Second-line treatment strategies for RAS wild-type colorectal cancer: A systematic review and Network Meta-analysis (NMA).

BACKGROUND: The optimal strategy for second-line (IIL) treatment in KRAS wt metastatic colorectal cancer (mCRC) is not determined yet. METHODS: A random-effect NMA of phase II/III RCTs was conducted to evaluate IIL treatment for all-RAS wt mCRC, comparing anti-EGFR or anti-VEGF, and chemotherapy (CT). RESULTS: Overall, 11 RCTs (3613 patients) were included. In KRAS wt patients, PFS was improved with anti-VEGF (HR 0.43) and anti-EGFR (HR 0.63) vs CT. However, anti-VEGF based therapy had the highest likelihood of being ranked as the best treatment in terms of PFS (SUCRA 99.3%) and OS (SUCRA 99.4%). Bevacizumab-based treatment is most likely to be the best treatment in terms of PFS (SUCRA 89.1%) and OS (SUCRA 86.7%). CONCLUSIONS: Second line treatment with anti-VEGF and anti-EGFR improved PFS in mCRC patients, however, anti-VEGF based therapy, particularly CT plus bevacizumab, is the best treatment according to SUCRA in terms of PFS and OS.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)-a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO.

INTRODUCTION: At the time of diagnosis, 15-20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5-20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients. Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario. METHODS: This study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery. DISCUSSION: Considering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03917173. Registered on 16 April 2019. PROTOCOL VERSION: v1, March 27, 2019. Protocol number: IRFMN-GCC-7813. EudraCT number: 2019-001478-27.

Analysis of workload generated in the two years following first consultation by each new cancer patient: studying the past to plan the future of cancer care.

INTRODUCTION: Prevalence of cancer patients is dramatically increasing. We aimed at quantifying the oncology workload generated by each new cancer patient in the two years following first consultation. METHODS: In this record-based retrospective study, we retrieved data of all newly diagnosed patients treated at the Oncology Department of Udine Academic Hospital between 01.01.2012 and 31.12.2017. We calculated mean number and standard deviation of the activity type generated by each new cancer patient during the following 2 years. RESULTS: Seven thousand four hundred fifty-two cancer patients generated a total of 85,338 clinical episodes. The two-years mean number of oncology episodes generated was 11.31 (i.e., for every 1,000 new cancer patients, 11,310 oncology activities are generated overall in the following two-year lapse). Patients with advanced disease generated the highest workload (24.3; SD 18.8) with a statistically significant difference compared to adjuvant and follow-up patients (p < 0.001). The workload generated in the period 0-6 and 0-12 months was significantly higher than in the following months (p < 0.001) and it was also higher for patients initially designated to treatment (p < 0.001). CONCLUSION: This is the first study reporting on the mean oncology workload generated during the 2 years following first consultation. Workload is the highest for patient with advanced disease, especially in the first months and in patients in active treatment. A detailed analysis of workloads in oncology is feasible and could be crucial for planning a sustainable framework for cancer care in the next future.

What to do in an oncology department to face the new COVID-19 era challenges?

Italy was the first European country to be hit by COVID-19 pandemic. As a consequence, Italian oncologists had to guarantee essential treatments although minimizing exposure to the virus, and accidental infection, of patients and healthcare professionals. As Department of Medical Oncology of the University Hospital of Udine, in this short report, we describe the measures that we have taken, and gradually updated, since February 26, 2020. All accesses to our Oncology facilities are currently regulated by entrance check-points where patients are screened for infections following dedicated algorithms. Up to date, after 6 weeks of systematic execution of swabs no physician, nurse or other individual of the staff has been found positive to COVID-19. Only one patient admitted for therapy has been identified as COVID-19 positive. The aim of our work is to propose a model, made up of a set of operative procedures, that may be adopted by all the oncologists that daily struggle to guarantee safety and care in Oncology during this COVID-19 emergency.

Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid.

Background: All-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and methods: RNA-sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis. Results: We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions: In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.

Occupational exposure to PCDDs, PCDFs, and DL-PCBs in metallurgical plants of the Brescia (Lombardy Region, northern Italy) area.

The concentration values of polychlorodibenzodioxins (PCDDs), polychlorodibenzofurans (PCDFs), and dioxin-like polychlorobiphenyls (DL-PCBs) in blood serum samples (pools) of metallurgical workers in the area of the city of Brescia (northern Italy) were statistically processed. As to workers' exposure characteristics, pools were divided into 34 professionally exposed (PE) and 11 non-professionally exposed (NPE). A further subdivision of PE pools was according to workplaces in which ferrous (N = 24) and non-ferrous (N = 10) materials were handled. To evaluate the aforesaid differences we applied the age-adjusted Generalized Linear Models. We identified significant (P ≤ 0.05) exposure models of the classification groups. The first subdivision was confirmed by the concentrations of 1,2,3,4,6,7,8-H7CDF, DL-PCB 105, and DL-PCB 189; the second was confirmed by the concentrations of PCDF TEQ97, PCDD + PCDF + DL-PCB (TEQTOT) TEQ97, 2,3,4,7,8-P5CDF, 1,2,3,6,7,8-H6CDD, 1,2,3,4,6,7,8-H7CDD, and PCB 189. Based on the literature, all mentioned congeners have been found in stack gas and fly ash samples of metallurgical plants: therefore, these indicators indicate the exposure to such work environments. Specifically, the concentrations measured in the workers' blood serum appear to depend on the type of material processed during work.

EMA and national drug agencies: cooperation or competition? / Contribución de la Agencia Española de Medicamentos y Productos Sanitarios al Comité Europeo de Evaluación de Medicamentos de Uso Humano

No disponible

[Dust and silica exposure on metallurgical furnace maintenance using refractory materials]. / Esposizione a polveri e a silice nella manutenzione dei rivestimenti refrattari dei forni metallurgici.

In the metallurgical industries the silica risk has long been known, particularly for the refractoryes maintenance workers. The maintenance of furnaces, ladles and tundisches refractory linings, on the current organization of production, is provided by companies under contract. The information available about the characterization of risk for this group of workers are at present inadequate. The study investigates the exposure to dust, also containing free crystalline silica (SLC), through the analysis of samples of commercial products used in the reconstruction of refractory linings of furnaces, ladles and tundisches, materials from the demolition of refractory articles and dust from work areas. It also presents the results of an environmental investigation conducted during the demolition and reconstruction of the refractory in three steel mills. The Authors, by the numerous inspections and the systematic survey of working conditions, have formulated a SLC risk profile and some proposals for prevention.

[Occupational risk and work-related diseases on steel foundries]. / Rischi per la salute e patologie do lavoro nelle fonderie di ghisa.

The iron foundries are still well represented in the area of Brescia and, despite having been involved in a major technological developments, have still risks to the health of workers. In order to verify the state of the art and effectiveness of prevention measures implemented by various companies, in recent years have carried out numerous inspections, environmental monitoring and biological. Furthermore, there were in the regional information system diseases reported and/or by the reported health. In particular it is shown that, in addition to chemical and physical risk factors, although in a much reduced compared to the 80s, are still present in our workplace pollutants (PAHs, silica, metal fumes, formaldehyde) at the base of classification of iron foundries in group 1, carcinogenic to humans, IARC, 1987 e 2012.

[Cumulative exposure to polychlorodibenzo-p-dioxins (PCDDS), polychlorodibenzofurans (PCDFS) and polychlorobiphenyls (PCB) in the metallurgic workers and the general population in Brescia province, northern Italy]. / Esposizione cumulativa a policlorodibenzodiossine (PCDD), policlorodibenzofurani (PCDF) e policlorobifenili (PCB) in lavoratori metallurgici e nella popolazione generale della provincia di Brescia.

High temperature metallurgical processes may significantly contribute to the release of polychlorodibenzo-p-dioxins (PCDDs) and polychlorodibenzofurans (PCDFs) into the environment. Aim of this study was to evaluate the exposure to PCDDs, PCDFs, dioxin-like PCBs (DL-PCBs) and non dioxin-like PCBs (NDL-PCBs) in a sample of 300 workers of metallurgical plants operating in the Brescia area and in a control group of 113 men. Serum samples were grouped in pools of 10 and analyzed for their concentration of PCDDs and PCDFs, DL- and NDL-PCBs. Metallurgical workers show serum concentrations of NDL-PCBs similar to those observed in non-occupationally exposed living in Brescia, except in the case of some congeners, such as PCBs 28, 52, 101 which result to be significantly higher in metallurgical workers. Their concentrations range of "dioxins" was of 32.5 - 84.8 pgTEQ g(-1) lb. No significant difference was found between metallurgical workers and the control group on the whole, but the difference became significant when comparing metallurgical workers with the group of the 47 subjects living in remote non industrialised areas. In conclusion, concentrations of total PCBs observed in metallurgy workers are comparable with those observed in the control group, with the exception of a few, more volatile, congeners which resulted to be higher in metallurgy workers. Concentrations of PCDDs and PCDFs showed a range of values similar to that observed in the general population of Brescia not professionally exposed. However, concentrations of PCDDs and PCDFs observed in subjects resident in "remote" areas were significantly lower than those assessed in metallurgy workers and subjects living in the town of Brescia. On the whole, men living in the town of Brescia show levels of PCBs, PCDDs and PCDFs higher than those observed in other groups of the Italian general population, this reflecting the intense industrial activity of the town.

[Critical in demolition and removal of asbestos cement materials]. / Criticità nei lavori di demolizione e rimozione di manufatti in cemento amianto.

Those involved in the asbestos removal is the main category of workers currently exposed to asbestos in the province of Brescia. Although Italy, since 1991, has special rules for the protection of workers exposed to asbestos, improved further by D. Lgs. n. 81 of 2008, the working conditions found in shipyards are still far from a satisfactory degree of protection of workers. Sanitary facilities are largely lacking, management of work clothing is left to chance, use of filtering face masks is often incorrect, wetting of surfaces with encapsulant is frequently inadequate, daily cleaning of work areas and areas of construction that may have been contaminated by asbestos fibers with extractors absolute filters is shortly implemented. Little attention is also paid to the protection of workers from the premises concerned to the replacement of the cover, as well as to the dispersion in the external environment of asbestos fibers that contaminate the gutters removed and sent for disposal. Finally, it is still very high risk of falling from, documented by the tribute of serious and fatal accidents that occur in these sites. Increased surveillance of Health Prevention Services of ASL is required to achieve higher levels of prevention.

Provision of information on regulatory authorities' websites.

BACKGROUND: Several organizations have raised concerns about the excessive secrecy maintained by regulatory authorities around the world, in particular in the European Union, France, UK, Canada and Australia. However, limited research has assessed the provision of information by regulatory authorities. This study aimed to assess the type and availability of information provided on the regulatory authorities' websites. METHODS: Regulatory authorities' websites in six countries (USA, Canada, UK, France, Australia and New Zealand) and at the European level (European Medicines Evaluation Agency) were surveyed by two reviewers between October 2005 and March 2006. The survey instrument included 16 criteria organized in 3 domains: information on marketed drugs, information on assessment of drugs and information on drug safety. RESULTS: There was a great variability in the level of information provided. Several medicine agencies did not provide basic information on marketed drugs, such as the summary of products' characteristics. Information on registration dossiers was scant on most websites except that of the US Food and Drug Administration. The European Medicines Evaluation Agency, the French agency and the Canadian agency released public assessment reports that contained only summarized information of registration data. Only one country, Canada, provided full access to pharmacovigilance data. The periodic safety update reports that companies have to provide regularly to regulatory authorities were not available in any country. CONCLUSION: Information on which regulatory authorities base their decisions for licensing new drugs and the rationales behind these decisions were often not publicly available.

Stopping a trial early in oncology: for patients or for industry?

BACKGROUND: The aim of this study is to assess the use of interim analyses in randomised controlled trials (RCTs) testing new anticancer drugs, focussing on oncological clinical trials stopped early for benefit. MATERIALS AND METHODS: All published clinical trials stopped early for benefit and published in the last 11 years, regarding anticancer drugs and containing an interim analysis, were assessed. RESULTS: Twenty-five RCTs were analysed. The evaluation of efficacy was protocol planned through time-related primary end points, >40% of them overall survival. In 95% of studies, at the interim analysis, efficacy was evaluated using the same end point as planned for the final analysis. As a consequence of early stopping after the interim analysis, approximately 3300 patients/events across all studies were spared. More than 78% of the RCTs published in the last 3 years were used for registration purposes. CONCLUSION: Though criticism of the poor quality of oncological trials seems out of place, unfortunately early termination raises new concerns. The relation between sparing patients and saving time and trial costs indicates that there is a market-driven intent. We believe that only untruncated trials can provide a full level of evidence which can be translated into clinical practice without further confirmative trials.