (HR 2.77, 95% CI 0.77-9.95) and IsoFluxTM≥ 11 CTC (HR 4.14, 95% CI 1.05-16.19) were established as the best cutoff points for predicting survival. Using castPCRTM we found KRAS mutations in CTC in 4 out of 8 patients from group 1 and in 2 out of 3 patients from group 2. None of these mutations were found in the primary tumor using standard methods, possibly reflecting intratumor heterogeneity or treatment selection pressure. We conclude that IsoFluxTM is more efficient than CellSearch® in the isolation of CTC in patients with advCRC, achieving, in a majority of cases, the established minimum of CTC for castPCRTM-based genetic analyses.

[Purpose] In the VELOUR study, aflibercept + FOLFIRI regimen resulted in improved survival in metastatic colorectal cancer (mCRC) patients who progressed after oxaliplatin. The use of aflibercept outside the clinical trial framework needs to be further assessed in terms of effectiveness and tolerability., [Methods] Early access to aflibercept through a named patient programme (NPP) was provided to mCRC patients receiving FOLFIRI as second-line treatment in Spain. The effectiveness of aflibercept was assessed as progression-free survival (PFS) achieved within the NPP population. Post hoc analyses on PFS were done according to certain baseline characteristics (K-RAS mutation, prior targeted therapy) or prognostic factors., [Results] Registries from 71 mCRC patients included in the NPP were reviewed retrospectively. The median age for the NPP population was 64 years (19.7 % aged ≥70 years) and 63.4 % patients had ≥2 metastases. A median PFS of 5.3 months (95 % CI, 3.6–8.5 months) was achieved, which did not depend on K-RAS mutation status or prior targeted therapy received. The risk of progression or death increased in patients with a poor prognosis as per the GERCOR score (performance status [PS] 1–2 and increased baseline lactate dehydrogenase [LDH] level) compared with patients with a good prognosis (PS 0 and normal LDH level) (median PFS: 2.6 vs. 8.3 months, respectively; p = 0.0124). Aflibercept was well tolerated, with a manageable toxicity profile., [Conclusions] Bearing in mind the differences in sample size, the PFS achieved with the aflibercept + FOLFIRI regimen in the real-life practice setting is comparable to that observed in the clinical trial setting., This study was supported by Sanofi. A. Del Campo (Pivotal SL) provided medical writing services on behalf of Sanofi Pharmaceuticals.

Sorafenib is the standard treatment of patients with advanced hepatocellular carcinoma, regardless of the liver functional reserve. We present a single institutional series of Child–Pugh A and Child–Pugh B patients treated with sorafenib with the aim to establish the efficacy and safety of sorafenib in patients of daily clinical conditions and to compare these results between Child–Pugh A and Child–Pugh B patients. A total of 51 patients were treated with sorafenib 400 mg/12 h until disease progression or unacceptable toxicity. The median progression-free survival and overall survival for the overall population were 3.5 and 8.2 months, respectively, with a 1-year survival rate of 27 %. Overall survival was significantly longer for patients Child–Pugh A compared with those with Child–Pugh B liver function (8.7 vs. 4.7 months, respectively). The most common adverse events were fatigue (62.7 %), diarrhea (58 %), hypertension (31.3 %), and hand–foot syndrome (31.3 %), and in most cases grade 1 or 2 according to the NCI-CTC 3.0. Grade 4 liver-related events occurred mainly in Child–Pugh B patients with decompensated cirrhosis at the time of sorafenib initiation (54.5 % of that group). The benefit of sorafenib in Child–Pugh B patients, if exist, may be limited by frequent liver-related events, especially in decompensated patients, and then, toxicity and impact in quality of life should be carefully monitored.

The presence of somatic mutations in the KRAS gene has been identified as a reliable strong negative predictor for the response to targeting the epidermal growth factor receptor (EGFR), in patients with metastatic colorectal cancer and the use of anti-EGFR monoclonal antibodies such as Cetuximab and Panitumumab is now restricted to patients with no detectable KRAS mutations. Between 30 and 40 % of colorectal cancers contain a mutated KRAS oncogene. The aim of this study was to evaluate concordance between three methods to analyze KRAS mutational status in regard to clinical testing. We analyzed KRAS mutations in codons 12 and 13 of exon 2 in one hundred formalin-fixed paraffin-embedded (FFPE) colorectal cancer samples by three different methods: Direct Sequencing and two commercial kits on allele-specific oligonucleotide hybridization (KRAS StripAssay, Vienna Lab.) and Amplification Refractory Mutation System/Scorpions (ARMS/S; TheraScreen KRAS Mutation kit DxS) based on q-PCR. We have found similar frequencies of KRAS mutations by TheraScreen and Strip-Assay (44 and 48 %), with a κ value of 0.90, indicating almost perfect agreement between methods. The frequency by direct sequencing was much lower (26 %) and the κ values were 0.67 (compared to TheraScreen) and 0.57 (compared to Strip-Assay) indicating low sensitivity. On analyzing KRAS mutation in FFPE tumor samples, direct sequencing sensitivity is too low to be used in a clinical setting. Choosing between ARMS/S; TheraScreen KRAS Mutation kit DxS and KRAS StripAssay, Vienna Lab, will depend on laboratory facilities and expertise.

In Spain 22,000 new cases of colorectal cancer are diagnosed each year, with 13,075 deaths resulting from this disease. Around 70% of colorectal cancers are localised in the colon and 30% in the rectum. A group of Spanish experts established recommendations on what would be the best strategy in the treatment of locally advanced rectal cancer (LARC). Adequate assessment of local tumour extension, including high-resolution magnetic resonance imaging and endorectal ultrasound, is essential for successful treatment. The three cornerstones in the treatment of LARC are surgery, radiotherapy and chemotherapy. Most patients will need a total mesorectal excision (TME). Preoperative chemo-radiotherapy (CRT) is preferred for the majority of patients with T3/T4 disease and/or regional node involvement, and adjuvant chemotherapy is recommended after a patient-sharing decision. Capecitabine, after showing a trend in improved downstaging in neoadjuvant stratum and the convenience of its oral administration, represents an alternative to 5-FU as perioperative treatment of LARC.

While hepatocellular carcinoma (HCC) is a relatively common tumour with an annual incidence in the EU of 8 cases/100,000 inhabitants, bile tract carcinoma (BTC) is much less common, with an incidence of 4 cases per 100,000 inhabitants per year. In both cases, when planning treatment it is essential to perform accurate staging, evaluate hepatic functional reserve and performance status, and obtain the opinion of the patient. The only curative treatment is surgery. However, several interventional radiological techniques can help to achieve local disease control and the alleviation of symptoms. In addition, sorafenib (HCC) and chemotherapy (BTC) may contribute to prolong survival in patients with disseminated disease. Therefore, the therapeutic strategy should always be discussed and planned within a multidisciplinary tumour board.

Background: The objective was to evaluate the efficacy of irinotecan-cetuximab-bevacizumab in combination as a salvage treatment for heavily pretreated metastatic colorectal cancer patients. Methods: A total of 39 patients resistant to both oxaliplatin and irinotecan were included in this retrospective study. Treatment consisted of irinotecan 180/m2 every 14 days, weekly cetuximab standard dose and bevacizumab 5 mg/kg every 14 days. Results: Partial response was observed in 8 patients (20%), stable disease in 24 (61%) and progressive disease in 7 (18%). Overall response rate in KRAS wild type was 6/22 (27%) and in mutated KRAS it was 2/15 (13%). Median time to progression was 8 months (6.4–9.4) and median overall survival 12 months (10.1–13.8). Overall, grade 3–4 adverse events were observed in 24 patients (62%). Conclusions: This regimen is active and moderately well tolerated in heavily pretreated advanced colorectal patients. However, caution is advisable when interpreting these results, because they run against the findings of two large phase III trials.

Colorectal cancer is the third most common malignant neoplasm and the second cause of death by cancer in western countries. In this manuscript, the clinical guidelines of the Spanish Society of Medical Oncology (SEOM) for diagnosis and adjuvant treatment of colon cancer and rectal cancer are reported.

To cite this article: Valero A, Ferrer M, Baro E, Sastre J, Navarro AM, Marti-Guadano E, Davila I, del Cuvillo A, Colas C, Antepara I, Alonso J, Mola O, Izquierdo I, Mullol J. Discrimination between moderate and severe disease may be used in patients with either treated or untreated allergic rhinitis. Allergy 2010; 65: 1609–1613. Abstract Background: Allergic rhinitis (AR) is a common disease with major socioeconomic burden and a significant impact on quality of life. Objective: The aim of this study was to discriminate between moderate and severe AR patients whether receiving treatment or not, using a modified criterion of allergic rhinitis and its impact on asthma (ARIA) classification. Methods: The modified ARIA severity classification (J Allergy Clin Immunol, 120, 2007, 359) categorizes AR as mild (no items affected), moderate (1–3 items affected), and severe (all four items affected). We applied these criteria to 1666 treated and 1058 untreated AR patients and compared their symptoms total four-symptom score (T4SS) and quality of life (ESPRINT-15), according to their clinical severity. Results: Allergic rhinitis clinical status was significantly worse (P

Pancreatic cancer (PC) represents one of the greatest oncological challenges of our century, due to its high mortality and incidence. A group of Spanish experts in PC treatment reviewed data available on different therapeutic combinations and established consensus on what would be the best strategy in PC management, depending on the stage of the disease. Surgery with complete resection may produce 5-year survival rates of 18-24%, but definitive control is still precarious. In the absence of consensus, the best evidence suggests that adjuvant chemotherapy with gemcitabine for 6 months using the CONKO-001 regime is the treatment of choice after resection of PC for patients with acceptable functional status. This group recommends chemoradiotherapy (CT-RT) in patients with factors for poor loco-regional prognosis. However, chemotherapy is an option for the treatment of locally advanced PC in patients with good general status and in the absence of metastatic disease the recommended treatment is CT-RT followed by gemcitabine-based chemotherapy. A period of chemotherapy followed by consolidation CT-RT may be appropriate, as it allows selection of patients with locally advanced disease who may benefit most from combined treatment. Erlotinib combined with gemcitabine shows significant survival improvement in PC and must be considered an option in the first-line treatment of advanced and metastatic PC. The gemcitabine-erlotinib combination is proposed as the standard treatment for metastatic PC in patients with PS=/2. In patients with PS2, gemcitabine-erlotinib is recommended as the first-line treatment option, supported by a maximum degree of evidence, without ruling out other options, such as gemcitabine-oxaliplatin, gemcitabine-capecitabine or gemcitabine alone.