Plusieurs études de phase II non comparatives ont évalué la vinorelbine orale métronomique (VOM) dans le cancer bronchique métastatique non à petites cellules (CBNPC), mais la petite taille de chaque étude limite leurs conclusions. Réaliser une méta-analyse sur données individuelles des patients inclus dans les études évaluant la VOM dans les cas de CBNPC métastatique afin de mesurer la survie et la sécurité du traitement avec ce schéma thérapeutique. Les études ont été sélectionnées si : – l'administration de vinorelbine par voie orale était donnée trois fois par semaine ; – avec une dose quotidienne fixe comprise entre 30 et 50 mg ; – la publication était antérieure au 4 octobre 2018. La base de données comprenait 8 variables caractérisant la maladie et la démographie, 3 variables informant sur le schéma thérapeutique et 12 variables décrivant la survie et la toxicité. Neuf études portant sur 418 patients remplissaient les critères de sélection, 80 % des patients présentaient des critères de fragilité tel qu'un âge de 75 ans ou plus, ou un indice de performance ECOG (PS) = 2. La survie globale (SG) médiane était de 8,7 mois (IC95 % : 7,6 à 9,5). Les taux de SG à six mois, un an et deux ans après le début du traitement par la vinorelbine étaient respectivement de 64 %, 30,3 % et 8,9 %. Dans le modèle de Cox, un PS = 2 et l'anémie quel qu'en soit le grade étaient des déterminants significatifs d'une SG plus brève. La survie sans progression médiane était de 4,2 mois (IC95 % : 3,9–5). À 6 mois et à un an, les taux de SSP étaient respectivement de 35 % et 11,9 %. Dans le modèle de Cox stratifié pour la variable « étude », un PS = 2 et un stade IV (vs IIIb) étaient des déterminants significatifs d'une PFS plus brève. Pour 40 % des patients, aucune toxicité n'a été rapportée, alors que 66 autres patients (15,8 %) ont présenté une toxicité de grade 3–4. La toxicité la plus fréquente était une anémie de tout grade (35,8 %) qui était la plus sévère avec la dose de 50 mg. La vinorelbine orale métronomique est une chimiothérapie active et bien tolérée pour le CBNPC métastatique et constitue une option de traitement gérable pour les patients fragiles.

The role of genetic molecular markers in neoadjuvant treatment for locally advanced esophageal cancer has been reviewed, focusing strictly on concurrent chemoradiation protocols followed by surgery. Eleven studies evaluated the role of mRNA expression profile; the end point was overall survival (OS) in two studies and different definitions of histological response in nine. Genes reported as significant were involved in cell cycle control (30), apoptosis (7), structural molecules (9), cell metabolism (6) and DNA repair (1). Seven studies reported about 15 microRNA (miRNA) molecules associated with OS (2) or histological response (13), however, defined with different classifications. Their target genes were prevalently involved in cell cycle control (4), apoptosis (1), cell adhesion (1), migration (1) and angiogenesis (1). Gene polymorphisms (single-nucleotide polymorphisms (SNPs)) have been evaluated in 8 studies reporting 10 variants associated with survival or pathological response. OS was the end point in six of these studies. SNPs reported as significant were involved in DNA repair system (4), detoxification (2), folate metabolism (6), drug efflux (2) and others (2). In a study, a panel including histology, pathological response and five SNPs discriminated two subsets of patients with 5-year survival rates of 79.3% and 26.3% (hazard ratio 6.25, P <0.0001). In another study, combination of stage, grade and 4 miRNAs improved prediction of pathological response ( P =10 −30 ). At present, given the great inconsistency of the data and the variability of the end points, definite conclusions are extremely difficult, if not impossible. More consistent data can derive only from analyses obtained from patients included in prospective randomized trials while panels combining genetic and clinical factors may improve prediction.

MicroRNAs (miRNAs) hold great promise in cancer research. The use of appropriate reference miRNAs for normalization of qPCR data is crucial for accurate expression analysis. We present here analysis and verification of current data, proposing a workflow strategy for identification of reference miRNAs in colorectal cancer (CRC). We performed a systematic review of studies aimed to identify stable reference miRNAs in CRC through high-throughput screening. Among the candidate miRNAs selected from the literature we excluded those predicted to target oncogenes or tumor suppressor gene. We then assessed the expression levels of the remaining candidates in exosomes, plasma and tissue samples from CRC patients and healthy controls. The expression stability was evaluated by box-plot, ∆Cq analysis, NormFinder and BestKeeper statistical algorithms. The effects of normalisers on the relative quantification of the oncogenic miR-1290 was also assessed. Our results consistently showed that different combinations of miR-520d, miR-1228 and miR-345 provided the most stably expressed reference miRNAs in the three biological matrices. We identified suitable reference miRNAs for future miRNA expression studies in exosomes plasma and tissues CRC samples. We also provided a novel conceptual framework that overcome the need of performing ex novo identification of suitable reference genes in single experimental systems.

Background: Metronomic therapy is the continuous administration of low doses of a single drug that through antiangiogenetic and cytostatic effects allows to delay disease progression and obtain symptom relieve. Here we report data of clinical outcome and pharmacokinetics in NSCLC pts receiving OMV at 3 different doses Methods: Vinorelbine (VNR) was administered every other day without break until progression or toxicity at the dose of 20 mg (10 pts), 30 mg (63), 50 mg (11). Pts were monitored weekly for one month, fortnightly for two months and then monthly with clinical visit, blood chemistry and pharmacokinetics. VNR and its active metabolite 4-O-deacetyl-VNR (dVNR) were determined by Liquid Chromatography and Mass Spectrometry Results: 84 patients (68 males), median age 73 yrs (range 29-88; 61% over 70), 50 with non squamous histology were given 1968 wks of OMV; 23 pts (median age 80) were chemotherapy naive, 28 (median age 74) were in 2nd line, 33 (39%) in 3rd-4th line; mostly were symptomatic (74%). OMV was administered for a median of 13 weeks (range 0.3-154). Median OS after OMV was 25 wks; 41 pts (median age 71) had a median intake of 28.4 wks (range 13.5-154) and a median OS after OMV of 52 wks. Treatment duration was similar in different age groups (<60 vs 60–70 vs 70-80 vs >80 yrs, P = NS) and not influenced by therapy line or histology. Seven pts experienced toxicity causing treatment discontinuation (4 neutropenia G4, 3 non haematological) and 8 required delay or dose reduction. Pharmacokinetics was analyzed in 62 pts using 460 blood samples (20 mg 7 pts; 30 mg 50 pts, 50 mg 5 pts). VNR and dVNR levels reached steady state after one month and remained stable. Median VNR + dVNR concentrations were similar in 30-50 mg pts (median 5.0 ng/mL, range 0.3-31) vs 2.7 ng/mL (range 0.8-8.8) in 20 mg pts (P = NS). Moreover they were not influenced by treatment line and various classes of age (p = 0.6); however higher levels were associated with severe toxicity (9.1 vs 4.5 ng/ml, p = 0.0003). Conclusions: a) Clinical outcome : OMV provided in 2nd or subsequent lines a survival comparable to other current and more expensive regimens in elderly pts with a favourable toxicity profile. b) Pharmacokinetics: i) this is the largest report in elderly NSCLC pts; ii) concentrations remained stable, showing constant absorption/elimination even after long term intake; higher levels were associated with toxicity; iii) systemic exposure suggest 30 mg as a suitable dose for this setting of pts.

Candidate genes involved in DNA repair, 5-fluorouracil metabolism and drug detoxification were genotyped in 124 patients receiving neoadjuvant chemoradiation treatment for locally advanced esophageal cancer and their predictive role for long-term relapse-free survival (RFS) and cancer-specific survival (CSS) were evaluated. A panel including MTHFR 677TT, MDR1 2677GT, GSTP1 114CC, XPC 499CC and XPC 939AC+CC, defined as high-risk genotypes, discriminated subgroups with significantly different outcomes. When the panel was combined with histology, patients split into two subsets with 5-year RFS and CSS rates of 65% vs 27% (hazard ratio (HR) 3.0, P<0.0001) and 69% vs 31% (HR 2.9, P<0.0001), respectively. Combining the 5-single-nucleotide polymorphism (5-SNP) panel with pathological response defined two major informative risk classes with 5-year PFS and CSS rates of 79.4% vs 17.7% (HR 6.71, P<0.0001) and 79.3% vs 26.3% (HR 6.25, P<0.0001), respectively. This classification achieved a sensitivity of 79%, a specificity of 85.4% and an accuracy of 81.8%.

So far, no reliable predictive clinicopathological markers of response to aromatase inhibitors (AIs) have been identified, and little is known regarding the role played by host genetics. To identify constitutive predictive markers, an array-based association study was performed in a cohort of 55 elderly hormone-dependent breast cancer (BC) patients treated with third-generation AIs. The array used in this study interrogates variants in 225 drug metabolism and disposition genes with documented functional significance. Six variants emerged as associated with response to AIs: three located in ABCG1, UGT2A1, SLCO3A1 with a good response, two in SLCO3A1 and one in ABCC4 with a poor response. Variants in the AI target CYP19A1 resulted associated with a favourable response only as haplotype; haplotypes with increased response association were also detected for ABCG1 and SLCO3A1. These results highlight the relevance of host genetics in the response to AIs and represent a first step toward precision medicine for elderly BC patients.

BackgroundEstrogen receptor alpha (ERα)-positive breast cancer is the most frequent tumour in women and tamoxifen (TAM), an ERα competitive antagonist, is diffusely used for its treatment and prevention. Unfortunately, a significant percentage of patients do not benefit the treatment because of intrinsic and acquired resistance. ERα is activated by estrogen binding and regulates its own and estrogen-sensitive genes (ESG, e.g., MGP) expression. Recently, ERα splice variants (ESV) have been detected in healthy and tumour tissues, with pharmacological characteristics partially different from the complete form (ERα66), and emerging data suggest that they may modulate TAM efficacy.Our study aimed to investigate the effect of TAM on ESV and ESG expression in vivo, using peripheral blood leukocytes as surrogate tissue.MethodsThirty-four women taking TAM as adjuvant therapy and 100 aged-matched healthy women were enrolled for this pilot study. Leukocytes from peripheral blood were collected to extract RNA. The expression of ESV and ESG were quantified by Taqman probes and SYBR-Green dye, respectively. T Student's test and correlation analysis were performed.ResultsOur data showed that ERα36 and ERα66 were the most expressed isoforms in leukocytes. Their levels were largely variable among patients and inversely correlated (P < 0.0001). TAM was associated with reduced levels of ERα exon 5 deleted variant (P = 0.01) and on average doubled levels of the ERα missing exon-7 isoform (P = 0.06), compared to controls. In patients, MGP expression levels were significantly down-regulated compared to subjects with no anti-estrogenic treatment (P < 0.0001) and correlated with ERα36 levels (R = 0.37, P = 0.03).ConclusionsLeukocytes may be used to study the expression profiles of ERα variants and sensitive genes, in patients taking TAM. TAM significantly affected 5- and 7-exon deleted isoforms and down-regulated MGP gene. The ERα36 isoform, that does not bind TAM, stimulated MGP transcription when ERα66 was inhibited by the drug, suggesting a role in treatment resistance.Funded by LILT (Italy). BackgroundEstrogen receptor alpha (ERα)-positive breast cancer is the most frequent tumour in women and tamoxifen (TAM), an ERα competitive antagonist, is diffusely used for its treatment and prevention. Unfortunately, a significant percentage of patients do not benefit the treatment because of intrinsic and acquired resistance. ERα is activated by estrogen binding and regulates its own and estrogen-sensitive genes (ESG, e.g., MGP) expression. Recently, ERα splice variants (ESV) have been detected in healthy and tumour tissues, with pharmacological characteristics partially different from the complete form (ERα66), and emerging data suggest that they may modulate TAM efficacy.Our study aimed to investigate the effect of TAM on ESV and ESG expression in vivo, using peripheral blood leukocytes as surrogate tissue. Estrogen receptor alpha (ERα)-positive breast cancer is the most frequent tumour in women and tamoxifen (TAM), an ERα competitive antagonist, is diffusely used for its treatment and prevention. Unfortunately, a significant percentage of patients do not benefit the treatment because of intrinsic and acquired resistance. ERα is activated by estrogen binding and regulates its own and estrogen-sensitive genes (ESG, e.g., MGP) expression. Recently, ERα splice variants (ESV) have been detected in healthy and tumour tissues, with pharmacological characteristics partially different from the complete form (ERα66), and emerging data suggest that they may modulate TAM efficacy. Our study aimed to investigate the effect of TAM on ESV and ESG expression in vivo, using peripheral blood leukocytes as surrogate tissue. MethodsThirty-four women taking TAM as adjuvant therapy and 100 aged-matched healthy women were enrolled for this pilot study. Leukocytes from peripheral blood were collected to extract RNA. The expression of ESV and ESG were quantified by Taqman probes and SYBR-Green dye, respectively. T Student's test and correlation analysis were performed. Thirty-four women taking TAM as adjuvant therapy and 100 aged-matched healthy women were enrolled for this pilot study. Leukocytes from peripheral blood were collected to extract RNA. The expression of ESV and ESG were quantified by Taqman probes and SYBR-Green dye, respectively. T Student's test and correlation analysis were performed. ResultsOur data showed that ERα36 and ERα66 were the most expressed isoforms in leukocytes. Their levels were largely variable among patients and inversely correlated (P < 0.0001). TAM was associated with reduced levels of ERα exon 5 deleted variant (P = 0.01) and on average doubled levels of the ERα missing exon-7 isoform (P = 0.06), compared to controls. In patients, MGP expression levels were significantly down-regulated compared to subjects with no anti-estrogenic treatment (P < 0.0001) and correlated with ERα36 levels (R = 0.37, P = 0.03). Our data showed that ERα36 and ERα66 were the most expressed isoforms in leukocytes. Their levels were largely variable among patients and inversely correlated (P < 0.0001). TAM was associated with reduced levels of ERα exon 5 deleted variant (P = 0.01) and on average doubled levels of the ERα missing exon-7 isoform (P = 0.06), compared to controls. In patients, MGP expression levels were significantly down-regulated compared to subjects with no anti-estrogenic treatment (P < 0.0001) and correlated with ERα36 levels (R = 0.37, P = 0.03). ConclusionsLeukocytes may be used to study the expression profiles of ERα variants and sensitive genes, in patients taking TAM. TAM significantly affected 5- and 7-exon deleted isoforms and down-regulated MGP gene. The ERα36 isoform, that does not bind TAM, stimulated MGP transcription when ERα66 was inhibited by the drug, suggesting a role in treatment resistance.Funded by LILT (Italy). Leukocytes may be used to study the expression profiles of ERα variants and sensitive genes, in patients taking TAM. TAM significantly affected 5- and 7-exon deleted isoforms and down-regulated MGP gene. The ERα36 isoform, that does not bind TAM, stimulated MGP transcription when ERα66 was inhibited by the drug, suggesting a role in treatment resistance.

The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1 , XPD , XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1 , TP53 and MDM2 genes in 61 patients who received radio-chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC ( P =0.015). The resultant variant was also involved in the onset of sporadic ESCC ( P =0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy.

neo-adjuvant 5-fluorouracil-based chemoradiotherapy (CRT) for locally advanced rectal adenocarcinoma is effective in downstaging more than half of patients before surgery. Interindividual variations in DNA repair and metabolism of pyrimidine nucleotides and folates may be important mechanisms of resistance to radio and chemotherapy and often their associations with anticancer treatment cannot be revealed by classical statistics, due to epistasis. The Multifactor Dimensionality Reduction (MDR) method was designed to identify and model gene to gene interactions. The aim of our study was to verify if genetic variants in DNA repair and pyrimidine/folate metabolism are associated with rectal cancer response to CRT, comparing different statistical approaches. Seventy patients with stage II and III rectal cancer were enrolled and treated for 5 weeks with concurrent 300 mg/m2/die of 5-fluorouracil protracted venous infusion and 56 Gy radiation, followed by surgical resection. Response was directly evaluated on surgical specimens and scored according to tumor residual mass as in TNM classification. PT0-2 were defined as major response. Genomic DNA was extracted from peripheral blood lymphocytes and ERCC1, XPD, XPC, XPA, XRCC1, XRCC3, UMPS, MTHFR and TYMS polymorphisms were analyzed by PCR-RFLP. Genotypes were associated with tumor outcomes to CRT using Chi square test and the MDR method. patients’ response to CRT was as follows: pT0 in 25.7%, pT1-2 in 34.3% and pT3-4 in 40%. Chi square test found no significant relationship between genotypes and local pathological response. Using the MDR method, we showed a significant association between the combination of XPC/TYMS/XRCC3 genetic variants and major response (P = 0.0001) that was correctly predicted in 81.8% of patients (VPP, 80.7%; 95% CI, 62.1–91.5; VPN, 86.4%; 95% CI, 73.3–93.6; sensibility, 77.8%; specificity, 88.4%). MDR proved to be an easy and valid method to detect genetic combinations identifying rectal cancer patients with a high probability of chemoradiotherapy response.

Introduction Gastrointestinal stromal tumours (GISTs) represent a major fraction of gastrointestinal sarcomas, frequently showing c-kit exon 11 mutations and associated with a good response to imatinib mesylate. Secondary resistance to imatinib has also been reported during therapy; therefore, clinicians need non-invasive tools for early assessment of treatment response due to traditional morphologic criteria [X-rays and computerized tomography (CT)] being unsuccessful. We report upon a patient with GIST with exon 11 mutation showing excellent response to imatinib mesylate, only a few days after initiation of the therapy and persisting for 18 months of follow-up. Here we also provide a short review of the recent literature on this topic. Conclusion There is evidence that F-FDG PET and PET/CT could be used to optimally monitor c-kit inhibitor therapy in GISTs, detecting early responders, non-responders and secondary resistance, there by allowing better patient management. Introduction Gastrointestinal stromal tumours (GISTs) are rare malignancies even though they represent the most relevant part of the gastrointestinal (GI) tract sarcomas. In most cases, GISTs are localized in the stomach and small intestine, followed by the colon and rectum1. GISTs are derived from Cajal cells in myenteric plexus; they are frequently marked by the expression of the c-kit tyrosine kinase receptor1. C-kit is a tyrosine kinase and is normally activated as a ligand by stem cell factor; a mutation of the c-kit proto-oncogene activates the tyrosine kinase in the absence of physiologic stimulation, there by leading to unrestrained cell proliferation2. The majority of GISTs (75%–80%) shows gain-of-function mutations of transmembrane receptor c-kit, which causes continuous activation of cell proliferation. The most common is the exon 11 mutation3. Genetic mutation analysis allows investigation of the relationship between the mutations occurred and response to drugs, such as imatinib mesylate. Imatinib mesylate is a tyrosine kinase inhibitor of tumour growth, and it has been demonstrated to be effective in GIST treatment. It is currently the first-line drug in advanced GISTs4. Recent studies3,5 show that 85% patients with c-kit exon 11 mutation respond to imatinib mesylate; nevertheless, it has been reported that resistance to this drug may occur during therapy6. This phenomenon needs to be disclosed as early as possible to change the therapeutic strategy, improve the clinical outcome and reduce the cost of ineffective therapies. In this regard, the response evaluation criteria in solid tumours (RECIST) criteria which relates to morphological examinations, mainly contrastenhanced computed tomography (CT), are unsatisfactory in assessment of GISTs response because changes in tumour size may be minimal at an early post-therapy evaluation or the lesion could be even larger because of intra-tumoural necrosis or haemorrhage7,8. There is recent evidence that a functional imaging modality such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) or a hybrid imaging modality such as PET/ CT could achieve this goal9–11. This paper reports the case of a GIST patient treated with imatinib mesylate and showing an excellent response as documented by 18F-FDG PET/CT only a few days after initiation of the therapy and persisting for 18 months of follow-up. We also reviewed the relevant literature pertaining to the response monitoring tools in GISTs. Discussion In April 2008, a 54-year-old male patient underwent surgery for GIST T2N0M0 with mutation of exon 11. In August 2010, a controlled CT revealed bone and liver GIST metastasis that was proven at biopsy. Therapy with imatinib mesylate was scheduled. Before initiating therapy, the patient underwent baseline 18F-FDG PET/CT and repeated an early PET/CT examination 10 days after initiation of the therapy. Subsequent PET/CT controls during imatinib mesylate therapy * Corresponding author Email: domenico.rubello@libero.it † Current address: Nuclear Medicine and Radiology Unit, Morgagni-Pierantoni Hospital, Forli, Italy 1 Department of Nuclear Medicine, Medical Physics, Radiology, Neuroradiology, PET/ CT Centre, ‘Santa Maria della Misericordia’ Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy 2 Department of Medical Physics, ‘Santa Maria della Misericordia’ Hospital, Rovigo, Italy 3 Department of Oncology, ‘Santa Maria della Misericordia’ Hospital, Rovigo, Italy Em er gi ng T ec hn ol og ie s

Neoadjuvant chemoradiotherapy (CRT) is now considered the standard of care by many centers in the treatment of both squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus. This study evaluates the effectiveness of a neoadjuvant CRT protocol, as regards pathological complete response (pCR) rate and long-term survival.

BACKGROUND:Tumour-released DNA in blood represents a promising biomarker for cancer detection. Although epigenetic alterations such as aberrant promoter methylation represent an appealing perspective, the discordance existing between frequencies of alterations found in DNA extracted from tumour tissue and cell-free DNA (cfDNA) has challenged their practical clinical application. With the aim to explain this bias of agreement, we investigated whether protocadherin 10 (PCDH10) promoter methylation in tissue was associated with methylation pattern in matched cfDNA isolated from plasma of patients with colorectal cancer (CRC), and whether the strength of concordance may depend on levels of cfDNA, integrity index, as well as on different clinical-pathological features.METHODS:A quantitative methylation-specific PCR was used to analyse a selected CpG site in the PCDH10 promoter of 67 tumour tissues, paired normal mucosae, and matched plasma samples. The cfDNA integrity index and cfDNA concentration were assessed using a real-time PCR assay.RESULTS:The PCDH10 promoter methylation was detected in 63 out of 67 (94.0%) surgically resected colorectal tumours and in 42 out of 67 (62.7%) plasma samples. The median methylation rate in tumour tissues and plasma samples was 43.5% (6.3-97.8%) and 5.9% (0-80.9%), respectively. There was a significant correlation between PCDH10 methylation in cfDNA and tumour tissue in patients with early CRC (P<0.0001). The ratio between plasma and tissue methylation rate increases with increasing cfDNA integrity index in early-stage cancers (P=0.0299) and with absolute cfDNA concentration in advanced cancers (P=0.0234).CONCLUSION:Our findings provide new insight into biological aspects modulating the concordance between tissues and plasma methylation profiles.

9155 Background: The use of chemotherapy in vulnerable and frail elderly pts still represents a challenge in geriatric oncology. PLD represents an appealing drug in elderly pts, because of reduced cardiac and haematological toxicity, while maintaining efficacy similar to that of the free drug. Aim of this study is the relation of PLD pharmacokinetics (PK) with clinical parameters in particular in the vulnerable and frail elderly subsets over 70. Methods: 20 patients aged between 70 and 86 years (median 78), 14 breast cancer, 3 ovarian cancer, 2 sarcomas and 1endometrial cancer all in stage III and IV, were enrolled. Comprehensive geriatric assessment (CGA) was performed before and at the end of the treatment. They received PLD 40 mg/m2 by intravenous infusion over 60 min every 4 weeks with standard pre-medication. Blood samples were taken at pre-infusion, 1 h, 7, 14 and 21 days after administration for the first 3 cycles. Plasma levels of doxorubicin were analyzed by HPLC. PK analysis was done by mono-compartmental model. Chi square and t test were used for statistical analysis. Results: CGA identified 4 (20%) fit, 9 (45%) intermediate and 7 (35%) frail pts. Median co- morbidity index was 2. Doxorubicin PK parameters varied widely among pts; mean values and coefficient of variation were as follows: Cmax = 22.6 mg/L, 19.4%; plasma half life (t1/2)= 82.1, 38%; AUC=115 mg × die/L, 45%. There was a significant linear correlation between increasing age and plasma t1/2 (p=0.007); pts aged > 78 had an AUC 58% higher than that of younger subjects (p=0.02). Pts with longer drug exposure (according to t1/2 median value= 89 h) had an increased risk of cutaneous toxicity (RR= 6.6, p=0.009). Responses rate (CR +PR) was 36%, SD 14% and PD 50%; pts achieving a response had a longer doxorubicin half life (108 h vs 66 h, p<0.01). Grade 4 toxicity and deterioration of the clinical status due to toxicity were not recorded. Conclusions: This study analyzed the PK of PLD in a subset of elderly pts over 70, mainly including frail and vulnerable subjects: drug exposure over time was statistically associated with increasing age and cutaneous toxicity, without affecting the general safety profile of the treatment. No significant financial relationships to disclose.

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase ( TYMS ) 5′UTR and 3′UTR polymorphisms and methylenetetrahydrofolate reductase ( MTHFR ) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P <0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P =0.041) and OS (HR=3.37; P =0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P =0.0008) and OS (HR=2.66; P =0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3–4 toxicity ( P =0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

e14571 Background: The aim of the study was to evaluate if genetic polymorphism of DNA repair genes may predict pathological response and survival in patients affected by locally advanced esophageal cancer, treated with a neoadjuvant schedule including weekly DTX (35 mg/mq) and CDDP (25mg/mq), protracted venous infusion of FU (150 mg/mq/die) and concomitant radiotherapy for 8 weeks followed by surgery. Methods: Fifty-seven patients were enrolled, aged 60±7 years old. Median follow-up was 27 months. Genomic DNA was extracted from peripheral blood lymphocytes and XPA, XPD, XRCC1, ERCC1 and XRCC3 were genotyped through RFLP analysis. Associations between gene polymorphisms and pathological response and survival were analysed through Chi square test and Log rank test respectively. Results: Thirty-two patients presented complete remission (pCR) and 10 patients microfocal residual disease (pMRD); the remaining 15 patients were considered stable or non-responders (pS-NR). The event free(EFS) and overall (OS) median survival times have not yet reached; significantly better 3-year survival rates were observed after pCR than in case of pMRD and pS-NR (EFS: 87% vs 42.8%, p=0.0004; OS: 86% vs 56%, p=0.02, respectively). No association was found between pathological response or survival with XRCC1, ERCC1 and XPD polymorphisms. On the contrary, the XPA 23AA genotype showed an increased risk of recurrence (HR=3.5; 95% CI 1.3 to 43.7, p=0.02) and death (HR=4.4, 95% CI 1.9 to 78.2, p=0.009); there was a trend for reduced risk of negative pathological response with decreasing number of allele 23A : MRD and S-NR were found in 71%, 45% and 35% cases for AA, AG and GG genotypes, respectively. The XRCC3 241MetMet variant was significantly associated with increased risk of death (HR= 6.0, 95% CI 3.0 to 40.0, p=0.008); a trend toward a higher recurrence (p=0.07) and worse response (60% vs 43%) was found. Conclusions: XPA and XRCC3 gene defective variants were significantly associated with worse outcome and could predict OS in esophageal cancer patients treated with a neo-adjuvant intensive radio-chemotherapy protocol. Founded by CARIPARO, Italy No significant financial relationships to disclose.

Parmi les différents thèmes priorisés dans le programme régional de télémédecine, le soin en établissements d’hébergement pour personnes âgées dépendantes (EHPAD) a été choisi pour cette expérimentation. Le projet cible le parcours de la personne âgée, de plus de 75 ans, posant le problème d’une plaie chronique dans un contexte de dépendance et de polypathologie.L’objectif de cette expérimentation est d’améliorer à la fois l’accès aux soins des personnes âgées et la continuité des soins ville/hôpital et de favoriser la formation des soignants.Cette expérimentation (septembre 2012 à septembre 2013) est basée sur la téléconsultation lors de laquelle l’équipe d’experts (gériatre, infirmière, ergothérapeute, diététicienne et secrétaire) intervient deux demi-journées par semaine au sein du pôle de gérontologie clinique (CHU Bordeaux, France). Après avoir obtenu le consentement du patient, le médecin traitant et l’équipe de l’EHPAD se connectent dans une salle virtuelle avec l’équipe du centre expert. Pour la structure demandeuse, cette connexion s’établit soit dans la chambre du patient à l’aide d’un chariot de télémédecine (EHPAD avec Wifi), soit depuis une salle dédiée (EHPAD sans Wifi). Suite à la téléconsultation, un compte rendu est écrit puis envoyé via une messagerie sécurisée à la structure demandeuse.Au total, six EHPAD (en Gironde et Dordogne) ont été inclus dans ce projet. Les résultats préliminaires rapportent un total de 51 téléconsultations avec la prise en soins et le suivi d’escarres (57,9 %), d’ulcères trophiques vasculaires (26,3 %) et de plaies d’origine traumatique (15,8 %). Ces premiers résultats montrent que la télémédecine améliore de manière significative la cicatrisation des plaies et diminue les dépenses en pansements en réduisant le rythme des changements de pansements (p = 0,005). Sans ces téléconsultations, les médecins généralistes auraient adressé leurs patients en consultation spécialisée dans 31,6 % des cas et en hospitalisation de jour dans 47,4 % des cas.Les enjeux de la télémédecine sont importants en gériatrie, notamment dans le suivi des personnes âgées avec des pathologies chroniques nécessitant des allers et retours répétés à l’hôpital. Une des perspectives est d’élargir les téléconsultations à tous les syndromes gériatriques (chutes, confusion, dénutrition, etc.) et d’assurer la formation continue aux professionnels de santé. L’outil peut également permettre le suivi des patients âgés par d’autres spécialistes afin d’assurer au mieux la continuité des soins.Of the three themes identified by the French Regional Program of Telemedicine, patient care in nursing homes was chosen for this study, targeting the care of elderly patients aged over 75 years with chronic wounds in the context of dependency and polypathology.The aim of this study was to improve both elderly patients’ access to care and continuity of care in the hospital and town setting, and to promote the training of caregivers.This study (September 2012 to September 2013) is based on teleconsultations organized two and a half days per week by an expert team (comprising a geriatrician, nurse, occupational therapist, dietician, and secretary) in a gerontology center (Bordeaux University Hospital, France). After obtaining patient consent, the general practitioner (GP) and the nursing home care team connect to a virtual room with the expert center, either from the patient's room using a mobile telemedicine chariot (nursing homes with Wifi) or in a dedicated room (nursing homes without Wifi). Following each teleconsultation, a report is written and sent via a secure messaging system to the GP.In total, six nursing homes (in the French departments of Gironde and Dordogne) were included in this project. Preliminary results reported a total of 51 teleconsultations, dealing with the treatment and follow-up of pressure ulcers (57.1 %), vascular ulcers (26.3 %), and traumatic ulcers (15.8 %). These results indicate that telemedicine significantly improved wound healing and decreased dressing expenditure by reducing the pace of dressing changes (P = 0.005). Without these teleconsultations, GPs would have referred their patients to specialized consultations in 31.6 % of cases and for day hospitalizations in 47.4 % of cases.The challenges of telemedicine are great in geriatrics, particularly in the monitoring of elderly patients with chronic diseases requiring repeated hospitalizations. One perspective is to expand teleconsultations to cover all geriatric syndromes (falls, confusion and behavioral disorders, malnutrition, etc.) and to provide continuing professional practice. The telemedicine tool discussed in this paper may also enable other specialists to monitor elderly patients in order to provide better continuity of care.