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Worldwide, social healthcare systems must face the challenges of a growing scarcity of resources and of its inevitable distributional effects. Explicit criteria are needed to define the boundaries of public reimbursement decisions. As Germany stands at the beginning of such a discussion, more formalised priority setting procedures seem in order. Recent research identified multi-criteria decision analysis (MCDA) as a promising approach to inform and to guide decision-making in healthcare systems. In that regard, this paper aims to analyse the relative weight assigned to various criteria in setting priority interventions in Germany. A discrete choice experiment (DCE) was employed in 2015 to elicit equity and efficiency preferences of 263 decision makers, through six attributes. The experiment allowed us to rate different policy interventions based on their features in a composite league table (CLT). As number of potential beneficiaries, severity of disease, individual health benefits and cost-effectiveness are the most relevant criteria for German decision makers within the sample population, the results display an overall higher preference towards efficiency criteria. Specific high priority interventions are mental disorders and cardiovascular diseases.

Neutrino oscillation experiments require a precise measurement of the neutrino energy. However, the kinematic detection of the final-state neutron in the neutrino interaction is missing in current neutrino oscillation experiments. The missing neutron kinematic detection results in a smaller detected neutrino energy than the true neutrino energy. A novel 3D-projection scintillator tracker, which consists of roughly ten million active cubes covered with an optical reflector, is capable of measuring the neutron kinetic energy and direction on an event-by-event basis using the time-of-flight technique thanks to the fast timing, fine granularity, and high light yield. The ν¯μ interactions tend to produce neutrons in the final state. By measuring the neutron kinetic energy, the ν¯μ energy can be reconstructed better, allowing a tighter incoming neutrino flux constraint. This article shows the detector’s ability to reconstruct neutron kinetic energy and the ν¯μ flux constraint achieved by selecting the charged-current interactions without mesons or protons in the final state. Neutrino oscillation experiments require a precise measurement of the neutrino energy. However, the kinematic detection of the final-state neutron in the neutrino interaction is missing in current neutrino oscillation experiments. The missing neutron kinematic detection results in a feed-down of the detected neutrino energy compared to the true neutrino energy. A novel 3D\textcolor{black}{-}projection scintillator tracker, which consists of roughly ten million active cubes covered with an optical reflector, is capable of measuring the neutron kinetic energy and direction on an event-by-event basis using the time-of-flight technique thanks to the fast timing, fine granularity, and high light yield. The $\bar{\nu}_{\mu}$ interactions tend to produce neutrons in the final state. By inferring the neutron kinetic energy, the $\bar{\nu}_{\mu}$ energy can be reconstructed better, allowing a tighter incoming neutrino flux constraint. This paper shows the detector's ability to reconstruct neutron kinetic energy and the $\bar{\nu}_{\mu}$ flux constraint achieved by selecting the charged-current interactions without mesons or protons in the final state.

Metronomic chemotherapy (mCHT) refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen, with no prolonged drug-free breaks, that leads to antitumor activity. Aim of the present study is to describe the use of mCHT in a retrospective cohort of metastatic breast cancer (MBC) patients in order to collect data regarding the different types and regimens of drugs employed, their efficacy and safety. Between January 2011 and December 2016, data of 584 metastatic breast cancer patients treated with mCHT were collected. The use of VRL-based regimens increased during the time of observation (2011: 16.8% - 2016: 29.8%), as well as CTX-based ones (2011: 17.1% - 2016: 25.6%), whereas CAPE-based and MTX-based regimens remained stable. In the 1st-line setting, the highest ORR and DCR were observed for VRL-based regimens (single agent: 44% and 88%; combination: 36.7% and 82.4%, respectively). Assuming VRL-single agent as the referee treatment (median PFS: 7.2 months, 95% CI: 5.3–10.3), the longest median PFS were observed in VRL-combination regimens (9.5, 95%CI 88.8–11.3, HR = 0.72) and in CAPE-single agent (10.7, 95%CI 8.3–15.8, HR = 0.70). The VICTOR-6 study provides new data coming from the real-life setting, by adding new information regarding the use of mCHT as an option of treatment for MBC patients.

Background Local ablation of pancreatic cancer has been suggested as an option to manage locally advanced pancreatic cancer (LAPC) although no robust evidence has been published to date to support its application. The aim of this study is to compare overall survival (OS) and progression-free survival (PFS) in patients receiving both radiofrequency ablation (RFA) and conventional chemoradiotherapy (CHRT) with patients receiving CHRT only. Methods This is a multicentre prospective randomized controlled trial (RCT). Patients with LAPC diagnosed by the Pancreas-Ablation-Team-Verona were randomly assigned to open RFA (Group A) or CHRT (Group B). Survival analyses were performed using the Kaplan-Meier method and compared using the log-rank test. Statistical significance was set at p Results One hundred LAPC patients were enrolled from January 2014 to August 2016. 33% of patients in Group A did not receive the designated procedure because of intraoperative findings of liver (18.7%) or peritoneal metastases (43.8%), or technical contraindications (37.5%). We did not observe any statistically significant survival benefit from RFA compared to CHRT, neither in terms of OS (medians of 14.2 months and 18.1 months, respectively, p = 0.639) nor PFS (medians of 8 months and 6 months respectively, p = 0.570). Mortality was nil and RFA-related morbidity was 15.6%. In 13% of subjects, conversion to surgery occurred (2 after RFA and 11 after CHRT). Conclusions This is the first RCT evaluating the impact of upfront RFA in the multimodal treatment of LAPC. Compared to CHRT, RFA alone did not provide any advantage in terms of OS or PFS. It could be considered as a therapeutic option for LAPC within a multimodal context and after neoadjuvant therapies.

Borexino is a 280-ton liquid scintillator detector located at the Laboratori Nazionali del Gran Sasso (LNGS), Italy and is one of the two detectors that has measured geoneutrinos so far. The unprecedented radio-purity of the scintillator, the shielding with highly purified water, and the placement of the detector at a 3800 m w.e. depth have resulted in very low background levels and has made Borexino an excellent apparatus for geoneutrino measurements. The new update of the Borexino geoneutrino measurement, using the data obtained from December 2007 to April 2019, has been presented. Enhanced analysis techniques, adopted in this measurement, have been also presented (poster presentation #39 by S. Kumaran). The updated statistics and the new elaborate analysis have led to more than a factor two increase in exposure ((1.12 ± 0.05) × 1032 protons × yr) when compared to the latest Borexino result from 2015. The resulting geoneutrino signal of 47.0 − 7.7 + 8.4 ( stat ) − 1.9 + 2.4 ( sys ) TNU has − 17.2 + 18.3 % total precision. The geological interpretations of this measurement have been discussed. In particular, the 99% C.L. observation of the mantle signal by exploiting the relatively well-known lithospheric contribution, the estimation of the radiogenic heat, as well as the comparison of these results to the predictions based on different geological models. The upper limits on the power of a hypothetical georeactor that might be present at different locations inside the Earth have been set.

Gravimetric methods are expected to play a decisive role in geophysical modeling of the regional crustal structure applied to geoneutrino studies. GIGJ (GOCE Inversion for Geoneutrinos at JUNO) is a 3D numerical model constituted by ~46 x 10$^{3}$ voxels of 50 x 50 x 0.1 km, built by inverting gravimetric data over the 6{\deg} x 4{\deg} area centered at the Jiangmen Underground Neutrino Observatory (JUNO) experiment, currently under construction in the Guangdong Province (China). The a-priori modeling is based on the adoption of deep seismic sounding profiles, receiver functions, teleseismic P-wave velocity models and Moho depth maps, according to their own accuracy and spatial resolution. The inversion method allowed for integrating GOCE data with the a-priori information and regularization conditions through a Bayesian approach and a stochastic optimization. GIGJ fits the homogeneously distributed GOCE gravity data, characterized by high accuracy, with a ~1 mGal standard deviation of the residuals, compatible with the observation accuracy. Conversely to existing global models, GIGJ provides a site-specific subdivision of the crustal layers masses which uncertainties include estimation errors, associated to the gravimetric solution, and systematic uncertainties, related to the adoption of a fixed sedimentary layer. A consequence of this local rearrangement of the crustal layer thicknesses is a ~21% reduction and a ~24% increase of the middle and lower crust expected geoneutrino signal, respectively. Finally, the geophysical uncertainties of geoneutrino signals at JUNO produced by unitary uranium and thorium abundances distributed in the upper, middle and lower crust are reduced by 77%, 55% and 78%, respectively. The numerical model is available at http://www.fe.infn.it/u/radioactivity/GIGJ, Comment: 35 pages, 9 figures, 4 tables

International audience; BACKGROUND: Despite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.METHODS: Individual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.RESULTS: OS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9-3.6) and 6-month PFS rate was 27% (95% CI 24-30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Surgery has been the mainstay of renal cell carcinoma (RCC) treatment for resectable tumours. In stages I-III disease, nephrectomy is the standard of care and may be curative. Historically, patients presenting with stage IV disease may achieve improved survival with debulking nephrectomy, which is commonly performed prior to systemic therapy. The response rate of immunotherapy is low, with a smaller percentage exhibiting complete remission upon treatment. Therefore, new therapeutic approaches against metastatic RCC are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC have been identified, and molecular targeted therapy has developed. Clear cell RCC commonly features mutation or inactivation of the von Hippel- Lindau (VHL) gene and resultant over-expression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival (PFS) when used in second-line treatment. This review describes recent advances in molecular targeted therapy for metastatic RCC, focusing on chemical structure and mechanism of action of VEGFR and mTOR inhibitors.

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Thalidomide produces a response rate from 32 to 66% of pre-treated myeloma patients with doses ranging from 100 to 800 mg/daily. Common, dose-related side effects are sedation, constipation, polyneuropathy. Increased incidence of thromboembolic events were observed in myeloma patients receiving thalidomide as front-line therapy or in association with chemotherapy. Less common adverse reactions are central nervous system (CNS) dysfunction and cutaneous reactions. We describe the update of our experience with low dose thalidomide plus monthly high dose dexamethasone and zolendronate. Most patients were able to tolerate this regimen with few side effects. Erythrocyte sedimentation rate (ESR) lowering was early observed in patients who subsequently responded.

In response to the increasing demand for elderly care, Italy has experienced an intense debate on what should be the most appropriate way to extend coverage for long-term care (LTC). This paper bridges a gap into existing literature by analysing household preferences for LTC coverage in light of an ad hoc survey. We present evidence on household stated willingness to pay (WTP) both for tax financed and private LTC insurance schemes. The distribution of WTP across different socio-economic groups provides insights on the political sustainability of the different institutional solutions. Moreover, estimates of the determinants of demand highlights the importance of income levels and opinion indicators in turning consumer preferences either to public or private schemes. We interpret the different patterns of WTP as evidence of the influence of the redistributive effects inherent to public insurance.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

We review the observational information on the constancy of the fine structure constant alpha. We find that small improvements on the measurement of ^{187}Re lifetime can provide significant progress in exploring the range of variability suggested by QSO data. We also discuss the effects of a time varying alpha on stellar structure and evolution. We find that radioactive dating of ancient stars can offer a new observational window., 9 pages with 3 ps figures included, to appear on the Proc. of ESO-CERN-ESA Symposium on Astronomy, Cosmology and Fundamental Physics, Garching bei Munchen, Germany March 4-7, 2002

The release of the World Health Report 2000 has brought to the fore the concept of responsiveness as an indicator of health system performance. Responsiveness relates to a system’s ability to respond to the legitimate expectations of potential users about non-health enhancing aspects of care (Valentine et al. 2003). A few studies have investigated how standard socio-demographic characteristics (such as income or education) have an influence on the evaluation of responsiveness by health care users (Puentes Rosas et al. 2006, Sirven et al. 2012, Rice et al. 2012). However, we are not aware of any study investigating the relationship between the frequency with which patients use health services and their evaluation of responsiveness. This paper narrows this gap by using data regarding a sample of patients hospitalized in 9 hospitals of Emilia Romagna, a Region of Italy. The data have been collected by the Agency for Health Care and Social Services of Emilia Romagna between January 2010 and December 2012. We investigate a representative sample of about 2500 in-patients, who have been asked to evaluate 29 different aspect of quality of care which refer to 6 domains of health system responsiveness (communication, social support, privacy, dignity, waiting times and quality of facilities). We make use of this structure of the data by adopting a panel data regression model. The adoption of a panel model helps in controlling for individual heterogeneity, which otherwise could bias our results. Given that responsiveness is evaluated on an ordinal and categorical scale (going from “very dissatisfied” to “very satisfied”) we estimate a panel ordered logit model. Our results suggest that if patients have already been hospitalized in the same ward over the last 5 years they evaluate responsiveness more positively compared to patients who have never been hospitalized before. However, this effect is statistically significant only if patients have been hospitalized in the last 6 months. More generally, the use of a proper methodology to investigate responsiveness at hospital level can allow a better identification of area of intervention for investments in staff training; moreover, it can allow to modify hospital characteristics which have a negative impact on patients’ reporting of responsiveness.

The present study was conducted to evaluate the effect of lipids with different fatty acid profiles on the intake, performance, and enteric CH4 emission of Nellore steers. A total of 45 Nellore animals with an average initial BW of 419 ± 11 kg (at 15 ± 2 mo) were distributed in a completely randomized design consisting of 5 treatments and 9 replicates. The roughage feed was maize silage (600 g/kg on a DM basis) plus concentrate (400 g/kg on a DM basis). The dietary treatments were as follows: without additional fat (WF), palm oil (PO), linseed oil (LO), protected fat (PF; Lactoplus), and whole soybeans (WS). The lipid source significantly affected (P0.05) nutrient intake. The greatest intakes of DM, OM, and CP were observed in the animals that were fed the WF or PF diets, and the lowest intakes were observed in the animals that were fed the PO diet. Intake of NDF decreased (P0.05) with the addition of PO. Enteric methane emission (g/kg DMI) was reduced by an average of 30% when the animals were fed diets containing WS, LO, and PO (P0.05), and these diets caused a larger reduction in the energy loss in the form of methane compared to those without added fat and with added PF (3.3 vs. 4.7%). The different fatty acid profiles did not affect the backfat thickness or the loin eye area of the animals (P0.05). However, animals fed PO displayed lower daily weight gain (0.36 kg/d), feed efficiency (0.08 kg ADG/kg DM), HCW (245 kg), and hot yield percentage (52.6%) compared to animals that were fed the other diets. Therefore, PO compared to the other lipid sources used in this study reduces intake, performance, feed efficiency, and carcass yield. Therefore, PO is not suggested for feedlot-finished animals.

Summary Background: A phase II trial of a new intra-arterial chemotherapy regimen for unresectable pancreatic cancer (UPC). Patients and methods: Ninety-six patients with UPC were treated with intra-arterial chemotherapy at three-weekly intervals. The schedule used was FLEC: 5-fluorouracil 1000 mg/m 2 , folinic acid 100 mg/m 2 , carboplatin 300 mg/m 2 ; epirubicin 60 mg/m 2 . Results: The overall response rates by CT-scan evaluation were: 15% partial response (PR), 44% stable disease (SD), 17% progressive disease (PD). The overall median survival was 9.9 months, and 10.6 and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in 42% of patients. A weight gain > 7% from baseline occurred in 8% of patients. A total of 341 courses of FLEC were administered. Grade 3-4 hematological toxicity was seen in 25% of patients; ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; and grade 3 alopecia in 16%. One sudden death, a pre-infarction angina, and a transitory ischemic attack were observed. The only complication related to the angiographic procedure was an intimal dissection of the iliac artery. Conclusions: The intra-arterial FLEC regimen was well tolerated and active. It requires only one day of hospitalization. Efficacy could only be assessed in a randomized study against a gemcitabine containing regimen.

Summary Background Although leucovorin (LV) + 5-fluorouracil (5-FU) is considered the treatment of choice for advanced colorectal cancer in most countries, the optimal schedule of this combination has not yet been established. Low-dose LV appears to be as active as high-dose LV in the daily-times-five regimen, but no randomized study of the levorotatory stereoisomer (6s-LV) given at two different dose levels has been published. Patients and methods Between November 1991 and June 1994, 422 patients (all with measurable disease previously untreated with chemotherapy) were randomized to 6S-LV (100 mg/sqm/i.v.) + 5-FU (370 mg/sqm/15 min i.v. infusion), both administered for 5 days every 28 days (arm A), or to 6S-LV (10 mg/sqm/i.v.) + 5-FU (doses as above), also given for 5 days every 28 days (arm B). The primary endpoint of the study was the comparison of response rates (WHO criteria); the secondary endpoint was the assessment of survival and tolerability. No evaluation of the quality of life or the symptomatic effect of treatment was planned. Results The response rate was 9.3% in arm A (95% CI: 5.4–13.1), with 2 CR and 18 PR, and 10.7% in arm B (95% CI: 6.5–14.9), with 3 CR + 19 PR, without any significant difference (P = 0.78). The median time to progression was eight months in both groups and overall survival was 11 months, with no difference between treatments. Toxicity mainly consisted of gastrointestinal side effects (mucositis and diarrhoea), which were rarely severe (grade 3–4: 5%–10% of patients) and similar in the two groups. Conclusions In this large-scale multicentre trial, the low and high doses of 6S-LV appeared to be equivalent in terms of the biochemical modulation of 5-FU in advanced colorectal cancer although, for several reasons (including the timing and the strict criteria of response evaluation, the high number of patients with unfavourable prognostic factors, the multi-institutional nature of the study, the dose and modality of 5-FU administration), the response rate was lower than that reported in some of the other published studies. Given the considerable difference in economic cost between the two dosages, the use of high-dose 6S-LV in the daily-times-five regimen is not recommended in clinical practice.

Objective: The very limited efficacy of current chemotherapeutic strategies in advanced pancreatic cancer (APC) and the pattern of metastastic spread, largely confined to the upper

Increasing the energy density of the diet by adding lipid sources is a nutritional strategy that is used for finishing cattle, which leads to satisfactory performance. The use of lipids in ruminant diets has been recommended because by reducing methanogenesis the energy efficiency is improved. There are several ways to provide lipids to the diet, which includes grain, oil and calcium salts. According to Allen (2000) the main problem of using lipids rich in unsaturated fatty acids (UFAs) in diets for ruminants is their effect on intake and, consequently, on ruminal digestibility of the fibrous fraction. Also, diets rich in cereal grains cause a pH decrease in the rumen, which inhibits lipolysis and biohydrogenation. To avoid the negative effects just described, the lipid supplement in the form of protected fat has been recommended for ruminants because it is considered an inert ruminal fat source (Harvatine and Allen, 2006). However, the use of fat supplementation is more typical for feedlot cattle than for grazing cattle. In addition, there are only few data on effects of fat supplementation on grazing cattle (Brokaw et al., 2001; Krysl et al., 1991). Likewise, reducing the fat supplementation frequency for grazing cattle, due to great territorial extension in some cases, may enhance logistic management in the farm. Thus, the objective of this study was to evaluate the effects of different lipid sources supplemented daily or thrice weekly on microbial protein synthesis of grazing heifers.

In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-α (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m 2 i.v. bolus) + 5FU (400 mg/m 2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 × 10 6 U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13–35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.

The simultaneous administration of irinotecan, 5-fluorouracil, folinic acid and oxaliplatin (FOLFOXIRI) has been compared with standard 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) in randomized trials in metastatic colorectal cancer patients. A superior efficacy of FOLFOXIRI has been reported by some authors, but others have failed to show any differences and do not recommend its use because of greater cost and toxicity. We performed a systematic review of the literature to analyse efficacy and toxicity of FOLFOXIRI.Odds ratios (OR) with 95% confidence intervals (CI) were used to analyse dichotomous variables. Hazard ratios (HR) for progression and death were combined with an inverse variance method based on logarithmic conversion. A fixed-effect model and Mantel-Haenszel's method were used. Heterogeneity was tested with Cochrane's Q test and I(2) test.A significant increase in response rate (OR 2.04; P0.01) was associated with treatment by FOLFOXIRI and a benefit was also shown by the HR for progression (HR 0.72; P0.01) and death (HR 0.71; P0.01). Analysis for toxicity found a significant increase associated with FOLFOXIRI except for anaemia, fatigue and febrile neutropenia.FOLFOXIRI confers significant benefit in progression-free survival, survival, response and R0 resection rates but is more toxic compared with FOLFIRI.

Borexino, at the I.N.F.N. Gran Sasso Underground Laboratory in Italy, is an experiment designed to detect, in real-time, low energy solar neutrinos. After a brief presentation of the Borexino physics and detector, we illustrate some recent results and their physics implications. Borexino perspectives are also discussed.

The authors present the experience of a single institution with selective arterial embolisation for primary and metastatic bone tumours. A total of 365 patients were treated with 454 embolisation procedures from December 2002 to April 2010. Embolisation was the primary treatment for benign bone tumours, adjuvant treatment to surgery for benign and malignant bone tumours and palliative treatment for bone sarcomas and metastases. Indications for repeat embolisation included pain or imaging evidence of progressive disease: 105 patients had repeat embolisation at the same location at an interval of 1-3 months; 260 patients had one embolisation, 78 had two and 29 had three or more. In all patients, N-2-butyl cyanoacrylate (NBCA) in 33% lipiodol was the embolic agent used. A total of 419 of the 454 embolisations (93%) were technically successful. In 35 cases, embolisation was not feasible because of poor lesion vascularisation (21 patients with bone metastases and two with aneurysmal bone cysts), origin of the Adamkiewicz artery in the embolisation field (four patients with bone metastases and one with aneurysmal bone cyst), atheromatosis and arteriosclerosis (five patients with bone metastases) and anatomical and technical problems such as small-calibre vessels, many branches and acute vessel angles (two patients with bone metastases). A clinical response was achieved in 406 of the 419 procedures (97%), and no response in 13 procedures in patients with pelvis and sacrum tumours. Complications included postembolisation syndrome in 81 patients (22%), transient paraesthesias in 41 (11%), skin breakdown and subcutaneous necrosis at the shoulder and pelvis in five (1.4%) and paresis of the sciatic nerve in one (0.3%). We recommend embolisation as primary or palliative treatment or an adjunct to surgery for tumours of variable histology. Strict adherence to the principles of transcatheter embolisation is important. Arteries feeding the tumour and collaterals must be evaluated carefully and catheterised superselectively to protect the normal tissues. NBCA is considered the most appropriate embolic agent for small-vessel occlusion without major complications.

We consider an extended point-particle action depending not only on the length but also on the curvature of the particle world-line. We derive constraints on such a higher derivative modification of standard dynamics, by using experimental results on the hyperfine structure of the hydrogen atom and on the electron (g − 2) anomaly.

It is pointed out that the mechanism of collective ion acceleration by means of electron beams may occur in solar flares. This mechanism remarkably provides the following features in agreement with the observational data: i) proton acceleration up to GeV energies within a 10−1 - 10−2 time interval, ii) proton and electron spectrum similarity and a scaling law that relates the number of the accelerated protons and electrons, iii) acceleration of nuclei, whose spectra are similar to that of electrons and protons.

In the literature good results have been reported for the treatment of Pseudomyxoma peritonei (PMP) by cytoreduction, peritonectomy and hyperthermic antiblastic peritoneal perfusion (H.A.P.P.). Forty-eight patients affected by PMP have been treated with this technique over the past ten years.Peritoneal perfusion has been performed with the original semiclosed tecnique after complete surgical cytoreduction in 188 patients affected by peritoneal carcinomatosis. In 48 of the cases the patients were affected from PMP. Aggressive surgical cytoreduction was performed with multiple visceral resections and peritonectomies.Seventeen patients (38%) presented major perioperative complications, and in five cases the reoperation of the patient was required. In spite of this high complication rate, there was no perioperative mortality. The results of the Kaplan-Meier 5- and 10-year survival analysis, were 94% and 82%, respectively, with a disease-free survival of 80% at 5 years and 70% at 10 years. Thirty-nine patients (81.2%) had no evidence of disease at follow-up (range 1-120 months).Up to date, the most effective treatment for PMP has been aggressive cytoreduction plus H.A.P.P.

Thalidomide is a potent anti-myeloma drug which can produce up to a 30-50% overall response rate (ORR) in pre-treated, chemorefractory multiple myeloma. Most authors agree with using 200 mg/daily with associated high dose dexamethasone (40 mg/daily x 4 days, 3 times monthly) considering lower doses investigational. We report our experience using thalidomide 100 mg/daily plus dexamethasone 40 mg/daily once a month, in 27 pre-treated patients. Thalidomide dose excalation and/or association with other drugs were established on the basis of the patient's response. Median age was 69 years (range 50-83 years) and 16 male and 11 female patients were treated. All patients had received more than 1 treatment line (range 1-5). Thalidomide was increased up to 300 mg/daily in 10 patients and 1 patient received up to 400 mg/daily. Two patients were not evaluable because of early death, 1 did not tolerate thalidomide because of pulmonary and neurological side-effects. Sixteen patients responded to this treatment, with an ORR of 66%. The combination of low-dose thalidomide plus monthly high-dose dexamethasone in chemorefractory myeloma showed interesting palliative results. According to our data, increasing thalidomide dosage and/or adding further drugs does not generally produce significant improvement.