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OBJECTIVES Obesity is associated with submucosal fatty tissue. The main aim of this study was to assess the impact of submucosal fatty tissue on the success of colonic endoscopic submucosal dissection (C-ESD) in a western population. METHODS This was a retrospective analysis of 125 consecutive C-ESDs performed between October 2015 and July 2017. Fatty tissue sign was defined as positive when the submucosal layer was covered with fatty tissue. The complexity of performing an ESD was assessed by the performing endoscopist, defined by the occurrence of intraprocedural perforation, inability to complete an en-bloc resection or a procedure time exceeding 180 min. RESULTS Fatty tissue sign positive was present in 44.8% of the procedures. There were 28 (22.4%) c-ESD defined as complex. Factors associated with complex ESD included; fatty tissue sign [odds ratio (OR) 12.5; 95% confidence interval (CI), 1.9-81.9; P = 0.008], severe fibrosis (OR 148.6; 95% CI, 6.6-3358.0; P = 0.002), poor maneuverability (OR 267.4; 95% CI, 11.5-6212.5; P

Objectives Colorectal endoscopic submucosal dissection (CR-ESD) is an evolving technique in Western countries. We aimed to determine the results of the untutored implementation of endoscopic submucosal hydrodissection for the treatment of complex colorectal polyps and establish the learning curve for this technique. Methods This study included data from 80 consecutive CR-ESDs performed by a single unsupervised western therapeutic endoscopist. To assess the learning curve, procedures were divided into four groups of 20 each. Results En bloc resection was achieved in 55, 75, 75 and 95% cases in the consecutive time periods (period 1 vs. 4, P = 0.003). Curative resection was achieved in 55, 75, 70 and 95%, respectively (P = 0.037). Overall, series results demonstrated R0 resection in 75% of cases, with 23.7% requiring conversion to endoscopic piecemeal mucosal resection, and 1.25% incomplete resections. Complications included perforations (7.5%) and bleeding (3.7%). Multivariate analysis revealed factors more likely to result in association with non en bloc vs. En bloc resection, where polyp size ≥35 mm [70 vs. 23.4%; odds ratio (OR) 13.2 (1.7-100.9); P = 0. 013], severe fibrosis [40 vs. 11.7%; OR 10.2 (1.2-86.3); P = 0.033] and where carbon dioxide for insufflation was not used [65 vs. 30%; OR 0.09 (0.01-0.53); P = 0.008]. Conclusion CR-ESD by hydrodissection has good safety and efficacy profile and offers well tolerated and effective treatment for complex polyps. As such, this technique may be useful in the West, in centers, where previous gastric ESD is not frequent or Japanese mentoring is not possible.

Complete surgical resection for locally advanced rectal cancer is the standard treatment after a clinical complete response following chemoradiotherapy. However, some novel clinical approaches could achieve better functional results, such as Robotic Resection, or avoiding surgical procedure and incrementing surveillance intensity, called Watch-and-Wait policy. We use computational techniques to compare these clinical approaches using quality adjusted life years (QALYs).A Markov decision analytic model was used in order to perform a cost-utility analysis, comparing standard resection (SR), Robotic Rectal Resection (RRR) and Watch-and-Wait (WW) strategies, estimating the incremental cost-effectiveness ratio per QALY to be gained from patients reaching a clinical complete response to chemoradiotherapy. Model parameter estimates were informed by previously published studies comparing WW to SR and from our database of RRR versus SR. Lifetime incremental cost-utility ratio was calculated among approaches, and a sensitivity analysis were performed in order to estimate the model uncertainty. A willingness-to-pay of per one additional QALY gained was measured to determine which strategies would be most cost-effective.WW is a dominating option over SR ( -75,486. 75 € and +2.04 QALYs) and RRR ( -75,486. 75 € and +0.41 QALYs). The cost-effectiveness plane shows that WW does not always dominate over RRR or SR. WW saves costs in 99.98% of the simulations when compared with either SR or RRR but only 86.9% and 55.38% (respectively) of these fall within the SR quadrant. WW is only more effective than SR 55% of the time which implies a significant uncertainty due to the high utility value assigned to cCR after chemoradiotherapy in the RRR alternative.This study provides data of cost-effectiveness differences among Standard Surgery, Watch-and-Wait and Robotic Resection approaches in clinical complete response in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy, showing a benefit for Watch-and-Wait policy.

Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment.Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method.A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04).Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness.

BackgroundSince first cases of SARS COV-2 were identified, the number of affected and dead people make necessary to identify factors related to worse evolution. Endothelial injury has been proposed as the main pathophysiological mechanism in the illness development, which provokes a hyper inflammation and prothrombotic state. Leukocytes and platelets play a role in inflammation and thrombogenesis so we propose to study if neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR), the novel neutrophil-to-platelet ratio (NPR), and the systemic immune-inflammation index (SII), could be useful to identify patients who will need admission at Intensive Care Units.MethodsA retrospective observational study was performed at HM Hospitales including 2245 patients with COVID-19 from March 1 to June 10, 2020. Patients were divided into two groups, admitted, and not admitted to ICU. ResultsPatients requiring ICU admission had significantly higher rates at the moment of hospital admission in NLR (6.9 [4–11.7] vs 4.1 [2.6–7.6], p

Background Spain is one of the European countries most affected by the COVID-19 pandemic. Epidemiologic studies are warranted to improve the disease understanding, evaluate the care procedure and prepare for futures waves. The aim of the study was to describe epidemiologic characteristics associated with hospitalized patients with COVID-19. Methods This real-world, observational, multicenter and retrospective study screened all consecutive patients admitted to 8 Spanish private hospitals. Inclusion criteria: hospitalized adults (age≥18 years old) with clinically and radiologically findings compatible with COVID-19 disease from March 1st to April 5th, 2020. Exclusion criteria: patients presenting negative PCR for SARS-CoV-2 during the first 7 days from hospital admission, transfer to a hospital not belonging to the HM consortium, lack of data and discharge against medical advice in emergency departments. Results One thousand and three hundred thirty-one COVID-19 patients (medium age 66.9 years old; males n= 841, medium length of hospital stayed 8 days, non-survivors n=233) were analyzed. One hundred and fifteen were admitted to intensive care unit (medium length of stay 16 days, invasive mechanical ventilation n= 95, septic shock n= 37 and renal replacement therapy n= 17). Age, male gender, leukocytes, platelets, oxygen saturation, chronic therapy with steroids and treatment with hydroxychloroquine/azithromycin were independent factors associated with mortality. The proportion of patients that survive and received tocilizumab and steroids were lesser and higher respectively than those that die, but their association was not significant. Conclusions Overall crude mortality rate was 17.5%, rising up to 36.5% in the subgroup of patients that were admitted to the intensive care unit. Seven factors impact in hospital mortality. No immunomodulatory intervention were associated with in-hospital mortality. Sin financiación 1.553 JCR (2020) Q4, 125/136 Microbiology 0.430 SJR (2020) Q3, 1417/2447 Medicine (miscellaneous) No data IDR 2020 UEM

Background The vast impact of COVID-19 call for the identification of clinical parameter that can help predict a torpid evolution. Among these, endothelial injury has been proposed as one of the main pathophysiological mechanisms underlying the disease, promoting a hyperinflammatory and prothrombotic state leading to worse clinical outcomes. Leukocytes and platelets play a key role in inflammation and thrombogenesis, hence the objective of the current study was to study whether neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) as well as the new parameter neutrophil-to-platelet ratio (NPR), could help identify patients who at risk of admission at Intensive Care Units. Methods A retrospective observational study was performed at HM Hospitales including electronic health records from 2245 patients admitted due to COVID-19 from March 1 to June 10, 2020. Patients were divided into two groups, admitted at ICU or not. Results Patients who were admitted at the ICU had significantly higher values in all hemogram-derived ratios at the moment of hospital admission compared to those who did not need ICU admission. Specifically, we found significant differences in NLR (6.9 [4–11.7] vs 4.1 [2.6–7.6], p p = 0.023), NPR (3 [2.1–4.2] vs 2.3 [1.6–3.2], p < 0.0001) and SII (13 [6.5–25.7] vs 9 [4.9–17.5], p < 0.0001) compared to those who did not require ICU admission. After multivariable logistic regression models, NPR was the hemogram-derived ratio with the highest predictive value of ICU admission, (OR 1.11 (95% CI: 0.98–1.22, p = 0.055). Conclusions Simple, hemogram-derived ratios obtained from early hemogram at hospital admission, especially the novelty NPR, have shown to be useful predictors of risk of ICU admission in patients hospitalized due to COVID-19.

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome, is a very uncommon and life-threatening hematologic disorder that occurs as a primary or acquired disease. Secondary HLH usually appears in the setting of infections, underlying rheumatologic disorders or lymphoid malignancies. Clinically the syndrome is characterized by fever, multiple cytopenias, hepatosplenomegaly and activated macrophages in hematopoietic organs. We describe a rare case of HLH in the context of abdominal pain and fever of unknown origin, dramatic worsening and, finally, successful evolution with immunosuppressive therapy. In addition, we review the available literature on this topic.

Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment. Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation. Nevertheless, some patients are primary unresponsive or develop ulterior resistance to these family of drugs. This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.

The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC).Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS).A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40).Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

e19374 Background: Chemoradiotheray (CR) followed by standard Surgical Resection (SR) is the standard treatment for distal locally-advanced rectal cancer (LARC) patients after a clinical compete response (cCR). Some novel approach suggested better functional results using robotic rectal resection (RRR) or avoiding surgical procedure, called Watch and Wait (WW) strategy. Methods: A Markov model-based, cost-utility analysis estimating mean costs and QALYs per patient was performed to compare SR, RRR and WW strategies for patients achieving a cCR to CRT. Rates of local regrowth, recurrence and distant metastasis were derived from series comparing WW to SR and from our previous comparative study of RRR versus SR. Lifetime incremental cost-utility ratio was calculated between strategies, and sensitivity analysis were performed to study model uncertainly. A willingness-to-pay of 30.000 per Quality Adjusted-Life Year (QALY) was used as a threshold to determine the most cost-effective treatment. Results: The base case 15-years cancer-specific survival was 93.5% (95% confidence interval [CI] 91.5-94.9] on a WW program, compared to 95.9% [95%CI 93.6-97.7] after RRR. WW was dominant relative to RRR with cost savings of $48,566.58 (95%CI $47,635.77 - $49,497.39 ) and incremental QALY of 7.47 (95%CI 1.46 – 7.48). WW was also dominant relative to LRR, with cost savings of $48,764.49 (95%CI $47,768.49 - $49,760.48 ) and incremental QALY of 7.44 (95%CI 7,43 – 7.45). WW remained dominant in sensitivity analysis unless the rate of SR fell to 73.0%). Conclusions: This study provides data of cost-effectiveness differences between SR, RRR, WW approaches in LARC after cCR, showing a benefit for WW.

Background Identification of clinical and molecular biomarkers to predict dynamic response or monitor in real-time the efficacy of antiangiogenic therapy represents a major point in the treatment of patients with advanced colorectal cancer. Several stu-dies have been conduced to identify some predictive biomarkers to select patients who will benefit from bevacizumab, the most widely used antiangiogenic monoclonal anti-body. Conclusion After a decade since the introduction of bevacizumab, no effective predictive biomarkers are available in routine clinical practice. In this review, we summarized the potential candidate dynamic biomarkers that may play a role in this setting.

e23022 Background: Raltitrexed is a antifolate chemotherapy agent with activity against metastatic colorectal cancer (mCRC). Most clinical trials with raltitrexed were performed before approval of anti-EGFR and anti-VEGF therapies. Its toxity profile suggests that might be a useful drug to treat elder patients, but there are no specific data in this population group. Methods: A retrospective review of elderly patients (70 years or older) with mCRC treated with raltitrexed monotherapy in our hospital between 2008 and 2017 was conducted. All of them had received previously oxaliplatin, irinotecan, fluoropyrimidines, and bevacizumab as standard therapy. All RAS native patients had received also anti-EGFR drugs. Results: Eighteen elder patients were reviewed, 11 (61%) male. Age ranged 70-85 years (median 78). All patients had ECOG PS 0 or 1. Locations were rectum (4), right colon (8), and left colon (6). Number of treatment lines ranged 2-5 (median 3). Three pts (16%) had received regorafenib previously. KRAS and BRAF were mutated in 61% and 5% respectively. Median number of cycles was 3 (1-13). Response rate was 11% (2 partial responses). Stable disease was achieved in 33%. Median progression-free and global survival were 2.8 (95% CI 1.2-10) and 5.9 (95% CI 1.6-18) months respectively. Grade 3-4 hematologic and non-hematologic toxicities were present in 22% and 5.5% respectively. Dose reduction was needed only in 11%. Sex, location, RAS status were not related to response or survival. Conclusions: Raltitrexed is a well tolerated option por elderly patients after standard treatment of mCRC.

Background: Nab-paclitaxel and gemcitabine have demonstrated a survival benefit over gemcitabine alone in advanced pancreatic cancer (PDA). This study aimed to investigate the clinical, biological, and imaging effects of the regimen in patients with operable PDA. Methods: Patients with operable PDA received two cycles of nab-paclitaxel and gemcitabine before surgical resection. FDG-PET and CA19.9 tumour marker levels were used to measure clinical activity. Effects on tumour stroma were determined by endoscopic ultrasound (EUS) elastography. The collagen content and architecture as well as density of cancer-associated fibroblasts (CAFs) were determined in the resected surgical specimen and compared with a group of untreated and treated with conventional chemoradiation therapy controls. A co-clinical study in a mouse model of PDA was conducted to differentiate between the effects of nab-paclitaxel and gemcitabine. Results: A total of 16 patients were enrolled. Treatment resulted in significant antitumour effects with 50% of patients achieving a >75% decrease in circulating CA19.9 tumour marker and a response by FDG-PET. There was also a significant decrement in tumour stiffness as measured by EUS elastography. Seven of 12 patients who completed treatment and were operated had major pathological regressions. Analysis of residual tumours showed a marked disorganised collagen with a very low density of CAF, which was not observed in the untreated or conventionally treated control groups. The preclinical co-clinical study showed that these effects were specific of nab-paclitaxel and not gemcitabine. Conclusion: These data suggest that nab-paclitaxel and gemcitabine decreases CAF content inducing a marked alteration in cancer stroma that results in tumour softening. This regimen should be studied in patients with operable PDA.

// Rodrigo A. Toledo 1,4,* , Antonio Cubillo 1,2,* , Estela Vega 1,2 , Elena Garralda 1,2 , Rafael Alvarez 1,2 , Lisardo U. de la Varga 1,2 , Jesus R. Pascual 1,2 , Gema Sanchez 1,4 , Francesca Sarno 1,4 , Susana H. Prieto 3 , Sofia Perea 1,4 , Pedro P. Lopez-Casas 4 , Fernando Lopez-Rios 3 and Manuel Hidalgo 4,5 1 Centro Integral Oncologico Clara Campal (CIOCC), Madrid, Spain 2 Universidad San Pablo CEU, Madrid, Spain 3 Laboratorio de Dianas Terapeuticas, Madrid, Spain 4 Spanish National Cancer Research Centre (CNIO), Madrid, Spain 5 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA * These authors have contributed equally to this manuscript Correspondence to: Rodrigo A. Toledo, email: // Manuel Hidalgo, email: // Keywords : colorectal cancer, cfDNA, liquid biopsy, anti-EGFR, cetuximab Received : October 13, 2016 Accepted : October 24, 2016 Published : November 11, 2016 Abstract Cancer genomics and translational medicine rely on the molecular profiling of patient’s tumor obtained during surgery or biopsy. Alternatively, blood is a less invasive source of tumor DNA shed, amongst other ways, as cell-free DNA (cfDNA). Highly-sensitive assays capable to detect cancer genetic events from patient’s blood plasma became popularly known as liquid biopsy (LqB). Importantly, retrospective studies including small number of selected patients with metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapy have shown LqB capable to detect the acquired clonal mutations in RAS genes leading to therapy resistance. However, the usefulness of LqB in the real-life clinical monitoring of these patients still lack additional validation on controlled studies. In this context, we designed a prospective LqB clinical trial to monitor newly diagnosed KRAS wild-type (wt) mCRC patients who received a standard FOLFIRI-cetuximab regimen. We used BEAMing technique for evaluate cfDNA mutations in KRAS , NRAS, BRAF, and PIK3CA in twenty-five patients during a 2-y period. A total of 2,178 cfDNA mutation analyses were performed and we observed that: a) continued wt circulating status was correlated with a prolonged response; b) smoldering increases in mutant cfDNA were correlated with acquired resistance; while c) mutation upsurge/explosion anticipated a remarkable clinical deterioration. The current study provides evidences, obtained for the first time in an unbiased and prospective manner, that reinforces the utility of LqB for monitoring mCRC patients.

In this report, we present an unusual case of jaundice in a patient with advanced colorectal cancer due to intraductal tumour invasion of the intra- and extrahepatic biliary tree. This complication proved to be fatal despite aggressive therapeutic management. A correct diagnosis of this type of involvement was achieved by a combination of diagnostic and therapeutic cholangiography. Despite adequate biliary decompression, the patient died from liver failure and biliary sepsis.

A high throughput screening for anticancer activity of FDA approved drugs identified mycophenolic acid (MPA), an inhibitor of inositol monophosphate dehydrogenase (IMPDH) as an active agent with an antiangiogenesis mode of action. Exposure of pancreatic cancer cell lines to MPA resulted in growth inhibition and reduced the expression of VEGF that was reversed by supplementing the media with guanosine supporting and IMPDH-dependant mechanism. In preclinical in vivo study, MPA showed a moderate inhibition of tumor growth in a panel of 6 human derived pancreatic cancer xenografts but reduced the expression of VEGF. To investigate the effects of MPA in human pancreatic cancer, a total of 12 patients with resectable pancreatic cancer (PDA) received increasing doses of mycophenolate mofetil (MMF) in cohorts of 6 patients each from 5-15 days prior to surgical resection. Treatment was well tolerated with one episode of grade 1 muscle pain, one episode of grade 2 lymphopenia (2 gr/day dose) and one episode of grade 2 elevantion in LFT (all in the 2 gr./day dose). Patients recovered from surgery uneventfully with no increased post-operative complications. Assessment of CD31, VEGF, and TUNEL in resected specimens compared to a non treated control of 6 patients showed no significant variations in any of the study endpoints. In conclusion, this study shows the feasibility of translating a preclinical observation to the clinical setting and to explore a drug mechanism of action in patients. MPA, however, did not show any hints of antiangiogenesis of anticancer clinical activity questioning if this agent should be further developed in PDA.

The inhibitors of the mammalian target of rapamycin (mTOR) improve outcomes in patients with advanced renal cell carcinoma. These agents are associated with unusual class-adverse events that represent a challenge to the clinician, making it critical to recognize and treat them appropriately. This study aims to highlight the clinical management of these toxicities by presenting evidence from the literature and suggesting treatment recommendations. A critical review of the literature is performed and a summary of the most relevant emergent toxicities and their management is presented. Treatment recommendations of metabolic disturbances induced by mTOR inhibitors, such as hypophosphatemia, hyperglycemia, and hyperlipidemia along with the management of drug-induced pneumonitis and possible pharmacological interactions are presented. Most of these toxicities, if recognized and treated accordingly, should resolve with minimal impact on patients' quality of life and in the efficacy of this anticancer therapy. Oncologists should be familiar with the recognition and appropriate medical management of these clinical scenarios.

e14029 Background: A usual inclusion criterion for phase I trials is life expectancy of more than 3 months. Prediction of early mortality (EM), in the first 90 days after starting treatment, is thus a challenge. Predictive scores may help to select more adequate patients (pts). Our main objective was to generate a predictive score in a training set of phase I pts and to confirm it in a validation score. Secondly, we figured out if our score also predicts overall survival (OS). Methods: Consecutive pts treated in our phase I unit between 2008 and 2013 were retrospectively reviewed. We collected 35 clinical and analytical characteristics at base line. Stepwise regression was used to correlate pts characteristics with EM and generate a predictive score. Log-rank regression and Kaplan Meier curves were used to study survival. Results: We identified 438 pts. Median age was 61 yr (18-87) and 52.7% were male. More frequent tumor types were gastrointestinal (37%), thoracic (17%), and breast (12%). Pts treated with chemotherapy were 32%, targeted therapy 36%, combination 29%, and immunotherapy 3%. Response rate was 12.4%. Median progression free survival (PFS) and OS were 2.6 and 8.5 months respectively. Most common causes of discontinuation were tumor progression (87.2%) and toxicity (5.7%). EM rate was 20.5%. We randomly included 243 pts in the training score. In multivariate stepwise regression, 6 features were related to EM: ECOG PS 2 (vs 0-1), gastrointestinal or thoracic tumors (vs other types), red cell counts below 4*106/ml, LDH above 600 U/L, calcium below 8.6 mg/dL, and ratio neutrophil/lymphocyte above 5. An EM score was generated ranging 0-7 (2 points for ECOG PS and 1 point for each other characteristic). Using cut off value of 0-2 vs 3 or more, we would reduce EM90 rate to half (11%) and avoid inclusion of 60% pts with EM. Our EM score was validated in the second cohort; we reduced EM rate to 10.5% avoiding undesirable inclusion of 59% pts. Applying score to all pts, median OS was 16, 8.4, 4.4, and 3 months for score 0, 1, 2, and 3-7 respectively (p < 0.01). Conclusions: Our score can avoid inclusion of 60% of pts who would die before 90 days, reducing EM rate from 20 to 10%. This score can identify four prognostic groups with different median OS.

e18202 Background: The faculty clinical activity in a comprehensive Cancer Center is difficult to measure. Time clinical units is the most common procedure worldwide. In our group we have developed a new system based on the daily real activity of each medical oncologist of our team. Methods: We collected the daily activity from january to december 2016 of each doctor considering different values( from 1 to 4)depending on the complexity of the activity. Follow up visit of a patient (1), treatment visit (2). Clinical trial visit or Inpatient visit (3) and New Patient First visit (4). Then we added all the daily values of each medical oncologist. Results: 2016 Clinical activity growth measured by traditional time methods was consider 31,5%. When we applicated our new method it was 33,4%. The clinical activity of each Oncology Unit changed clearly when we applied our method. For example , breast cancer unit change from 25% to 20 % of the global activity, GI Unit from 47% to 50%, Lung Unit from 13% to 15% . In Genitourinary and Gynecological cancer and Prostate tumor units there are no change. This changes draw the different complexity of each Oncology Unit. It was clearly usefull to get a better information of the real clinical activity of each team and cancer center. Conclusions: This tool can be useful to unifique and compare the different complexity in the clinical activity of Medical Oncology Teams, units and hospitals allocating resources based on this new system.

e23059Background: RAS/RAF/PIK3CA mutations are frequent drivers of secondary drug resistance to cetuximab in mCCR, which typically occurs within 3-12months from the start of therapy. The emergence ...

e15126Background: There is a need to develop biomarkers to predict the outcome of patients with metastatic colorectal cancer (CRC) treated with chemotherapy (Ch) plus Bevacizumab (B). It has been r...

4109Background: nab-paclitaxel + gemcitabine is approved for the treatment of metastastic pancreatic cancer. So far, few studies have investigate this regimen in patients with nonmetastatic disease...

Purpose To investigate the feasibility of personalizing chemotherapy in patients with rectal cancer. Methods Patients with cT3 or cN1 and cM0 rectal cancer were eligible. A set of 6 molecular markers including KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), ERCC-1, and thymidylate synthase (TS) using immunohistochemistry were performed in a tumor biopsy. All patients were treated with capecitabine 625 to 825 mg/m/12 h M-F in combination with either irinotecan or oxaliplatin based on Topo-1 and ERCC-1 expression plus either bevacizumab or cetuximab based on the mutation status. All patients received intensity-modulated radiation therapy. A surgery was performed 6 to 8 weeks after the treatment. Results Fifteen patients (94%) had T3 tumor and 10 (62%) N+ disease of 16 patients enrolled. In all patients, the full set of markers was analyzed within 10 days. Seven patients had K-ras mutation, and 4, 5, and 10 expressed Topo-1, ERRC-1 and TS, respectively. All patients had wild-type BRAF and PI3K tumors. The median time from obtaining informed consent to the treatment period was 18 days and all patients completed the chemoradiation treatment. Fifty percent achieved a complete pathologic response to treatment. Four patients (25%) developed grade 3 proctitis or diarrhea. There were no relevant surgical complications. Sixty-nine percent of the patients received adjuvant XELOX. Conclusions The individualization of neoadjuvant chemotherapy in patients with rectal cancer is feasible and leads to a high rate of pathologic response.

Sir, In response to Boeck et al We read with interest the comments made by Boeck et al (2014) about our study. We appreciate their attention to the units used to report CA19.9 levels, which indeed should have been U ml−1 and not U dl−1 as stated. We certainly agree that a high level of CA19.9 at diagnosis may be an indication of advanced disease and that this should be considered in the selection criteria in preoperative studies. Indeed in our study, with small sample size, one patient with very high CA19.9 level who actually progressed during chemotherapy skewed that average level of CA19.9. This patient was not operated and therefore does not affect the tissue results. As Boeck et al mention, levels of CA19.9 should be either a selection criteria or a stratification factor in outcome-oriented preoperative studies that should also include better imaging methods to determine responses and histological, rather than cytological, diagnosis. In our study, however, as the goals were to determine the effects of Nab-paclitaxel in tumour tissue, this criterion was not part of the eligibility criteria. We agree, however, that future controlled studies to confirm our observations should exclude patients with elevated CA19.9 and plan to do so. In clinical practice, however, one of the goals of preoperative treatment is to identify patients with more advanced or resistant disease who can be spared from surgery, as surgery would not be beneficial for those patients. Thus, for patients with resectable or borderline resectable disease by CT scan and high (>180 U ml−1) CA19.9, we usually administer chemotherapy upfront and explore surgically those patients who do not progress after two cycles of treatment provided laparoscopic assessment of peritoneal disease is negative as well. In response to Ramirez et al We read with great interest the comments made by Ramirez et al (2014) in which they highlight the importance of tumour stroma in pancreatic cancer (PDAC) and the role of ‘pancreatic stellate cells' in the development of tumour stroma. The current data, while with still some inconsistencies, show that in preclinical models of PDAC, the combination of gemcitabine and Nab-paclitaxel (PTX) increases the delivery of gemcitabine to the tumour. Mechanistically, this has been explained by a decrease in the expression of the gemcitabine catabolism enzyme cytidine deaminase and hence increasing the intracellular retention time of the active gemcitabine metabolites or by elimination of the PDAC stroma (Von Hoff et al, 2011; Frese et al, 2012). In the only clinical study available so far, we have shown that Nab-PTX markedly alters the PDAC stroma and decreases the number of CAF (Alvarez et al, 2013). The precise mechanisms underlying these observations remain obscure. Selective binding of albumin-coated Nab-PTX to SPARC-positive cells or uptake of nutrient-rich drug by cancer cells by pynocitosis have been proposed and are the subject of specific studies. The role of SPARC has been studied in the MPACT randomised clinical trial and we hope to have these results available in the near future (Von Hoff et al, 2013). As these authors propose, the effects of Nab-PTX on cancer stroma could be a consequence of the direct elimination of cancer cells and interruption of the cancer cell–stroma interactions. Certainly, additional preclinical and translational clinical studies are needed to determine the precise mechanism of action of this, otherwise, clinically effective regimen.

Background Surgical resection remains the gold standard for the treatment of localized adenocarcinoma of the extrahepatic bile ducts. Yet, treatment of loco-regional recurrences is not well defined. Case Presentation We present an unusual case of distal adenocarcinoma of the extrahepatic bile ducts that was treated with surgery and relapsed two years later with a solitary recurrence on the tract of a previous Redon drain. In addition, a review of the literature on management of loco regional relapses is presented. Conclusions The ideal management of these patients still remains undefined. Decisions are made based on clinical parameters from retrospective series, such as tumor grade, surgical margins or lymph node involvement. Prospective studies, that include molecular and genetic markers, are needed to improve patient selection and outcomes on this population.

Aim: There is a need to develop biomarkers to predict the outcome of patients with metastatic colorectal cancer (CRC) treated with chemotherapy (Ch) plus Bevacizumab (B). It has been reported that during exposure to B there is a switch in the plasma levels of angiogenesis growth factors and related cytokines called angiogenic switch (AS). It is not known if changes in these circulating factors affect the response of patients with CRC to Ch + B. The aim of this study is to determine the influence of AS in the PFS in pts with metastatic CRC treated with Ch + B. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were eligible. Patients received induction treatment with XELOX-B or XELIRI-B at standard doses x 6 cycles followed by maintenance treatment with B plus Capecitabine until progression. Angiogenic related cytokines (HGF, PIGF, MCP-3, MM-9, Eotaxin, bFGF and IL-18) were prospectively analyzed at baseline and at the time of each CT evaluation (every eight weeks). AS + was defined by A) doubling of PIGF compared to baseline or B) PIGF elevation with a simultaneous elevation of any two of bFGF, HGF, MCP-3, IL-18 or MMP-9 compared to baseline. Results: Of 62 patients enrolled, 24 (36.7%) have progressed. Median PFS is 15.6 (95% CI: 8.3 to 16.4) months for the entire population. Twenty-five pts (40.3%) were AS + , out of which 23 were detected at first on-study evaluation (week 8). 18 were classified as AS+ based on both criteria, 4 based on criteria A) and 3 based on criteria B). One year (95% CI) PFS for AS+ pts was 82.6% (53.0% to 94.4%) versus 32.9% (13.9% to 53.5%) for AS- pts (p Conclusions: There is a statistically significant improved PFS amongst metastatic CRC AS+ pts treated with first line Ch + B combination compared with AS–pts. Disclosure: All authors have declared no conflicts of interest.

3543 Background: Chemotherapy (Ch) options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the efficacy in terms of progression free survival (PFS) of a biomarker panel to guide treatment selection in this setting. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were accrued. Pts were prospectively analyzed with a predefined set of 10 molecular targets, including: KRAS, BRAF, and PI3K mutations and Topoisomerase-1(Top-1), ERCC-1, Thymidylate synthase (TS) and Thymidine phosphorylase (TP) expression by inmunohistochemistry ( IHC) performed in a tumor biopsy. Ch combination schema plus Cetuximab (C) or Bevacizumab (B) at standard doses was customized based on: Topo-1 +:Irinotecan (I). Topo-1- and ERCC-1 -:Oxaliplatin(O). Topo-1- and ERCC1 +:investigator option (I or O). TS -:Fluoropyrimidines (FP).TS +:No FP. TP -:5-FU, TP +:Capecitabine. Maintenance C or B treatment was allowed. Primary outcome measure was PFS. Results: 74 pts were accrued and all of them received biomarker guide treatment. All of them began personalized. Interim analysis on 61 pts (38 males, median age 65) showed.Topo-1 + in 33 pts (54%),ERCC-1- in 36( 59%) TS + in 44 (73%), TP – in 61 ( 100%), K-ras nativein 34 ( 55%), BRaf mutated in 2 (3,2%). With a median follow up time of 9,1 months (m). Median PFS (95% CI) is 8,6 (6,2-10,9) m, with a 41,3% (27,4-55,2) 12mPFS . Overall clinical benefit (Response + Stabilizations) was 74,5% (65,6-83,4).Toxicities Grade ≥ 3 included 18% neutropenia, 4,9% asthenia and 3,3% anemia. 12 pts (23%) received loco-regional treatment ( surgery or radiosurgery). Median Overall survival has not been reached. Conclusions: Target- Guided Personalized Ch in first line CRC pts is feasible and results in promising PFS with low toxicity. Update of final results and more detailed data will be presented. Clinical trial information: NCT01453257.

Introduction Chemotherapy (Ch) options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the efficacy in terms of progression free survival (PFS) of a biomarker panel to guide treatment selection in this setting. Methods Treatment naive, ECOG 0-1, metastatic CRC pts were accrued. Pts were prospectively analyzed with a predefined set of 10 molecular targets, including: KRAS, BRAF, and PI3K mutations and Topoisomerase-1(Top-1), ERCC-1, Thymidylate synthase (TS) and Thymidine phosphorylase (TP) expression by immunohistochemistry (IHC) performed in a tumor biopsy. Ch combination schema plus Cetuximab (C) or Bevacizumab (B) at standard doses was customized based on: Topo-1 +: Irinotecan (I). Topo-1- and ERCC-1 -: Oxaliplatin(O). Topo-1- and ERCC1 +: investigator option (I or O). TS -: Fluoropyrimidines (FP).TS +: No FP. TP -: 5-FU, TP +: Capecitabine. Maintenance C or B treatment was allowed. Primary outcome measure was PFS. Results 74 pts were accrued and all of them received biomarker guide treatment. All of them began personalized. Interim analysis on 61 pts (38 males, median age 65) showed Topo-1 + in 33 pts (54%), ERCC-1- in 36 (59%) TS + in 44 (73%), TP – in 61 (100%), K-ras native in 34 (55%), BRaf mutated in 2 (3.2%), with a median follow up time of 9.1 months (m). Median PFS (95% CI) is 8.6 (6.2-10.9) m, with a 41.3% (27.4-55.2) 12 m PFS. Overall clinical benefit (Response + Stabilizations) was 74.5% (65.6-83.4).Toxicities Grade ≥ 3 included 18% neutropenia, 4.9% asthenia and 3.3% anemia. 12 pts (23%) received loco-regional treatment (surgery or radiosurgery). Median Overall survival has not been reached. Conclusion Target-Guided Personalized Ch in first line CRC pts is feasible and results in promising PFS with low toxicity. Update of results and more detailed data will be presented.

4040 Background: Nab-paclitaxel in combination with gemcitabine has shown interesting clinical activity in patients with advanced pancreatic cancer (PDA) likely related to its ability to eliminate pancreas cancer stroma. In this study we explore clinical and pathological effects of the combination in patients with operable PDA. Methods: Patients with resectable o borderline resectable pancreatic cancer were treated with gemcitabine(1000mg/m2 days 1, 8 and 15) and nab-paclitaxel(125mg/m2 days 1, 8 and 15) for two cycles prior to surgery. Response was assessed by FDG-PET, CA199 levels and elastography, an EUS-based non invasive assessment of tumor stroma. Results: 16 patients were included into the study. 2 patients (12.5%) showed a progression disease (both with hepatic metastases) and were not operated. Median value for PET SUVmax decreased from 7,1 pre-treatment to 4,6 post-treatment(p=0.004), including 7(50%) of patients with a partial metabolic response and the mean CA199 decreased from 2654 to 52(p=0.02) with 43% patients having a more that 75 % decrement in tumor marker. The elastography ratio value diminished from 36 pre-treatment to 18 post-treatment(p=0.003) and correlated with improvement in SUVmax(p=0.04) and CA199 response(p=0,07). Grade 3-4 toxicities were neutropenia in 18% (none febrile neutropenia), thrombocytopenia in 12.5 and 6.2% transaminase elevation. So far 9 patients have been operated and in 8(89%) a complete resection (R0) was achieved. 1 patient had a complete pathological response and 4 patients had near complete responses with only a few(< 5%) residual tumor. In-depth analysis of stromal composition after treatment showed, compared to a series of 10 cases untreated and treated with conventional chemoradiation, decreased myofibroblast content, increase vessel density and distorted collagen fibers. Conclusions: Neoadjuvant treatment with gemcitabine plus nab-paclitaxel is feasible and results in significant clinical activity. Non-invasive elastography appears and attractive method to monitor tumor response. The rate of pathological responses and R0 resections in substantial for this setting. Biological studies of resected specimens show unique effects in tumor stroma.

250 Background: Mechanisms of resistance to docetaxel (D) are not fully understood. Preclinical work showed that administration of temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD), toxicity, pharmacokinetics (PK) and preliminary activity of D in combination with T in CRPC patients (pts). Methods: Pts aged ≥ 18 with advanced solid tumors refractory to standard therapy, ECOG ≤2, adequate bone marrow and renal function were eligible. D was given once q. 3 weeks along with T on days 2, 9 &16. The protocol was later amended and day 9 of T omitted due to excessive myelotoxicity. A 3+3 rule dose escalation was used with the next dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. An expanded cohort for pts with CRPC who have progressed to D will enroll pts once the RPTD has been defined. Results: To date 13 pts have been enrolled, median age = 65 (range 35–76), 9 male and 8 ECOG 0, Forty-seven cycles (median: 2; range: 1–9) were administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%) and hypercholesterolemia (65.9%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), and hypophosphatemia (23%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional pts treated with no DLTs. No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreas, 2 CRPC, 1 rectal and 1 sarcoma) achieved stable disease. One pt with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. The expanded cohort for CRPC patients is opened and recruiting. Conclusions: T and D can be safely combined at reduced doses of both agents with no PK interaction. Preliminary antitumor activity has been observed in CRPC patients. Data on the expanded cohort will be presented.

Background: Mechanisms of resistance to docetaxel (D) are not well defined. Preclinical work has shown that the administration of the mTOR inhibitor Temsirolimus (T) between courses of D delays the growth of PTEN deficient tumors in xenografts. (Wu et al. Cancer Res 2005) The current study aims to determine the recommended phase II dose (RPTD) of D in combination with T, their toxicity profile, pharmacokinetics (PK) and preliminary clinical activity. Methods: Patients (pts) aged ≥ 18 with any advanced solid tumor refractory to standard therapy, ECOG ≤2 with adequate bone marrow, renal, pulmonary and hepatic functions were eligible. D was given once every 3 weeks with T administered initially on days 2, 9 and 16. However, the protocol was later amended and day 9 of T was omitted due to excessive hematological toxicity. A 3+3 rule dose escalation was used with the following dose levels (DL) planned: DL1: D 50mg/m2, T 15 mg; DL2: D 65mg/m2, T 15 mg; DL3: D 75mg/m2, T 15 mg; DL4: D 75mg/m2, T 25 mg. Blood samples were collected for PK studies, using a validated LC-QqQ-MS procedure. An expanded cohort for patients with castration resistance prostate cancer (CRPC) who have progressed to D is planned once the RPTD has been reached. Results: To date 13 pts have been enrolled with median age = 65 (range 35–76), 9 were male and 8 had ECOG 0, Forty-seven cycles (median: 2; range: 1–9) have been administered. The most frequent related adverse events (AEs) of all grades expressed as % of cycles were: leucopenia (80.8%), hyperglycemia (70.2%), anemia (68.1%), hypercholesterolemia (65.9%), neutropenia (53.2%) hypertriglyceridemia (53.2%) and asthenia (44.7%). The most common Grade 3–4 AEs as % of cycles were: leucopenia (27.6%), neutropenia (29.7%), hypophosphatemia (23%) and lymphopenia (17.0%). Two pts in DL2 experienced dose limiting toxicities (DLT) consisting of intolerable grade 2 mucositis and febrile neutropenia respectively. DL1 was expanded and 3 additional patients were treated with no DLTs. Clearance (litres/h) and volume of distribution (litres) for D, T, and sirolimus (S) were (mean, SD): D, 196.5 (126.1), 2345.0 (1984.0); T, 25.3 (13.3), 128.8 (60.4); S, 24.1 (23.7), 456.3 (131.9). No drug-drug PK interactions were observed. Among 13 pts evaluable for response, 6 (2 pancreatic, 2 prostate, 1 rectal and 1 sarcoma) achieved stable disease. One patient with CRPC who had previously progressed on docetaxel received 9 cycles of treatment with sustained clinical benefit. Conclusions: The combination of D and T seems clinically tolerable at reduced doses of both agents and presents no PK interactions. Additive haematological toxicity and mucositis are the limiting factors to progress on dose escalation. The RPTD is D 50 mg/m2 on day 1 with T 15 mg on days 2 and 16 of a three-weekly schedule. Preliminary antitumor activity has been observed and an expanded cohort for patients with CRPC will start recruitment soon. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C65.

11074 Background: Treatment options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the feasibility of developing an implementing a biomarker panel to guide treatment selection in this setting. Methods: Colorectal cancer tumors were prospectively analyzed with a predefined set of 11 molecular targets, including: KRas and PI3K mutations, EGFR amplification (FISH), and ERCC-1, TS, TP expression by IHC. Clinical characteristics and response to chemotherapy were registered. To establish the utility of this panel, we determine as congruent-treatment if the panel predict the best treatment in patients with more of 1 chemotherapy line and no-congruent-treatment if do not. Results: A total of 84 patients were studied. Only 6 % required a repeated biopsy to obtain sufficient tumor for marker analysis. In 81 % of patients was feasible to study almost 8/11 targets. There were 29 pts (39%) with KRas mutant CRC; 3 pts with PI3K mutations (4%, all of them with KRas mutation); and 2 patients with EGFR amplification. ERCC-1 was positive in 5/78 (6.4%) and TS was positive in 47%. None of 54 pts had TP positivity. Clinical floow up was available in 66 pts (44 males, median age 59, 93% ECOG 0–1). Nineteen patients had early CRC; 23 with metastatic CRC treated with a first line chemotherapy and 24 with advanced CRC treated with 2 or more prior regimens. In this last group for whom the response to multiple agents is known, the panel predictive the most effective treatment in 14 of 24 cases. Conclusions: This targeted-therapy-panel is feasible to implement and should be explore to predict treatment response to CRC . No significant financial relationships to disclose.