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Introduction The European Union (EU) do not publish the quality of cause-of-death statistics, when is possible to assess quality by reliability. Quality does not present consolidated indicators. Ill-defined and other inaccurate causes have presented different groupings. Objective To assess the quality of official cause-of-death statistics of the European Union by member states from 2006 to 2020. Methods Cases and population were from the WHO repertory. We selected causes in EU27 countries by up to fourth code-character of ICD10 -on the EuroStat website were not available-. Case counts were grouped into ill- defined, unspecific, less specific (the latter two, in inaccurate), and judicial (inaccurate external causes) categories, based on literature and expertise. We calculated age-adjusted rates to the Standard European Population by country, sex, period (2006-, 2011- and 2016-2020), and quality category. We tested the Comparative Mortality Ratio (CMR) of each country to the European Union median by a Bayesian approach, at 5% statistical significance. We plotted the rates proportion of each quality category in its all causes. Results We included 25 countries. Some did not report all years. Six countries showed >19% for ill-defined causes and 3 member states had Discussion Literature showed that incorrect causes of death were random distributed. Probably major causes were biased and underestimated. Conclusions Quality of cause of death is a useful indicator of mortality statistics reliability. Quality indicators targeted national gaps across EU. We need a new EU task force on statistics of causes of death in accordance with the XXI century. Key messages • Quality indicators of causes of death statistics targeted national gaps across the European Union. • The statistics of death causes underestimated the main causes of death in the European Union.

Background Mortality is the arrow of aggregated individual’s life style of living beside the national public health and health care system outcomes. The contribution of specified death-causes to the temporal evolution of its great cause, is targeting the community framework for public health action reduction. Objective To assess yearly contribution of specified death-causes to temporal trend-shifts of its major death- cause in Spain, 1975 to 2016. Methods causes of death were selected based on magnitude and relevance in public health. Coding-linkage was established between ICD-9 to 10 revisions. Annual-standardized rates were calculated by the direct method according to the European Standard Population from 1975 to 2016. Linear trend period changes were measured through Joinpoint regression models as annual percentage change (APC) and 95% confidence intervals (CI). Joinpoint v4.0.4 and R v3.2.2 software were used at p < 0.05 for statistically significance level. Results Neoplasm rates have been going downwards (extreme years came from 162.2/100,000 inhabitants to 145.5) on ending year-periods of 1995-2008-2016. Lung and colorectal cancers replicated neoplasm shape in lower magnitudes. Cardiovascular displayed two decreasing trajectories in 1975-1993 and 1993-2013, and a last flat stage in 2013-2016, while cardiac ischaemia and ictus crossed their trend periods. Ictus has evolved quite in parallel to cardiovascular disease. Influenza and pneumonia conformed a close profile to respiratory great cause contribution, in different periods: 1975-1988 [-8.03% (-9.08, -6.96%)] and 1988-2016 [-2.38% (-2.85, -1.91%)]. Traffic accidents have been modulating external causes dropping shape with a nonsignificant slope period- trend in the 1994-2001 years. Conclusions The contribution of any singular causes of death into temporal development of its great causes, is a plausible tool for public health surveillance issues addressed to action. Key messages The great cause of death in temporal evolution is a moving aggregate result of its singular causes of death components over last time. Inflection-trends years-period of death causes are a plausible tool to public health surveillance.

e15534 Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients (pts). Despite the benefits of CRT, its use in non-responder pts can be associated with increased toxicities and resection delay. The identification of CRT response biomarkers, such as long non-coding RNAs (lncRNA), could improve the management of these pts. LincRNA-p21 is a lncRNA involved in the p53 pathway and angiogenesis regulation that acts as prognostic marker in several tumors. We aim to study lincRNA-p21 expression in pretreatment samples from RC pts treated with CRT to evaluate whether lincRNA-p21 can act as a predictive biomarker for CRT response. Methods: RNA from pretreatment endoscopy biopsies from 58 RC pts treated with preoperative CRT at Mutua Terrassa University Hospital were analyzed. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR and was correlated with CRT response and, time to relapse (TTR), disease-free survival (DFS) and overall survival (OS). Results: Samples from 58 pts were analyzed. Most of them males (n = 40, 69%). Median age at diagnosis of 67 (44-82) years. Fifty (86.2%) pts reported stage III and, 42 (72.4%) pts assessed TRG 0-3 with a 70.7% of downstaging reported. LincRNA-p21 was upregulated in stage III tumors (p < 0.0001) and also in tumors with worst response to CRT regarding TRG, TGR0-3 (TRG0-3, n = 42 vs TRG4, n = 16, p = 0.019). In this line, the ROC curve analysis showed that lincRNA-p21 expression had capacity to distinguish pts with maximum response (TRG4) from others (AUC:0.7; p = 0.02). The binary logistic regression analysis validated its independence as response biomarker. LincRNA-p21 levels correlated with pts relapse after surgery. When the pts were classified in 3 groups, high, medium and low, according to lincRNA-p21 levels, RC pts with highest lincRNA-p21 expression had the shortest TTR. TTR for pts with high levels was 74.5 months (m) (95% CI:31-117), while it was 114 m (95% CI:95-133) for those with Medium levels and 123 m (95% CI:111-134) for those with low levels (p = 0.047). Conclusions: LincRNA-p21 is a marker of advanced disease and worse response to CRT. LincRNA-p21 may add valuable information for individualizing pre-operative CRT in locally advanced RC pts.

Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer (RC) patients, but its use in non-responders can be associated with increased toxicities and resection delay. LincRNA-p21 is a long non-coding RNA involved in the p53 pathway and angiogenesis regulation. We aimed to study whether lincRNA-p21 expression levels can act as a predictive biomarker for neoadjuvant CRT response. We analyzed RNAs from pretreatment biopsies from 70 RC patients treated with preoperative CRT. Pathological response was classified according to the tumor regression grade (TRG) Dworak classification. LincRNA-p21 expression was determined by RTqPCR. The results showed that lincRNA-p21 was upregulated in stage III tumors (p = 0.007) and in tumors with the worst response regarding TRG (p = 0.027) and downstaging (p = 0.016). ROC curve analysis showed that lincRNA-p21 expression had the capacity to distinguish a complete response from others (AUC:0.696, p = 0.014). LincRNA-p21 was shown as an independent marker of preoperative CRT response (p = 0.047) and for time to relapse (TTR) (p = 0.048). In conclusion, lincRNA-p21 is a marker of advanced disease, worse response to neoadjuvant CRT, and shorter TTR in locally advanced RC patients. The study of lincRNA-p21 may be of value in the individualization of pre-operative CRT in RC.

Until recently, completion ALND has been considered the standard of care after a positive SN in breast cancer patients. However, most patients will not display further axillary involvement. The Tenon score is a simple nomogram that can be used intraoperatively to avoid completion ALND in low-risk patients. We aimed at validating the Tenon score on a SN-positive patient sample that had been preoperatively selected using axillary US examination. We used a retrospective analysis of our bicentric database that included 246 breast cancer patients with a positive SN. We calculated sensitivity, specificity, as well as positive and negative predictive values for each cut-off point. ROCs were constructed and corresponding AUC values were calculated as a measure of discriminative capacity. At least one non-SN was positive in 52 patients (21.1 %). 118 patients (48 %) had a score up to 5. Among them, three had at least one positive non-SN. NPV was 97.5 %. Using that threshold, the ROCs analysis showed an AUC of 0.822 (95 % CI 0.764–0.880). Use of preoperative axillary US examination led to a modification of the proposed Tenon cut-off value from 3.5 to 5 to attain good predictive power for non-SN status. Straightforward intraoperative use of the Tenon score may be considered an advantage over other available nomograms.

Our aim was to compare histologic and immunohistochemical features, surgical treatment and clinical course, including disease recurrence, distant metastases, and mortality between patients with invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC). We included 1,745 patients operated for 1,789 breast tumors, with 1,639 IDC (1,600 patients) and 145 patients with ILC and 150 breast tumors. The median follow-up was 76 months. ILC was significantly more likely to be associated with a favorable phenotype. Prevalence of contralateral breast cancer was slightly higher for ILC patients than for IDC patients (4.0% versus 3.2%; p = n.s). ILC was more likely multifocal, estrogen receptor positive, Human Epidermal Growth Factor Receptor-2 (HER2) negative, and with lower proliferative index compared to IDC. Considering conservative surgery, ILC patients required more frequently re-excision and/or mastectomy. Prevalence of stage IIB and III stages were significantly more frequent in ILC patients than in IDC patients (37.4% versus 25.3%, p = 0.006). Positive nodes were significantly more frequent in the ILC patients (44.6% versus 37.0%, p = 0.04). After adjustment for tumor size and nodal status, frequencies of recurrence/metastasis, disease-free and specific survival were similar among patients with IDC and patients with ILC. In conclusion, women with ILC do not have worse clinical outcomes than their counterparts with IDC. Management decisions should be based on individual patient and tumor biologic characteristics rather than on lobular versus ductal histology.

In 2011, the St Gallen panel introduced several changes in breast cancer classification, thereby creating the luminal B Her2- subtype. In 2013, the panel also included Ki67 overexpression and PR20 % as risk factors, while excluding GH3 in the absence of increased Ki67. We compared the classification of 2011 modified with the new 2013 St Gallen classification.Consecutive breast cancer patients referred to the Breast Unit of the University Hospital Mútua Terrassa and Hospital of Terrassa for surgical treatment of either primary or recurrent tumors were prospectively included between 1997 and 2014. Eventually, 1,874 cases were included for the four-subtype analysis. The median follow-up was of 66 months.Using the 2013 St Gallen classification no significant differences were found in specific mortality rates between luminal A and B subtypes. There were significant differences at 5, 10, and, 15 years if we excluded luminal A GH3 patients in the absence of increased Ki67 (p = 0.004, 0.005, and 0.007). Luminal A sub-type patients showed significantly less distant metastases than the rest, including luminal B Her2- patients (p0.001). Also, luminal B patients showed significantly less distant metastases than pure Her2 (0.05) and triple negative (TN) (p0.001). There were no differences between pure Her2 and TN patients (0.055), neither among the different luminal B sub-types.GH3, PR, and Ki67 may all be discriminatory factors for metastasis and specific mortality. Therefore, we suggest including GH3 in the luminal B subtype in the absence of Ki67.

Background Genotyping on cfDNA offers potential advantages in clinical practice for pt selection and serial monitoring of treatment (Tx) efficacy. Clinical relevance of sequential RASmut in cfDNA at different time points during 1L of pt with RASwt solid biopsies (SB) was evaluated. Methods Prospective, multi-center study in mCRC pt with RASwt according to SB and treated following standard practice. Liquid biopsies (LB) were collected before starting 1L, at 20 (± 2) weeks (w) and at disease progression (PD). Beaming PCR was used for cfDNA analysis; 3 mutant allele fraction (MAF) cutoffs were considered: 1%, 0.1% & 0.02%. Results Median progression-free survival (PFS) was 11.7 months (m) (9.9-13.0) (n = 102). There were no differences in the overall response rate (ORR) according to baseline LB at any cut off, being at MAF 0.02%: 78.7% (68.2- 87.1) in RASwt pt (n = 80) vs 61.5% (31.6 - 86.1) in RASmut pt (n = 13) (OR: 2.32; p = 0.180). MAF was not correlated with total cfDNA levels (p = 0.957). The % of mut cfDNA pt varied along time, with the smallest % at 20 w (Table). There were no emergent mutations at 20 w. Ten pt wt according to baseline LB presented mutations at PD. ORR was 76.9% (63.2 - 87.5) in pt always wt (n = 52) vs 76.2% (52.8 - 91.8) in pt with mut cfDNA at any time point (n = 21) (p = 1.0). There were also no differences in PFS between these 2 groups of pt: 13.0 m (10.9 - 15.4) vs 11.4 m (7.1 – 13.7) at MAF 0.02% (p = 0.095). Table . 531PD MAF≥1% MAF≥0.1% MAF≥0.02% Baseline 3 (2.9%) n = 102 6 (5.9%) n = 102 14 (13.7%) n = 102 PFS RASwt: 11.7 m (9.9-13.0) RASmt: NR (5.9-NR) (p = 0.689) PFS RASwt: 11.7 m (9.9-13.1) RASmt: 7.8 m (5.9-NR) (p = 0.662) PFS RASwt: 11.7 m (9.9-13.1) RASmt: 11.4 m (5.9-18.5) (p = 0.495) 20 ± 2 weeks 0 (0%) n = 76 3 (4.0%) n = 76 4 (5.3%) n = 76 PD 1 (2.0%) n = 49 9 (18.4%) n = 49 12 (24.5%) n = 49 Proportions of mutated patients based on the number of samples analysed at each time point and progression-free survival (PFS) according to the baseline plasma sample PD Progression of the disease; MAF: Mutant Allele Fraction; NR: not reached Conclusions RAS mutational status assessed in cfDNA before starting 1L or sequentially during P+CT Tx in pt with RASwt SB was not a significant predictor of PFS and ORR in none of the cutoffs considered, although in RASmut pt clinical results tended to increase as MAF decreased. The highest proportion of mutated pt was observed at PD, which may be linked to the emergence of resistance. Mutated cfDNA by itself did not predict a lack of clinical benefit to CT and P in our study. Editorial acknowledgement Marta Munoz-Tuduri (TFS, S.L.). Legal entity responsible for the study Amgen S.A. Funding Amgen S.A. Disclosure M. Valladares-Ayerbes: Honoraria (self): Amgen, Merck, Roche, Servier, Bayer, Bristol-Myers; Advisory / Consultancy: Merck, Sanofi, Amgen; Speaker Bureau / Expert testimony: Roche, Servier, Bayer; Research grant / Funding (self): Roche; Travel / Accommodation / Expenses: Merck, Servier, Amgen, Roche. J.M. Vieitez: Travel / Accommodation / Expenses, attendance at conferences: Amgen, Roche, Servier; Research grant / Funding (self): Roche, Amgen. J.J. Cruz-Hernandez: Honoraria (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Farma; Advisory / Consultancy, Advisory Board: Bristol-Myers Squibb, Merck, MSD, Roche Farma, Pfizer, Janssen Cilag; Advisory / Consultancy, Consulting: Roche Farma. M. Llanos: Advisory / Consultancy, collaboration in lectures: Servier, Roche, Ipsen, Merck, Bristol, Sanofi, Eisai; Advisory / Consultancy: Amgen. A. Lloansi Vila: Shareholder / Stockholder / Stock options, employee and stakeholder of Amgen S.A: Amgen. All other authors have declared no conflicts of interest.

Breast cancer can no longer be considered only one condition. It should be regarded rather as a heterogeneous group of diseases with different molecular outlines. The aim of this study is to establish a correlation between immunohistochemical tumor sub-typing and surgical treatment, local recurrence rates, distant metastases, and cancer-specific mortality at 5 and 10 years. At least, four tumor sub-types have been described, which were associated with variable risk factors, different natural clinical course, and different response to both local and systemic therapies. For Luminal A: ER + and/or PR + HER2− Ki67

As far as recent breast cancer molecular subtype classification is concerned, much work has dealt with clinical outcomes for triple negative and Her2 patients. Less is known about the course of patients in the remaining subtypes. Molecular classification based on immunohistochemistry is widely available and correlates well with genetic microarray assessment, but at a lower cost. The aim of our investigation was to correlate immunohistochemical subtypes of breast cancer with clinical characteristics and patient outcomes. Since 1998, 1167 patients operated for 1191 invasive breast tumours were included in our database. Patients were regularly followed up until March 2010. Disease-free survival, overall mortality, and breast cancer-specific mortality at 5 years were calculated for the cohort. 72% of tumours were ER+PR±HER2- group, 13% triple negative (ER-PR-HER2-), 10% ER+PR±HER2+ group, and 5% Her2 (ER-PR-HER2+). Cancer-specific survival was 94.2% for the ER+PR+HER2- subtype, 84.8% for the Her2 subtype, 83.3% for the ER+PR-HER2- subtype, and 78.6% for triple negatives. Distant metastases prevalence ranged from 7% to 22% across subtypes, increasing stepwise from ER+PR+HER2-, ER+PR+HER2+, ER+PR-HER2-, ER+PR-HER2+, ER-PR-HER2+ through triple negative. Small, low-grade tumours with low axillary burden were more likely to belong to the ER+PR±HER2- group. Conversely, larger high-grade tumours with significant axillary burden were more likely to belong to Her2 or triple negative groups. ER+PR±HER2- group patients with negative PR receptors performed more like Her2 or triple negative than like the rest of ER+PR±HER2± groups patients. Molecular classification of breast tumours based only on immunohistochemistry is quite useful on practical clinical grounds, as expected. ER+PR±HER2- group patients with negative PR receptors seem to be at high risk and deserve further consideration.

e15602Background: Tumor biopsies are widely used in clinical practice to assess RAS mutation status in mCRC patients. However, new techniques of genotyping based on circulating tumor (ct) DNA prese...

This phase II study evaluated the activity of gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line treatment of advanced epithelial ovarian cancer. Forty-two chemonaive patients with advanced (stage III and IV) epithelial ovarian cancer received gemcitabine 1,250 mg/m(2) on days 1 and 8 and cisplatin 100 mg/m(2) on day 1, every 3 weeks, up to eight cycles. The median number of cycles completed was 5 (range 2-8). Of the 41 patients evaluable for tumor response, 20 had a partial response and nine had a complete response, for an overall clinical and pathologic response rate of 70.7% (95% CI 56.8-84.6%). Median overall survival for all 42 patients was 23.4 months (95% CI 15.9-29.9 months) and the median progression-free survival time was 10.4 months (95% CI 9.4-13.5 months). The combination was generally manageable. Hematologic toxicity (grade 3/4 neutropenia: 31.0/21.4%; grade 3/4 thrombocytopenia: 9.5/4.8%; grade 3/4 anemia: 11.9/0%) and nausea and vomiting (grade 3/4: 35.7/31.0%) were the most common toxicities. There was one toxic death (septic shock due to hematologic toxicity-induced infection). We conclude that gemcitabine plus cisplatin is active and feasible as first-line treatment of advanced epithelial ovarian cancer. Further clinical trials with the addition of gemcitabine to first-line treatment appear warranted.

PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the combination of mitomycin plus tegafur in prolonging the disease-free survival and overall survival of patients with resected stage III gastric cancer. PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly assigned, using sealed envelopes, to receive either chemotherapy or no further treatment. Chemotherapy was started within 28 days after surgery according to the following schedule: mitomycin 20 mg/m2 intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400 mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia, Spain, were included in the study. The median follow-up period was 37 months. The tolerability of the treatment was excellent. The overall survival and disease-free survival were higher in the group of patients treated with chemotherapy (P = .04 for survival and P = .01 for disease-free survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control group. CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.

Small cell carcinoma of the bladder is a rare and highly aggressive tumor. We report our experience with 5 consecutive patients treated with systemic chemotherapy and adjuvant radiotherapy. TNM stages were T2N0M0 (1 patient), T3aN0M0 (3 patients) and T3bN1M0 (1 patient). The chemotherapy protocol was the one used with small cell lung cancer patients at our hospital: six cycles of alternating PE/CAV (PE: cisplatin, etoposide; CAV: cyclophosphamide, doxorubicin, vincristine). Cystoscopy was performed after the third cycle. Four out of 5 patients were free of macroscopic disease. The fifth patient had persistent lesions and was treated by cystectomy. This patient developed a local-regional recurrence 4 months later and died shortly afterwards. Four patients completed the planned six cycles. Cystoscopy with bladder biopsy was then performed on each, and all had complete remission. They were treated with external radiotherapy (45 Gy pelvis, 60 Gy bladder). One patient had invasive bladder recurrence 12 months later and cystectomy was performed. At the last follow-up 42 months later, he was alive and well. The other 3 patients were alive and free of disease 60, 48 and 27 months after diagnosis, respectively. These results are clearly more favorable than previous reports. Cystectomy might, therefore, be unnecessary in some patients.

We assessed the diagnostic yield of axillary ultrasound, alone or in combination with fine-needle aspiration axillary biopsy and magnetic resonance imaging in patients with invasive breast carcinoma compared with final axillary histology by sentinel node biopsy or by axillary lymph node dissection. From January 2003 to March 2009, 520 axillary ultrasound examinations and 105 axillary magnetic resonance imaging studies were included. Compared with final axillary histology, ultrasound fine-needle aspiration showed positive predictive value of 87%, negative predictive value of 82%, sensitivity of 53% and specificity of 100%. In cases of negative ultrasound, the rate of positive nodes was 17% (micro-metastases excluded). Ultrasound examination of the axilla, combined with fine-needle aspiration as appropriate must be included in the preoperative work-up of patients considered for sentinel node biopsy to definitively establish such an indication while minimizing the risk of false-negative sentinel node. Axillary magnetic resonance imaging did not improve the preoperative work-up.

Patients with fever and granulocytopenia are at risk of developing severe infection. We performed a prospective, randomized trial to evaluate the efficacy of low-dose cefepime plus amikacin (C-A) compared to low-dose piperacillin/tazobactam plus amikacin (PT-A). Patients received cefepime (2 g/12 h) plus amikacin (15 mg/kg/day) or piperacillin/tazobactam (4 g/500 mg/8 h) plus amikacin. A total of 317 episodes of febrile granulocytopenia in 190 patients were studied (152 in the C-A group, 165 in the PT-A group). A microbiologically documented infection was present in 53 (35%) episodes in the C-A group and 41 (25%) episodes in the PT-A group (p = ns); a clinically documented infection was observed in 39 (26%) and 47 (28%) episodes, respectively. Toxicity was observed in 6 (4%) episodes in the C-A group and in 5 (3%) episodes in the PT-A group. The antibiotic success rate (no change or addition of antibiotics) was recorded in 89 (59%) and 105 (64%) cases, respectively (p = ns). Mortality related to infection was similar in each arm (3.9% vs. 3.6%). Combination therapy of low-dose beta-lactam with an aminoglycoside achieves very good response rates and low rates of toxicity. It might be an attractive option in an environment of increasing resistance among gram-negative bacteria.

Purpose: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC). Experimental Design: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter. Results: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m2 every 3 weeks and 80 mg/m2/wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to ≥50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients. Conclusions: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.

Perinatal mortality has been decreasing in Spain; nevertheless completeness of death certificates was questioned because of the underreporting observed.To quantify perinatal mortality reporting of birth and infant-death certificates and obstetrics and neonatal hospital records of the Autonomous Community of Murcia in 2003.Newborns with a weight of at least 500 g or 22 weeks gestation, who died before the 8th day, were included. The dates came from birth certificates (stillbirths and infants died before one day of life) and death certificates (more than one day, and obstetrics-neonatal hospital records. Detection rates were calculated for death certificates and hospital registrations.One hundred fifty WHO-cases, of which 72 agreed with both sources. Sixty one percent of coincident cases were stillbirths. The underreporting was 26 % in Obstetrics and 10 % in Neonatology. Only 16 % of deaths were reported in the Official Statistics.Medical perinatal mortality reporting remains inadequate. Official Statistics and Obstetrics - Neonatology records add independent and complementary information.

From January 1978 to January 1988, 859 patients with T3-T4, NO-3, MO were randomly allocated to receive either: Group A —60Co 60, 60 Gy in 30 fractions; Group B—60Co, 70.4 Gy in 64 fractions; Group C—60Co, 60 Gy in 30 fractions plus chemotherapy (5 Fu, 250 mg/m2/IV every 2 days). Chemotherapy and radiotherapy were combined simultaneously. The average age was 56 years; the male/female ratio was 802/57. Median performance status (ECOG scale) was 1 (range 0–2). The TNM distribution as UICC criteria was T3 529 patients; T4 330 patients; No 217 patients; N1 52 patients; N2 319 patients; and N3 271 patients. The primary sites were nasopharynx 92, oral cavity 252, hypopharynx 119, larynx 310, and others (sinuses and unknown primary) 86. Complete response was achieved in 188 277 patients in Group A (67.8%), 254 282 patients in Group B (90%), and 289 300 in Group C (96.3%). All patients were followed and statistical analysis shows a significant improvement in median duration of response, as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis, skin toxicity, bone marrow depression. A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3–10.5 Kg.

OBJETIVO: Determinar el impacto clínico de la PET en la actitud terapéutica de los pacientes oncológicos. MATERIAL Y MÉTODOS: Hemos incluido en este trabajo los cien primeros estudios oncológicos consecutivos de PET con 18FDG de cuerpo completo (75 varones/22 mujeres, edad media de 67 años) procedentes de un mismo hospital público de nuestra comunidad. El impacto de la PET se calculó mediante los resultados de una encuesta enviada a cada uno de los médicos solicitantes de la prueba. Este cuestionario se diseñó fundamentalmente para valorar el tipo de cambio de tratamiento (intramodalidad/intermodalidad) ocasionado tras los hallazgos de la PET. RESULTADOS: Las tres neoplasias estudiadas más frecuentes fueron: carcinoma broncogénico (34%), neoplasia colo-rectal (24%) y nódulo pulmonar solitario (15%). La PET cambió la actitud terapéutica inicialmente prevista en 53 (55%) de los 97 casos evaluados (tipo intramodalidad en 5 e intermodalidad en 48). Diecisiete pacientes (17.5%) candidatos a cirugía curativa fueron finalmente tratados con un tratamiento sistémico de quimioterapia con o sin radioterapia. Los médicos encuestados consideraron que la PET constituía una herramienta diagnóstica útil en el 69% de los casos y que evitaba maniobras diagnósticas agresivas en 56%. CONCLUSIÓN: En nuestra serie de pacientes, la PET con FDG ha sido una herramienta diagnóstica de gran utilidad. Mejora la estadificación inicial de las neoplasias, en especial del carcinoma broncogénico y estadifica de forma más precisa la recidiva tumoral de diferentes tipos de tumores, especialmente de la neoplasia colo-rectal. De este modo, la PET ayuda a seleccionar el tratamiento óptimo en cada caso, evitando cirugías innecesarias.

This randomised, open-label trial compared oral tegafur (FT)/leucovorin (LV) with the intravenous bolus 5-fluorouracil (5-FU)/LV as first-line chemotherapy for advanced colorectal cancer (CRC). Patients were randomised to receive oral FT 750 mg/m2/day for 21 days and LV 15 mg/m2 every 8 h in cycles repeated every 28 days (n=114), or intravenous LV 20 mg/m2 followed by 5-FU 425 mg/m2 daily for 5 days every 4 weeks for 2 cycles, and later every 5 weeks (n=123). Response rate was significantly higher in the FT/LV arm (27%, 95% CI 19-35) than in the 5-FU/LV arm (13%, 95% CI 7-19) (p0.004). The median time to progression was 5.9 months (95% CI, 5.3-6.5; FT/LV arm) and 6.2 months (95% CI, 5.4-6.9; 5-FU/LV arm). Median overall survival was 12.4 months (95% CI, 10.3-14.5 months; FT/LV arm) and 12.2 months (95% CI, 8.9-15.7 months; 5-FU/LV arm) (p=n.s.; hazard ratio FT/LV:5-FU/LV=1.02). 5-FU/LV showed a higher incidence of grade 3/4 neutropenia (4.1 vs. 0%). Non-hematological toxicities showed similar incidences in the two treatment arms. Oral FT/LV was more active than IV 5-FU/LV in terms of objective response rate with similar overall survival, and with a favorable toxicity profile. This makes FT/LV a valid alternative to the IV 5-FU schedule in CRC patients.

Objectives The aim of this study was to correlate the overexpression of HER2 with clinical pathologic characteristics and its influence on local/distant recurrence and survival. Methods From 1998 to 2010, prospective data of 146 patients with invasive breast cancer with HER-2 overexpression was studied. The sample was divided into three groups: Negative hormonal receptors (NHR); Luminal B1 (Estrogen receptor +/-, Progesterone receptor +), Luminal B2 (Estrogen receptor +, Progesterone receptor -). Histological type (HT), size tumor (T), differentiation grade (DG), and nodal status were determined. Correlation with local and distant recurrence, and 5-year overall survival was done. Results NHR: 33.5%, luminal B1: 47.5%; Luminal B2: 19% Clinical pathologic characteristics: Age (%) Size(%) HT (%) 50-69 >70 T1 T2 T3 T4 Ductal Lobular NHR 23 51 26 39 37 4 10 98 2 Luminal B1 33 51 16 51 39 9 1 99 1 Luminal B2 22 64 14 53 43 30 4 96 4 DG (%) Nodal Status G1 G2 G3 Negative Positive NHR 0 21 79 59 41 Luminal B1 11 37 52 48 52 Luminal B 0 28 73 57 43 Local and distant recurrence and overall survival at 5 years follow-up: Local Recurrence(%) Metastasis Recurrence(%) Overall Survival (%) NHR 6 20 81.5 Luminal B1 2 8 88.5 Luminal B2 4 15 86.5 Conclusions Patients with NHR and patients with PR- had more aggressive differentiation grade, less axillary infiltration and increased risk of distant metastasis. At 5-year follow-up, overall survival was better in the PR+ group. Disclosure All authors have declared no conflicts of interest.

OBJECTIVE: To know the training need priorities in Spanish physicians in death certification. DESIGN: Study of needs by consensus technique Delphi. SETTING: Health care and medical-legal institutions in Spain. PARTICIPANTS: Physicians who ask for information in death certification, after reading an article in a medical magazine (n=38), and agree to participate (n=33). METHODS: Priorities were established by means of a list of items, based on teaching experience and professional advice. The scores obtained for each priority were hierarchized, and the participants´ professional profiles were described. An analysis of hierarchical clusters was done to determine profiles of training. RESULTS: The median age of the participants was 42 years, with 18 years´ experience in general/family, emergency or forensic medicine, which usually certified in median 8 death a year (rank from 0 to 50). The maximum training priorities were how to register a death and which doctor should make out the official documents. Intermediate priorities included the role of doctors in violent or accidental deaths. In the main three grouping needs were, in one, include certification as a degree subject and learn how different documents are made out; although in the others two, were how to register a death, which physician make out the documents, and when it should certify the family doctor and when the coroner. CONCLUSIONS: The priorities in certification training are how to register a death and who should make out the documents, pointing out that the shortcoming continues in medical training in death certification.

This paper aimed to study the usefulness of the Statistical Bulletin of Deaths (SBD) for identifying extrahospital deaths due to acute coronary ischaemia, and to determine the most efficient strategy in the selection of death causes that appear in the SBD, which are the most efficient for the identification.Those extrahospital deaths, which, among the causes of death, recorded a diagnostic code indicating that they might have been caused by coronary ischaemia, were included. To study the usefulness of the death certificate we calculated the sensitivity and the positive predictive value of cardiac ischaemia. To determine the most efficient strategy for selecting causes of death we compared two selection strategies: the first, using only the basic cause of death; and the second using all the causes appearing in the SBD.Of the 395 SBD selected, 161 were classed as acute heart attacks. In those SBD in which cardiac ischaemic disease was given as the basic cause of death, we obtained a sensitivity of 82.6% (CI 95%: 75.9-88.1) and a positive predictive value of 72.7% (CI 95%: 65.6-79). The most efficient strategy in SBD selection proved to be the investigation of death certificates in which cardiac ischaemia appeared as one of all the causes of death, and death certificates in which the basic cause of death was coded as diabetes mellitus, essential arterial hypertension, hypertensive heart disease, cardiac dysrhythmia, and cardiac insufficiency.The information provided by death certificates for extrahospital deaths due to coronary ischaemia is reliable. A sensitive and efficient SBD selection strategy is proposed for the detection of cases.

OBJECTIVE: Epidemiological studies and interventions to reduce inequalities in community health require the assignation of exhaustive and easy-to-obtain social indicators. Occupation and education are two of the most often used. In this study we attempt to evaluate the association between education and occupation among adult working population because if, in the absence of one of these two variables, it will be feasible to use the remaining with the lesser lost of socio-economic information. DESIGN: From a representative sample (n = 3091) of general population (18-65 years old) drawn out from a prevalence survey on chronic disease risk factors performed in the Region of Murcia, a log-lineal analysis has been made between education and occupation among working people (65.8% of males and 34.2% of females from the original sample). RESULTS: Men present significant association between managerial positions and university education. The association drops between clerks and high school graduates to increase among all manual workers with or without primary schooling education. Among women –with a lesser number of participants– the education/occupation association describes the same pattern but with higher magnitudes in the positive associations between managerial positions and university education. For both genders, the greatest associations are found in both diagonals of the education by occupation tables indicating: better occupation, more education, and the opposite. CONCLUSIONS: The classification of working people according to education and occupation presents association, internal consistency and gradient. In absence of comprehensive information regarding occupation, education could be an alternative as socio-economic indicator.

The problems of air pollution became noticeable in Cartagena in the seventies, high SO2 and particle levels having been reached from time to time. Our aim is to assess, using the EMECAM methodology, the acute impact of SO2 and particle air pollution on the daily death rate of the city of Cartagena in the 1992-1996 period.A daily listing is provided of the total number of non-accidental deaths within the population as a whole and for those over age 70, the cardiovascular and the respiratory deaths due to dioxide and particle air pollution for the 1992-1996 period using autoregressive Poisson models which control seasonality, weather, time of year, flu, special events, and time lags.In the period under study, there has been a drop in the SO2 air pollution as compared to previous years, which was not as marked for the particles. The analyses reveal significant relationships in the total non-accidental deaths in those over age 69, with the average particle count and those particles with cardiovascular deaths for the months of May to October. In the six-month period of the year, when the weather is cold, we found a positive statistically significant relationship to exist in the maximum daily hourly value of the particles and the deaths due to cardiocirculatory and respiratory diseases. However, there is no consistency in the between on assessing the reliability of the models.

To analyze the associations between educational attainment and major cardiovascular disease risk factors in the Murcia Region (Southern Spain).During 1992 we conducted a survey by interview, with multi-stage random sampling, representative of the general adult population. We calculated odds ratios (OR) and trends by logistic regression as a measure of the association between educational levels and cardiovascular risk factors, taking the university level as the reference category.A total of 1514 men and 1577 women aged between 18 and 65 years was included in the study. Rate of response to the questionnaire was 61%. Seventy-eight percent of the respondents provided a blood sample. A telephone survey on a representative sample of non-respondents (n = 347), showed no statistical differences in the level of studies.We asked for educational level (highest schooling qualification completed), and according to the WHO MONICA protocol we measured: blood pressure, cigarette smoking, height, weight and total cholesterol, triglycerides and HDL-cholesterol. We also obtained the leisure-time physical activity by a validated questionnaire.In a context of a low level of schooling, mainly among the older age groups, the prevalence of risk factors except smoking in women is higher in the lower educational levels. Systolic blood pressure tends slightly to increase as schooling level decreases (both genders, p0.02). Conversely, serum total cholesterol and triglycerides decrease with higher level of schooling in men. The high levels of HDL-cholesterol observed in all educational groups show no trend in both genders. Arterial hypertension in men and women and overweight in women tend to decrease with higher educational attainment. Moreover, higher level of education is associated with vigorous physical exercise in both genders and cigarette smoking in women. We observed the strongest significant magnitude association in nonschooling with hypertension in men (OR: 1.82; 95% CI: 1.15, 2.89), in women (OR: 2.39; 95% CI: 1.05, 5.44), and with overweight in women (OR: 3.22; 95% CI: 1.97, 5.27), meaning that compared to people at the university level, people without schooling showed two to three times higher prevalence of hypertension and overweight (only women). Also non-schooling obtained the lowest significant association with protective physical exercise for coronary heart disease in men (OR: 0.32; 95% CI: 0.18, 0.56) and in women (OR: 0.31; 95% CI: 0.15, 0.62) pointing out that people at the university level of education had three times the prevalence of vigorous physical activity than their non schoolarized counterparts.After adjusting for environmental factors, in our adult general population, educational attainment is inversely associated with arterial hypertension in both genders and with overweight in women, and directly associated with cigarette smoking in women and with leisure-time physical activity in both genders.

PURPOSE The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

1001 Background: Chemotherapy for patients with metastatic breast cancer is not curative. Anthracyclines and taxanes are among the most active drugs. Optimal duration of chemotherapy in women with metastatic breast cancer is an open issue. Should they receive chemotherapy to progression or should chemotherapy be stopped after a fixed number of courses? The excellent safety profile of weekly paclitaxel prompted us to evaluate its role as maintenance treatment in this setting. The primary objective was to determine if addition of maintenance weekly paclitaxel prolongs progression-free survival in women with metastatic breast cancer on first-line chemotherapy. Secondary objectives included overall survival and toxicity. Methods: Following Ethical Committee approval and informed consent, from 2002 to 2006 180 women with metastatic breast cancer and no prior chemotherapy for metastatic disease were randomized 1:1 in the TASMAN phase III trial to: 3 courses of epirubicin 100 mg/m2 day 1 q 21 days, followed by 3 courses of paclitaxel 225 mg/m2 day 1 q 21 days, without further chemotherapy or hormonal therapy until progression (arm A), or 3 courses of epirubicin followed by 3 courses of paclitaxel and then maintenance with paclitaxel 60 mg/m2 day 1 q 7 days until progression or unacceptable toxicity (arm B). Results: Median age: 51 years (range: 30–73). Median performance status (ECOG): 0 (0–2). Sites of metastases: bone (36%), liver (20%), pleura and/or lung (19%), skin and/or lymph nodes (18%). No grade 3–4 toxicities were seen with maintenance chemotherapy. As of January 1, 2009, 18 patients remained progression-free and 48 were alive, with a minimum follow-up of 2 years. Median progression-free survival was 8 months for arm A versus 12 months for arm B (p = 0.1, logrank). Median overall survival was 24 months for each arm (p = 0.7). Conclusions: Maintenance chemotherapy with weekly paclitaxel following first-line chemotherapy with anthracycline and taxane is well tolerated but does not significantly increase progression-free survival. No significant financial relationships to disclose.

7031 Background: To evaluate the presence of mediastinal lymph node spread of NSCLC after changing the clinical staging protocol from routine to selective surgical mediastinal exploration (SME) based on PET. Methods: From 1994 to 2003, routine SME (mediastinoscopy, parasternal mediastinotomy or extended cervical mediastinoscopy) was performed to 655 patients (pts) with NSCLC as the last clinical staging procedure prior to thoracotomy. Those with no mediastinal involvement underwent thoracotomy with lung resection (T) and systematic nodal dissection (SND). From 2004, PET was routinely done in 90 pts and SME was reserved for those with positive mediastinal or hiliar uptake on PET, mediastinal lymph node diameter greater than 1cm in shorter axis on computerized tomography, and in tumors contacting with the mediastinum. All other pts and those with negative SME underwent T and SND. Results: Among 655 pts studied between 1994 and 2003, 236 (36%) had positive SME; 419 underwent T and SND and 40 (6.1%) were classsified as pN2. Of the 90 evaluable pts with PET, 27 had increased uptake in the mediastinum an 17 had positive SME; the remaining 10 ptes with negative SME underwent T and SND and 7 of them were found to have no nodal disease (false positive PET), but three of them were found to have nodal disease. Of the 63 pts with no uptake in the mediastinum, 29 underwent SME for reasons stated above: 5 SME was positive; in 24 SME was negative and the patients underwent T and SND: 21 were pN0 and 3 were pN2. Only 1 tumor of the remaining 34 pts with negative PET who underwent T and SND without SME was classified pN2. Additionally, in 1 pt PET detected N2 disease but not N3. 4 (4.5%) pts with pN2 disease were clinically understaged (negative PET and negative SME) and underwent thoracotomy. 3 pts with positive PET who underwent SME were classified pN0, but they were pN2 (false negative SME). In total, 7 (7.8%) pts with pN2 disease were clinically understaged and underwent T. This rate is not statisticallly different from the 6.1% pN2 tumor found after routine SME. Conclusions: In this preliminary study, this new clinical staging protocol with routine PET and selective SME saves up to 35% of SME and yields a similar rate of pN2 disease compared to routine SME. No significant financial relationships to disclose.

603 Background: Primary hormonal therapies have demonstrated great activity in elderly women with locally advanced and hormone-dependent breast tumors. Exemestane, a steroidal aromatase inactivator, is effective in a metastatic setting. The primary aim of this study was to analyze the efficacy of exemestane as a neoadjuvant treatment. Methods: 55 patients (p) were recruited. Inclusion criteria were histologic diagnosis of infiltrating breast carcinoma, no metastatic disease, tumor >3 cm (T2, T3, T4a-b), >50% ER+, and no previous hormonal treatment/chemotherapy. At baseline, all p were considered noneligible for breast-conserving surgery. Treatment: oral exemestane 25 mg/d for 6 months. Response was estimated by mammography and breast ultrasound every 2 months (RECIST criteria). Secondary endpoints were rate of breast-conserving surgery, time to progression, duration of response, and toxicity. To date, 50 p have been evaluated for response and 5 remain under treatment. Results: Patient characteristics: med...

Twenty-seven patients with histologically proved advanced breast cancer were given VP 16-213 and cyclophosphamide. Twenty-one had shown resistance to other chemotherapy schedules and six had experienced relapse during adjuvant chemotherapy. There were four complete responses (15%) and seven partial responses (26%). Median survival was 61 weeks and median duration of response was 31.4 weeks. All patients experienced gastrointestinal toxicity and 22 patients (81%) showed bone marrow toxicity. This regimen is effective in advanced breast cancer resistant to other chemotherapy regimens.

Eleven members of the same family were studied after an incidental detection of raised serum alkaline phosphatase activity in one of them without any apparent underlying cause. Three other members were found to have the same abnormality; none of them had an associated disease. In the four cases with elevated serum alkaline phosphatase levels, its activity showed a preponderance of the bone isoenzyme. Studies of the erythrocyte and histocompatibility antigens in nine members of the family, as well as idiograms of karyotypes of four of them, did not show any relation between histocompatibility antigens and the raised levels of serum alkaline phosphatase. Also, no chromosomal abnormality is shown from karyotypes. The data suggest a probable autosomal dominant pattern of inheritance.

INTRODUCTION: Preoperative chemoradiotherapy (CRT) is a standard treatment for locally advanced rectal cancer patients. Despite the benefits of CRT, its use in non-responder patients can be associated with increased toxicities and surgical resection delay. The identification of CRT response biomarkers, such as microRNAs, could improve the management of these patients. We have studied the microRNA expression in pretreatment endoscopy biopsies from rectal cancer patients treated with CRT to identify potential microRNAs able to predict CRT response and clinical outcome of these patients. MATERIAL AND METHODS: RNA from pretreatment endoscopy biopsies from 96 rectal cancer patients treated with preoperative CRT were studied. Pathological response was graded according to the tumor regression grade (TRG) Dworak classification. In the screening phase, 377 miRNAs were studied in 12 patients with extreme responses (TRG0-1 vs TRG4). The potential role as predictive biomarkers for CRT response, disease-free survival (DFS) and overall survival (OS) of the miRNAs identified in the screening phase were validated in the whole cohort. RESULTS: In the screening phase, an 8-miRNAs CRT-response signature was identified: let-7b, let-7e, miR-21, miR-99b, miR-183, miR-328, miR-375 and miR-483-5p. In the validation phase, miR-21, miR-99b and miR-375 emerged as CRT response-related miRNAs while miR-328 and let-7e emerged as prognostic markers for DFS and OS. Interestingly, ROC curve analysis showed that the combination of miR-21, miR-99b and miR-375 had the best capacity to distinguish patients with maximum response (TRG4) from others. CONCLUSIONS: miR-21, miR-99b and miR-375 could add valuable information for individualizing treatment in locally advanced rectal cancer patients.

• Eleven members of the same family were studied after an incidental detection of raised serum alkaline phosphatase activity in one of them without any apparent underlying cause. Three other members were found to have the same abnormality; none of them had an associated disease. In the four cases with elevated serum alkaline phosphatase levels, its activity showed a preponderance of the bone isoenzyme. Studies of the erythrocyte and histocompatibility antigens in nine members of the family, as well as idiograms of karyotypes of four of them, did not show any relation between histocompatibility antigens and the raised levels of serum alkaline phosphatase. Also, no chromosomal abnormality is shown from karyotypes. The data suggest a probable autosomal dominant pattern of inheritance. ( Arch Intern Med 1982;142:188-189)