Anticancer Effects of Nutraceuticals in the Mediterranean Diet: An Epigenetic Diet Model.

Epidemiological and clinical studies support the association between nutrition and development or progression of different malignancies such as colon, breast, and prostate cancer, defining these tumors as diet-associated cancer. The Mediterranean diet shows inverse associations with metabolic diseases, cardiovascular pathologies and various types of cancer. Many bioactive nutrients of the Mediterranean diet have been identified as factors protective against these types of pathologies. The epigenome has been identified as the primary goal of modulations in gene expression related to these molecular nutrients. In fact, they can modify the epigenome and can be incorporated into the 'epigenetic diet', which translates into a diet regimen that can be used therapeutically for health or preventative purposes. Most epigenetic changes are influenced by lifestyle and nutrition. Epigenetic therapy is a new area for the development of nutraceuticals whose absence of toxicity can represent a valid asset in cancer prevention strategies. Recent advances in understanding the mechanisms of nutrigenomics, nutrigenetics and nutraceuticals have led to the identification of superfoods capable of favorably conditioning gene expression. In this review, we highlight the importance of nutraceuticals present in the Mediterranean diet as epigenetic modifiers both in the mechanisms of tumor onset and as protective agents.

COVID-19 Pandemic and the Crisis of Health Systems: The Experience of the Apulia Cancer Network and of the Comprehensive Cancer Center Istituto Tumori "Giovanni Paolo II" of Bari.

On 11 March 2020, the World Health Organization declared a new disease caused by a novel virus characterized by rapid human-to-human transmission and named severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2) a pandemic. In terms of this ongoing international scenario, we report the situation in Apulia, a region of southern Italy that, as of April 2, has not yet been overwhelmed by this health emergency. In particular, we consider the care models that have been adopted, especially those that manage the requests of cancer patients.

Novel insight into triple-negative breast cancers, the emerging role of angiogenesis, and antiangiogenic therapy.

Triple-negative breast cancer (TNBC) is a heterogeneous group of tumours characterised by lack of expression of oestrogen-, progesterone- and human epidermal growth factor receptors. TNBC, which represents approximately 15% of all mammary tumours, has a poor prognosis because of an aggressive behaviour and the lack of specific treatment. Accordingly, TNBC has become a major focus of research into breast cancer and is now classified into several molecular subtypes, each with a different prognosis. Pathological angiogenesis occurs at a late stage in the proliferation of TNBC and is associated with invasion and metastasis; there is an association with metabolic syndrome. Semaphorins are a versatile family of proteins with multiple roles in angiogenesis, tumour growth and metastasis and may represent a clinically useful focus for therapeutic targeting in this type of breast cancer. Another important field of investigation into the control of pathological angiogenesis is related to the expression of noncoding RNA (ncRNA) - these molecules can be considered as a therapeutic target or as a biomarker. Several molecular agents for intervening in the activity of different signalling pathways are being explored in TNBC, but none has so far proved effective in clinical trials and the disease continues to pose a defining challenge for clinical management as well as innovative cancer research.

Impact of body mass index (BMI) on the prognosis of high-risk early breast cancer (EBC) patients treated with adjuvant chemotherapy.

The association between obesity and prognosis in early breast cancer (EBC) is unclear, especially when aggressive phenotypes are considered. We evaluated the influence of BMI on the prognosis of women with high-risk EBC enrolled in a phase III trial of adjuvant chemotherapy (CT). The association was assessed in 1066 patients with rapidly proliferating tumors, randomized to receive adjuvant CT with or without anthracyclines. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier; multivariate analysis was performed according to age, tumor size, nodal, estrogen receptor (ER), and HER2 status and type of CT. Information on BMI was available for 959 women. Of these, 529 (55.2 %) were overweight or obese. Median age was 52 years. A total of 457 (47.7 %) patients had nodal involvement. Centralized pathology was performed in 850 cases: 522 (61.4 %) were ER positive, and 194 (22.8 %) were HER-2 positive. At a median follow-up of 103 months (range 1-188), 5-year DFS was 81 % (95 % CI 77-85), 82 % (95 % CI 77-86), and 76 % (95 % CI 70-83), in normal, overweight, and obese women, respectively (p = 0.44). Five-year OS was 92 % (95 % CI 89-95), 94 % (95 % CI 91-96), and 89 % (95 % CI 84-93), respectively (p = 0.60). BMI was not associated by multivariate analysis with differences in DFS or OS. Higher BMI had no influence on prognosis in high-risk EBC patients treated with CT. These data are consistent with prior observations and suggest that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor.

Application of OECI accreditation program to cancer institutes of the Alleanza Contro il Cancro Italian Network: a special project supported by the Italian Ministry of Health.

The Ministry of Health of the Italian government requires for Italian Comprehensive Cancer Centers, called Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), to be certified according to international models. In this perspective, considering of particular interest the recent model for accreditation of cancer centers developed by the Organisation of European Cancer Institutes (OECI), the network of Italian IRCCS participating in Alleanza Contro il Cancro activated a project, supported in 2010 by the Ministry of Health, with the primary objective to verify the applicability of the OECI model to the Italian network of IRCCS. All 11 cancer IRCCS took part in the project. We describe in detail the activities performed, the results reached, and the impact of the initiative on the National Health Service. The initiative was concluded in November 2015 with the certification of all the Italian cancer IRCCS. Italy is the only European country that has applied the modern and tailored accreditation model of OECI to all their cancer centers.

The European accreditation of Istituto Tumori Giovanni Paolo II of Bari.

The National Cancer Institute of Bari (Istituto di Ricovero e Cura a Carattere Scientifico, IRCCS) has been involved since the conception of the project of the Italian Ministry for Health aimed to validate the applicability of the Organisation of European Cancer Institutes (OECI) accreditation and designation (A&D) model to the Network of Italian Cancer Centers, IRCCS, of Alleanza Contro il Cancro. The self-assessment phase of the Institute started in September 2013 and ended in June 2014. All documents and tools were transferred to the OECI A&D Board in June 2014 and a 2-day peer review visit was conducted in October 2014 by an international qualified audit team. The Institute received its final designation and certification in June 2015. The OECI A&D Board, in its final report, came to the conclusion that Istituto Tumori "Giovanni Paolo II" of Bari has a strong research component with some essential elements of comprehensive cancer care still under development; the lack of a system for using outcome data for the strategic management approach to decision-making and missing a regular internal audit system eventually helping further quality improvement were reported as examples of areas with opportunities for improvement. The OECI A&D process represented a great opportunity for the cancer center to benchmark the quality of its performance according to standard parameters in comparison with other international centers and to further develop a participatory group identity. The common goal of accreditation was real and participatory with long-lasting positive effects. We agree with the OECI comments about the next areas of work in which the Institute could produce future further efforts: the use of its powerful IT system as a means for outcome analysis and empowerment projects for its cancer patients.

Participation of Italian Cancer Centres of the Alleanza Contro Il Cancro (ACC) in the Organisation of European Cancer Institutes (OECI) Accreditation and Designation program: a successful first national initiative.

The Organisation of European Cancer Institutes (OECI) launched a program for accreditation and designation (A&D) of cancer centers in Europe based on voluntary participation in 2008. In 2012, the Italian Ministry of Health decided to fund cancer centers in Italy, members of the Alleanza Contro il Cancro (ACC), to go through the OECI accreditation program. Ten centers participated in the program and 10 completed the full cycle of the OECI A&D process in consecutive series over a 2-year period. The process was successfully completed within the planned timeline and the overall findings were presented to the Italian Ministry of Health and representatives of all the participating centers in November 2015. The program had a considerable team-building effect, which will likely continue as the improvement plans are implemented. Centers fed back to OECI that the A&D program had led to better formal organization of multidisciplinary teams (MDTs) and cancer care pathways, and had helped them to harmonize the integration of research into clinical practice. Centers also concluded that they benefited from recognition through an international accreditation system, and that it had led to them developing better patient information and involvement. The importance of the improvement plans that each center had to produce following the audit reviews cannot be underestimated. The OECI concludes that implementation of the A&D program at the national level is feasible despite national peculiarities related to health planning and organization in each member state. This is a good example of an EU project working well, with member states helping each other and learning from best practice, to improve the overall quality of cancer care and research and to establish consistency. The initial accreditation is the first part of an ongoing process of improving comprehensive cancer care, integrating bench to bedside.

Irradiation-induced angiosarcoma and anti-angiogenic therapy: a therapeutic hope?

Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin. They can be sporadic or caused by therapeutic radiation, hence secondary breast angiosarcomas are an important subgroup of patients. Assessing the molecular biology of angiosarcomas and identify specific targets for treatment is challenging. There is currently great interest in the role of angiogenesis and of angiogenic factors associated with tumor pathogenesis and as targets for treatment of angiosarcomas. A primary cell line derived from a skin fragment of a irradiation-induced angiosarcoma patient was obtained and utilized to evaluate cell biomarkers CD31, CD34, HIF-1 alpha and VEGFRs expression by immunocytochemistry and immunofluorescence, drugs cytotoxicity by cell counting and VEGF release by ELISA immunoassay. In addition to previous biomarkers, FVIII and VEGF were also evaluated on tumor specimens by immunohistochemistry to further confirm the diagnosis. We targeted the VEGF-VEGFR-2 axis of tumor angiogenesis with two different class of vascular targeted drugs; caprelsa, the VEGFR-2/EGFR/RET inhibitor and bevacizumab the anti-VEGF monoclonal antibody. We found the same biomarkers expression either in tumor specimens and in the cell line derived from tumor. In vitro experiments demonstrated that angiogenesis plays a pivotal role in the progression of this tumor as cells displayed high level of VEGFR-2, HIF-1 alpha strongly accumulated into the nucleus and the pro-angiogenic factor VEGF was released by cells in culture medium. The evaluation of caprelsa and bevacizumab cytotoxicity demonstrated that both drugs were effective in inhibiting tumor proliferation. Due to these results, we started to treat the patient with pazopanib, which was the unique tyrosine kinase inhibitor available in Italy through a compassionate supply program, obtaining a long lasting partial response. Our data suggest that the study of the primary cell line could help physicians in choosing a therapeutic approach for patient that almost in vitro shows chances of success and that the anti-angiogenetic agents are a reliable therapeutic opportunity for angiosarcomas patients.

Accreditation for excellence of cancer research institutes: recommendations from the Italian Network of Comprehensive Cancer Centers.

A panel of experts from Italian Comprehensive Cancer Centers defines the recommendations for external quality control programs aimed to accreditation to excellence of these institutes. After definition of the process as a systematic, periodic evaluation performed by an external agency to verify whether a health organization possesses certain prerequisites regarding structural, organizational and operational conditions that are thought to affect health care quality, the panel reviews models internationally available and makes final recommendations on aspects considered of main interest. This position paper has been produced within a special project of the Ministry of Health of the Italian Government aimed to accredit, according to OECI model, 11 Italian cancer centers in the period 2012-2014. The Project represents the effort undertaken by this network of Comprehensive Cancer Centers to find a common denominator for the experience of all Institutes in external quality control programs. Fourteen shared "statements" are put forth, designed to offer some indications on the main aspects of this subject, based on literature evidence or expert opinions. They deal with the need for "accountability" and involvement of the entire organization, the effectiveness of self-evaluation, the temporal continuity and the educational value of the experience, the use of indicators and measurement tools, additionally for intra- and inter-organization comparison, the system of evaluation models used, the provision for specific requisites for oncology, and the opportunity for mutual exchange of evaluation experiences.

The impact of folate status on the efficacy of colorectal cancer treatment.

Over the past three decades, numerous reports have addressed several aspects of drug resistance phenomena. However, little is known regarding the impact that dietary components and nutritional supplements have on the mechanisms of resistance that malignant cells develop to chemotherapeutic agents. The increased fortification of cereals, grains and bread with folic acid (FA) has resulted in a marked rise in folate levels in blood and tissues. Vitamin fortification that includes FA is rather commonly used by cancer patients, but FA is also used to protect against pemetrexed induced side effects in the treatment of non-small cell lung cancer and mesothelioma or that of the antifolate methotrexate in rheumatoid arthritis. Moreover, the reduced folate leucovorin (LV, 5-formyltetrahydrofolate) is also used along with 5-fluorouracil in the treatment of colorectal cancer. Likewise, LV is used to reduce toxicity of methotrexate in the treatment of leukemia. FA can also increase efficacy of unrelated regimens, containing cisplatin. Hence there is growing evidence that dietary supplements as folic acid, can mimic, intensify, or attenuate the effects of unrelated chemotherapeutic agents. The aim of this review is to highlight some new insights in the cellular and molecular mechanisms affected by folate status, leading to chemotherapy resistance, especially towards antifolates in colorectal cancer treatment. This encompasses the effect of folate status on drug export, as well as on the increased expression of mutated target enzymes involved in folate metabolism and on the augmentation of cellular folate pools that impair polyglutamylation of antifolates, ultimately affecting treatment efficacy.

Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer.

Adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have proven highly effective in rapidly proliferating breast cancer (RPBC). It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant epirubicin (E) followed by CMF is superior to the inverse sequence in RPBC. Patients with node-negative or 1-3 node-positive RPBC (Thymidine Labeling Index > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%) were randomized to receive E (100 mg/m(2) i.v. d1, q21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m(2) i.v. d1 and 8, q28 days for 4 cycles) (E â†’ CMF) or CMF followed by E (CMF â†’ E) or CMF for 6 cycles. From November 1997 to December 2004, 1066 patients were enrolled: E â†’ CMF 440, CMF â†’ E 438, and CMF 188. At a median follow-up of 69 months, 5-year OS was 91% (95% CI 88-94) for E â†’ CMF and 93% (95% CI 90-95) for CMF â†’ E, with adjusted hazard ratio of 0.88 (95% CI 0.58-1.35), and DFS was 80% in both arms, with adjusted hazard ratio of 0.99 (95% CI 0.73-1.33, Cox model). Adverse events were similar, apart from a higher rate of neutropenia in the CMF â†’ E arm. No important differences in clinical outcome were observed between the two different sequences, making both a valid option in early breast cancer. Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence.

Towards quality, comprehensiveness and excellence. The accreditation project of the Organisation of European Cancer Institutes (OECI).

There are important gaps in the health status of citizens across Europe, as measured by life expectancy, mortality or morbidity data (Report for the European Commission on the health status of the European Union, 2003). Among the main determinants of the major causes of mortality and morbidity, stated in this report, stands recurrently access to quality healthcare. There is a fundamental need to define quality indicators and set minimal levels of performance quality criteria for healthcare. There is a need to integrate research into healthcare and to provide patients with equity of access to such high quality care. Oncology is a specialty particularly suited to experimenting a first application of accreditation at European level. The Organisation of European Cancer Institutes is a growing network of cancer Centres in Europe. The focus of the OECI is to work with professionals and organisations with regard to prevention, care, research, development, patient's role and education. In order to fulfil its mission, the OECI initiated in 2002 an accreditation project with three objectives: * to develop a comprehensive accreditation system for oncology care, taking into account prevention, care, research, education and networking. * to set an updated database of cancer centres in Europe, with exhaustive information on their resources and activities (in care, research, education and management) * to develop a global labelling tool dedicated to comprehensive cancer centres in Europe, designating the various types of cancer structures, and the comprehensive cancer centres of reference and Excellence. An accreditation tool has been established, defining standards and criteria for prevention, care, research, education and follow-up activities. A quantitative database of cancer centres is integrated in the tool, with a questionnaire, that provides an overall view of the oncological landscape in OECI cancer centres in Europe. Data on infrastructures, resources and activities have been collected. This OECI accreditation tool will be launched in autumn 2008 for all cancer centres in Europe. It serves as a basis for the development of the labelling tool for cancer structures in Europe, with a focus on Comprehensiveness and Excellence labels. Quality assessment and improvement is a critical need in Europe and is addressed by the OECI for cancer care in Europe. Accreditation is a well accepted process and is feasible. Standards and criteria as well as an accreditation tool have been developed. The OECI questionnaire gives an accurate vision of cancer institutions throughout Europe, helping assessing the needs and providing standards. The accreditation project is a long-term complete and voluntary process with external and internal added value, an active process of sharing information and experience that should help the whole cancer community reach comprehensiveness and excellence.

The effect of gefitinib (Iressa, ZD1839) in combination with oxaliplatin is schedule-dependent in colon cancer cell lines.

BACKGROUND: Clinical trials of gefitinib (Iressa, ZD1839) in combination with cytotoxic agents have been carried out or are ongoing in several varieties of tumor. To provide a rationale for future clinical trials, the effects of combining gefitinib with oxaliplatin in different sequences of administration and different dose ratios in two colon cancer cell lines were evaluated. MATERIALS AND METHODS: The colon cancer cell lines HT-29 and LoVo were used. The methods consisted of median effect and combination index analysis, Western blot, mass spectrometry, and a cell death ELISA. RESULTS: In vitro analysis demonstrated that the combination effects of the two agents were sequence-dependent. Changing the sequence of administration from gefitinib first to gefitinib last changed the combination effect from antagonism to synergy. The dose ratio between the two agents affected the combination effects. When equiactive doses of the two agents were used with the sequence gefitinib following oxaliplatin, the greatest level of synergism was obtained (CI=0.6+/-0.2, P=0.032). Further evaluation revealed that gefitinib significantly inhibited removal of Pt-DNA adducts ( P<0.05), providing a potential explanation for the sequence-dependent synergy observed with gefitinib following oxaliplatin. However, this effect was not dose-dependent. Additional studies demonstrated that gefitinib enhanced the effects of oxaliplatin by maintaining oxaliplatin-induced apoptosis, and equiactive dose of gefitinib following oxaliplatin induced prominent enhancement of apoptosis. CONCLUSIONS: Oxaliplatin followed by an equiactive relative dose of gefitinib is an appropriate combination for evaluation in colon cancer.