Regorafenib monotherapy as second-line treatment of patients with RAS-mutant advanced colorectal cancer (STREAM): an academic, multicenter, single-arm, two-stage, phase II study.

BACKGROUND: Maintaining angiogenesis inhibition and switching the chemotherapy backbone represent the current second-line therapy in patients with RAS-mutant metastatic colorectal cancer (mCRC). Regorafenib, an oral multikinase inhibitor, prolonged overall survival (OS) in the chemorefractory setting. MATERIALS AND METHODS: STREAM was an academic, multicenter, single-arm phase II trial, evaluating the activity of regorafenib in RAS-mutant mCRC, in terms of the rate of patients who were progression-free after 6 months from study entry (6mo-PF). Patients were pretreated with fluoropyrimidine, oxaliplatin, and bevacizumab. According to Simon's two-stage design, ≥18 patients 6mo-PF were needed in the overall population (N = 46). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS), and OS. Early metabolic response by [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography ([18F]-FDG PET/CT) scan was an exploratory endpoint. EudraCT Number: 2015-001105-13. RESULTS: The number of patients 6mo-PF was 8/22 at the first stage and 14/46 in the overall population. The ORR was 10.9%, disease control rate was 54.6%, median (m)PFS was 3.6 months [95% confidence interval (CI) 1.9-6.7 months], mOS was 18.9 months (95% CI 10.3-35.3 months), and mPFS2 (from study entry to subsequent-line progression) was 13.3 months (95% CI 8.4-19.7 months). Long benefiter patients (>6mo-PF) significantly more often had a single metastatic site and lung-limited disease. No unexpected toxicity was reported. Grade ≥3 events occurred in 39.1% of patients, with hand-foot syndrome (13%), fatigue, and hyperbilirubinemia (6.5%) occurring mostly. Baseline metabolic assessment was associated with OS in the multivariate analysis, while early metabolic response was not associated with clinical outcomes. CONCLUSIONS: The study did not meet its primary endpoint. However, regorafenib was well tolerated and did not preclude subsequent treatments. Patients with good prognostic features (single metastatic site and lung-limited disease) reported clinical benefit with regorafenib. The exploratory metabolic analysis suggests that baseline [18F]-FDG PET/CT might be useful to select patients with a favorable outcome. A chemotherapy-free interval with regorafenib was associated with durable disease control in a selected group of patients with favorable clinical characteristics.

A multicentre study on spontaneous in-cage activity and micro-environmental conditions of IVC housed C57BL/6J mice during consecutive cycles of bi-weekly cage-change.

Mice respond to a cage change (CC) with altered activity, disrupted sleep and increased anxiety. A bi-weekly cage change is, therefore, preferred over a shorter CC interval and is currently the prevailing routine for Individually ventilated cages (IVCs). However, the build-up of ammonia (NH3) during this period is a potential threat to the animal health and the literature holds conflicting reports leaving this issue unresolved. We have therefor examined longitudinally in-cage activity, animal health and the build-up of ammonia across the cage floor with female and male C57BL/6 mice housed four per IVC changed every other week. We used a multicentre design with a standardised husbandry enabling us to tease-out features that replicated across sites from those that were site-specific. CC induce a marked increase in activity, especially during daytime (~50%) when the animals rest. A reduction in density from four to two mice did not alter this response. This burst was followed by a gradual decrease till the next cage change. Female but not male mice preferred to have the latrine in the front of the cage. Male mice allocate more of the activity to the latrine free part of the cage floor already the day after a CC. A behaviour that progressed through the CC cycle but was not impacted by the type of bedding used. Reducing housing density to two mice abolished this behaviour. Female mice used the entire cage floor the first week while during the second week activity in the latrine area decreased. Measurement of NH3 ppm across the cage floor revealed x3 higher values for the latrine area compared with the opposite area. NH3 ppm increases from 0-1 ppm to reach ≤25 ppm in the latrine free area and 50-100 ppm in the latrine area at the end of a cycle. As expected in-cage bacterial load covaried with in-cage NH3 ppm. Histopathological analysis revealed no changes to the upper airways covarying with recorded NH3 ppm or bacterial load. We conclude that housing of four (or equivalent biomass) C57BL/6J mice for 10 weeks under the described conditions does not cause any overt discomfort to the animals.

NEPA (netupitant/palonosetron) for the antiemetic prophylaxis of nausea and vomiting induced by chemotherapy (CINV) with Folfirinox and Folfoxiri even during the COVID-19 pandemic: a real-life study.

OBJECTIVE: The outbreak of coronavirus disease 2019 (COVID-19) has affected the treatment of cancer patients, with particular regard to the management of both chemotherapy and side effects. Chemotherapy-induced nausea and vomiting (CINV) are amongst the most troublesome side effects that impair patients' adherence to treatments and their quality of life (QoL). NEPA (Akynzeo®), is an oral fixed-dose combination of netupitant [a neurokinin-1 receptor antagonist (NK1RA), 300 mg] and palonosetron [(5-hydroxytryptamine (serotonin or 5HT) type3 receptor antagonist (5HT3RA), 0.5 mg] which has been shown to be effective in preventing CINV. PATIENTS AND METHODS: This prospective study started before the outbreak of COVID-19 and was carried out during the pandemic period. The aim was to evaluate the efficacy and safety of a single oral dose NEPA plus 12 mg of dexamethasone (DEX) in patients treated with Folfoxiri plus Bevacizumab and Folfirinox. The patients were diagnosed with advanced colorectal cancer (CRC) or advanced pancreatic ductal adenocarcinoma (PDAC). They were divided into two groups: naïve patients and patients previously treated with serotonin receptor antagonists (5HT3-RA) and neurokin-1 receptor antagonists (NK1-RA). RESULTS: During the overall phase, the complete response (CR) rate was 96.8% in naïve patients treated with Folfoxiri plus Bevacizumab, and 94.6% in patients treated with Folfirinox. During the acute and delayed phases, the CR rate was 92.8% and 94.2%, with Folfoxiri and Bevacizumab, as well as 96.2% and 94.6%, with Folfirinox. There was no adequate control of CINV events in patients on antiemetic prophylaxis with 5HT3-RA or NK1-RA associated with cortisone. During the overall phase, the CR rate was 74.6% with Folfoxiri plus Bevacizumab and 75.8% with Folfirinox. During the acute and delayed phases, the CR rate was 72.5% and 74.8% with Folfoxiri plus Bevacizumab, as well as 75.2% and 74.6% with Folfirinox. CONCLUSIONS: This study has shown the therapeutic benefits of NEPA in the management and prophylaxis of CINV events, both in naive patients and patients previously treated with 5HT3-RA and NK1-RA. In addition, NEPA has been shown to be safe, both before and during the COVID-19 pandemic.

The recommended lifetime immunization schedule from the board of vaccination calendar for life in Italy: A continuing example of impact on public health policies.

The Vaccination Calendar for Life is an alliance of scientific and professional societies of public health physicians, paediatricians and general practitioners in Italy which provides a periodical update on the ideal, scientifically driven vaccination calendar throughout lifetime. Since 2012, the Lifetime Immunization Schedule has represented a benchmark for Regional and National Authorities to set up the updated list of vaccines provided actively and free of charge to infants, children, adolescents, adults and the elderly by inclusion in the Triennial National Vaccination Plan (TNVP), and in the Essential Levels of Care (LEA). The impact of the different editions of the Lifetime Immunization Schedule on the TNVP was deep, representing the inspiring source for the present vaccination policy. The 2019 edition called for more attention to pregnant women immunization; risk groups vaccination; uniform high coverage with the MMRV vaccine; extension of Meningococcal B vaccination also at adolescent age; use of quadrivalent conjugate meningococcal vaccine also at 1 year of life; progressive decrease of the age of free-of-charge offer of influenza to ≥ 60 and then to ≥ 50 year-old population; implementation of flu immunization ages 6 months-6 years; HPV vaccination also offered to 25-year old women at the time of the first screening (gender neutral immunization already offered); sequential PCV13-PPV23 pneumococcal vaccination in 65 year-old subjects; increased coverage with rotavirus vaccine in infants and zoster vaccine in the elderly.

Maintain and increase vaccination coverage in children, adolescents, adults and elderly people: Let's avoid adding epidemics to the pandemic: Appeal from the Board of the Vaccination Calendar for Life in Italy: Maintain and increase coverage also by re-organizing vaccination services and reassuring the population.

The Board of the Vaccination Calendar for Life (Bonanni et al., 2014, 2017) [1,2]), a coalition of four major scientific and professional societies of public health physicians, pediatricians and general practitioners in Italy, made an appeal to health authorities in order to sustain vaccination in COVID-19 times. The five pillars to maintain and increase vaccination coverage at all ages are described as follows: 1) Guarantee paediatric vaccination coverage to all newborns and paediatric boosters and adolescent immunizations, not interrupting active calls and scheduled sessions. 2) Re-organise the way paediatric and adolescent vaccinations are offered. 3) Set-up recovery programs for vaccinations not carried out after the start of the COVID-19 emergency. 4) Provide the preparation of tenders for the supply of flu vaccines with suitable quantities to increase coverage in all Regions and Autonomous Provinces with extreme urgency. 5) Prepare plans to increase coverage for influenza, pneumococcal, tetanus diphtheria and shingles. The Board of the Calendar for Life appeals to the National and Local Health Authorities for a strong and coordinated commitment in favor of the widest offer and acceptance of vaccinations, whose vital importance for collective health is now even more evident to all, in order to avoid that delays in the necessary initiatives should add damage from other epidemics to those suffered by our population due to the COVID-19 pandemic.

Overall survival with 3 or 6 months of adjuvant chemotherapy in Italian TOSCA phase 3 randomised trial.

BACKGROUND: Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. MATERIAL AND METHODS: TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. RESULTS: From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was <1%. CONCLUSIONS: The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov, registration number: NCT0064660.

Towards large scale automated cage monitoring - Diurnal rhythm and impact of interventions on in-cage activity of C57BL/6J mice recorded 24/7 with a non-disrupting capacitive-based technique.

BACKGROUND AND AIMS: Automated recording of laboratory animal's home cage behavior is receiving increasing attention since such non-intruding surveillance will aid in the unbiased understanding of animal cage behavior potentially improving animal experimental reproducibility. MATERIAL AND METHODS: Here we investigate activity of group held female C57BL/6J mice (mus musculus) housed in standard Individually Ventilated Cages across three test-sites: Consiglio Nazionale delle Ricerche (CNR, Rome, Italy), The Jackson Laboratory (JAX, Bar Harbor, USA) and Karolinska Insititutet (KI, Stockholm, Sweden). Additionally, comparison of female and male C57BL/6J mice was done at KI. Activity was recorded using a capacitive-based sensor placed non-intrusively on the cage rack under the home cage collecting activity data every 250 msec, 24/7. The data collection was analyzed using non-parametric analysis of variance for longitudinal data comparing sites, weekdays and sex. RESULTS: The system detected an increase in activity preceding and peaking around lights-on followed by a decrease to a rest pattern. At lights off, activity increased substantially displaying a distinct temporal variation across this period. We also documented impact on mouse activity that standard animal handling procedures have, e.g. cage-changes, and show that such procedures are stressors impacting in-cage activity. These key observations replicated across the three test-sites, however, it is also clear that, apparently minor local environmental differences generate significant behavioral variances between the sites and within sites across weeks. Comparison of gender revealed differences in activity in the response to cage-change lasting for days in male but not female mice; and apparently also impacting the response to other events such as lights-on in males. Females but not males showed a larger tendency for week-to-week variance in activity possibly reflecting estrous cycling. CONCLUSIONS: These data demonstrate that home cage monitoring is scalable and run in real time, providing complementary information for animal welfare measures, experimental design and phenotype characterization.

The prognostic impact of primary tumour location in patients with stage II and stage III colon cancer receiving adjuvant therapy. A GISCAD analysis from three large randomised trials.

PURPOSE: Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. PATIENTS AND METHODS: Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. RESULTS: Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89-1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04-1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14-1.62, p < 0.001). CONCLUSION: This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours.

Mercury in the Black Sea: New Insights From Measurements and Numerical Modeling.

Redox conditions and organic matter control marine methylmercury (MeHg) production. The Black Sea is the world's largest and deepest anoxic basin and is thus ideal to study Hg species along the extended redox gradient. Here we present new dissolved Hg and MeHg data from the 2013 GEOTRACES MEDBlack cruise (GN04_leg2) that we integrated into a numerical 1-D model, to track the fate and dynamics of Hg and MeHg. Contrary to a previous study, our new data show highest MeHg concentrations in the permanently anoxic waters. Observed MeHg/Hg percentage (range 9-57%) in the anoxic waters is comparable to other subsurface maxima in oxic open-ocean waters. With the modeling we tested for various Hg methylation and demethylation scenarios along the redox gradient. The results show that Hg methylation must occur in the anoxic waters. The model was then used to simulate the time evolution (1850-2050) of Hg species in the Black Sea. Our findings quantify (1) inputs and outputs of HgT (~31 and ~28 kmol yr-1) and MeHgT (~5 and ~4 kmol yr-1) to the basin, (2) the extent of net demethylation occurring in oxic (~1 kmol yr-1) and suboxic water (~6 kmol yr-1), (3) and the net Hg methylation in the anoxic waters of the Black Sea (~11 kmol yr-1). The model was also used to estimate the amount of anthropogenic Hg (85-93%) in the Black Sea.

A phase III trial comparing oral S-1/cisplatin and intravenous 5-fluorouracil/cisplatin in patients with untreated diffuse gastric cancer.

BACKGROUND: The effect of histology-based treatment regimen on diffuse gastric adenocarcinoma has not been evaluated in clinical trials. This international phase III trial evaluated the efficacy and safety of S-1 (a contemporary oral fluoropyrimidine)/cisplatin versus 5-fluorouracil (5-FU)/cisplatin in chemotherapy-naïve patients with diffuse-type adenocarcinoma involving the gastroesophageal junction or stomach. PATIENTS AND METHODS: Eligibility criteria included untreated, measurable, advanced diffuse adenocarcinoma confirmed by central pathology and performance status of 0-1. Patients were randomized (2 : 1) to receive S-1/cisplatin or 5-FU/cisplatin. Primary end point was overall survival (OS), and secondary end points were progression-free survival, time to treatment failure, overall response rate, and safety. A multivariable analysis was also carried out. RESULTS: Overall, 361 patients were randomized (S-1/cisplatin, n = 239; 5-FU/cisplatin, n = 122); half (51%) were men, and median age was 56.0 years. In each group, median number of treatment cycles per patient was 4 (range, S-1/cisplatin: 1-20; 5-FU/cisplatin: 1-30), and dose intensity was >95%. OS was not different in the two groups {median OS with S-1/cisplatin, 7.5 [95% confidence interval (CI): 6.7, 9.3]; 5-FU/cisplatin, 6.6 [95% CI: 5.7, 8.1] months; hazard ratio, 0.99 [95% CI: 0.76, 1.28]; P = 0.9312}. Overall response rate was significantly higher in the S-1/cisplatin than 5-FU/cisplatin group (34.7% versus 19.8%; P = 0.01), but progression-free survival and time to treatment failure were not different. Safety was similar between the 2 groups; however, fewer patients treated with S-1/cisplatin than 5-FU/cisplatin had ≥1 grade 3/4 treatment-emergent adverse event or ≥1 adverse event resulting in treatment discontinuation. One treatment-related death occurred in each group. Slow accrual led to early termination. CONCLUSIONS: These data suggest that S-1/cisplatin and 5-FU/cisplatin are similar in efficacy and safety in untreated patients with advanced diffuse adenocarcinoma of the gastroesophageal junction or stomach. The primary end point was not met. CLINICALTRIAL.GOV REGISTRATION NUMBER: NCT01285557.

Modeling of SAM Impedance Onto Gold and Silver Thin-Film Mass-Produced Electrodes and Their Use for Optimization of Lactic Acid Detection.

In this work, we demonstrate how an innovative, out-of-cleanroom customized CD/DVD fabrication process can be successfully used for mass production of biosensors with thin-film electrodes. We show that silver and gold electrodes can be used for impedimetric and voltammetric biosensing applications, both in presence and absence of a redox mediator. We modeled the redox/non-redox electrodes impedance through equivalent electrical circuits, and we evaluated their transfer function sensitivity with a one-factor-at-a-time approach. Using this approach, we introduced a new prediction method to find which equivalent electrical circuit elements contribute more to the transfer function variations, then we experimentally validated the predictions measuring the electrodes electrochemical impedance spectroscopy responses with relevant self-assembled monolayer molecules immobilized on them, i.e., MCH and DTSP. We also assess the silver electrodes long-term stability with impedance spectroscopy measurements over a period of 1200 hours, proving their possible use in point-of-care applications. Finally, we also prove that the sensors correctly perform in a practical case, i.e., as a lactic acid biosensor, by studying the optimization of the biosensor efficiency through different enzyme immobilization methods. By comparing lactate oxidase enzyme direct adsorption and covalent binding to DTSP self-assembling monolayers, we found that covalent binding to DTSP can boost the catalytic current of about 40% with respect to that obtained from the direct adsorption of the same enzyme concentration.

Phase III trial comparing 3-6 months of adjuvant FOLFOX4/XELOX in stage II-III colon cancer: safety and compliance in the TOSCA trial.

BACKGROUND: Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems. PATIENTS AND METHODS: TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data. RESULTS: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34). CONCLUSIONS: TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations. CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00646607.

A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma.

BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472.

Randomized trial on adjuvant treatment with FOLFIRI followed by docetaxel and cisplatin versus 5-fluorouracil and folinic acid for radically resected gastric cancer.

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.

[A full economic evaluation of extensive vaccination against rotavirus with RIX4414 vaccine at National and Regional level in Italy]. / Una valutazione economica completa della vaccinazione estensiva contro i rotavirus con il vaccino RIX4414 a livello nazione e regionale in Italia.

Vaccination of all healthy children against rotavirus (RV) has been recommended, since the availability of vaccines, both in Europe (PIDJ) and Italy (pediatricians). The aims of universal vaccination against RV include the protection of children against moderate/severe gastroenteritis forms by RV (GARV), prevent hospitalizations, reduce the severity and duration of the disease, and reduce morbidity and socioeconomic costs. Payers need to informed regarding the efficacy and the healthcare utilization related to RV vaccination in order to decide in favour of its extensive implementation. The aim of this paper is to assess the clinical and financial impact of the extensive vaccination aganist RV both at National and Regional level. Particular attention, compared to the previous analysis (Standaert et al, 2008) has been given to the influence of herd immunity (HI) on cost-utility results of vaccination against-RV. Methods. The analysis was conducted with the Markovian model previously used by Standaert B et al and updated for comparing costs and benefits associated with a situation of vaccination anti-RV that includes efficacy data due to HI, with a situation without vaccination. For the base case is assumed an annual coverage of 90%, where the effect of HI is present in the population at risk (0-5 years) and extended to children who have not been vaccinated, adding as conservative assumption, a further 10% to the efficacy of the vaccine, compared to 15% determined by several published studies. Two analysis have been made based on this model: a cost-utility analysis that compared vaccination with two doses of RIX441410 administered at 2 and 3 months after birth compared with no vaccination from National Health Service and Society perspective; a budget impact analysis at National and Regional level. The evaluation has as its main element the reduction of cases of infection through universal vaccination and consequent reduction of Garv events and nosocomial infections. Results. From the NHS perspective, in a cohort of 555,791 born in Italy in 2011, the annual number of hospitalizations due to RV infections in the absence of vaccination is estimated to be 14,550 units. Assuming that 90% of newborns receive two doses of the vaccine, and including an additional effect of HI to the efficacy of the vaccine, vaccination would lead to a reduction of 71% of cases of Garv (176,804 cases in less) and a 86% of hospitalizations due to Garv (12,913 fewer cases), with an impact on quality of life and mortality as a consequence of vaccination. The introduction of the vaccine would lead to a gain of 0.0014 QALYs and 0.0022 life-years gained per child compared to a situation without vaccination (assuming a discount rate of 3% on future benefits). The reduction of GARV also would lead to a strong economic impact. The introduction of the vaccine would lead to a saving of € 25.41 per child or a saving of more than € 14 million for the whole population included in the analysis. Cost reduction increase significantly from the perspective of society and introducing the indirect costs due to lost productivity. In this case, the savings due to the introduction of vaccination would increase to € 67,747,654 in the total cohort, or € 121.89 per child. In an alternative scenario, where HI is excluded, RIX4414 remains dominant (0.0013 QALYs gained and € 22.14 per child saved). The budget impact analysis shows that, as early as the second year, the additional cost of the vaccine is more than offset by a reduction in costs of the disease, which leads to savings for the NHS, which increases from year 3. In a time horizon of 5 years (without the discount rate), the savings for the NHS amount to € 34,440,314. These savings would amount to a cost reduction of € 4.64 per child over 5 years (€ 0.93 per year). The savings due to the introduction of the vaccine were mainly due to a reduction in costs associated with hospitalizations. The budget impact analysis at regional level, has taken a vaccine cost of € 30.00 per dose. Cases of diarrhoea before after vaccination are reduced in each region, based on the number of births, ranging from a minimum of 399 cases avoided for Valle d'Aosta to a maximum of 31,116 cases avoided in Lombardy. In a similar way, the number of hospitalizations due to GARV are reduced considerably, from a minimum of 36 cases in Valle d'Aosta to a maximum of 3,096 in Lombardy. Obviously, these reductions are greater in regions with 30,000 or more births per year. Conclusions. This study suggests that a universal vaccination anti-RV with 2 doses of RIX4414 brings significant clinical and economic benefits both at National and Regional level. The indirect effects of the vaccine (HI) could generate protection even in unvaccinated children with health gain and a number of cases by GARV much less than those that would vaccinating small groups of children and with a cost of illness, for NHS, which would be reduced significantly, despite the additional costs of the vaccine as early as the second year of vaccination. Productivity losses due to absence from work of a parent, as well as all other costs included in the model, show that is precisely the society to pay the consequences, from economic and social point of view. Considering the citizen in the role of private payer, we must stress as for him, the savings generated by vaccination, whether universal or with demand for cost-sharing by the health service, prove significant with a major health gain for the population under study.

Cutaneous Force Feedback as a Sensory Subtraction Technique in Haptics.

A novel sensory substitution technique is presented. Kinesthetic and cutaneous force feedback are substituted by cutaneous feedback (CF) only, provided by two wearable devices able to apply forces to the index finger and the thumb, while holding a handle during a teleoperation task. The force pattern, fed back to the user while using the cutaneous devices, is similar, in terms of intensity and area of application, to the cutaneous force pattern applied to the finger pad while interacting with a haptic device providing both cutaneous and kinesthetic force feedback. The pattern generated using the cutaneous devices can be thought as a subtraction between the complete haptic feedback (HF) and the kinesthetic part of it. For this reason, we refer to this approach as sensory subtraction instead of sensory substitution. A needle insertion scenario is considered to validate the approach. The haptic device is connected to a virtual environment simulating a needle insertion task. Experiments show that the perception of inserting a needle using the cutaneous-only force feedback is nearly indistinguishable from the one felt by the user while using both cutaneous and kinesthetic feedback. As most of the sensory substitution approaches, the proposed sensory subtraction technique also has the advantage of not suffering from stability issues of teleoperation systems due, for instance, to communication delays. Moreover, experiments show that the sensory subtraction technique outperforms sensory substitution with more conventional visual feedback (VF).

Gene expression profile of human colon cancer cells treated with cross-reacting material 197, a diphtheria toxin non-toxic mutant.

Cross-Reacting Material 197 (CRM197) is a diphtheria toxin non-toxic mutant that has shown antitumor activity in mice and humans. It is still unclear whether this anti-tumorigenic effect depends on its strong inflammatory-immunological property, its ability to inhibit heparin-binding epidermal growth factor (HB-EGF), or even its possible weak toxicity. CRM197 is utilized as a specific inhibitor of HB-EGF that competes for the epidermal growth factor receptor (EGFR), overexpressed in colorectal cancer and implicated in its progression. In this study we evaluate the effects of CRM197 on HT-29 human colon cancer cell line behaviour and, for CRM197 recognized ability to inhibit HB-EGF, its possible influence on EGFR activation. In particular, while HT-29 does not show any reduction of viability after CRM197 treatment (MTT modified assay), or changes in cell cycle distribution (flow cytometry), in EGFR localization, phospho-EGFR detected signals (immunohistochemistry) or in morphology (scanning electron microscopy, SEM) they show a change in the gene expression profile by microarray analysis (cDNA microarray SS-H19k8). The overexpression of genes like protein phosphatase 2, catalytic subunit, alpha isozyme (PPP2CA), guanine nucleotide-binding protein G subunit alpha-1(GNAI1) and butyrophilin, subfamily 2, member A1 (BTN2A1) has been confirmed with real-time-qPCR. This is the first study where the CRM197 treatment on HT-29 shows a possible scarce implication of endogenous HB-EGF on EGFR expression and cancer cell development. At the same time, our results show the alteration of a specific and selected number of genes.