Circulating microRNAs and therapy-associated cardiac events in HER2-positive breast cancer patients: an exploratory analysis from NeoALTTO.

PURPOSE: The relevance of cardiotoxicity in the context of HER2-positive breast cancer is likely to increase with increasing patient treatment exposure, number of treatment lines, and prolonged survival. Circulating biomarkers to early identify patients at risk of cardiotoxicity could allow personalized treatment and follow-up measures. The aim of this study is to examine the relationship between circulating microRNAs and adverse cardiac events in HER2-positive breast cancer patients. METHODS: We based our work on plasma samples from NeoALTTO trial obtained at baseline, after 2 weeks of anti-HER2 therapy, and immediately before surgery. Eleven patients experienced either a symptomatic or asymptomatic cardiac event. Circulating microRNAs were profiled in all patients presenting a cardiac event (case) and in an equal number of matched patients free of reported cardiac events (controls) using microRNA-Ready-to-Use PCR (Human panel I + II). Sensitivity analyses were performed by increasing the number of controls to 1:2 and 1:3. Normalized microRNA expression levels were compared between cases and controls using the non-parametric Kruskal-Wallis test. RESULTS: Eight circulating microRNAs resulted differentially expressed after 2 weeks of anti-HER2 therapy between patients experiencing or not a cardiac event. Specifically, the expression of miR-125b-5p, miR-409-3p, miR-15a-5p, miR-423-5p, miR-148a-3p, miR-99a-5p, and miR-320b increased in plasma of cases as compared to controls, while the expression of miR-642a-5p decreases. Functional enrichment analysis revealed that all these microRNAs were involved in cardiomyocyte adrenergic signaling pathway. CONCLUSION: This study provides proof of concept that circulating microRNAs tested soon after treatment start could serve as biomarkers of cardiotoxicity in a very early stage in breast cancer patients receiving anti-HER2 therapy.

Cancer burden in adolescents and young adults in Europe.

BACKGROUND: Cancer epidemiology is unique in adolescents and young adults (AYAs; aged 15-39 years). The European Society for Medical Oncology/European Society for Paediatric Oncology (ESMO/SIOPE) AYA Working Group aims to describe the burden of cancers in AYAs in Europe and across European Union (EU) countries. PATIENTS AND METHODS: We used data available on the Global Cancer Observatory. We retrieved crude and age-standardised (World Standard Population) incidence and mortality rates. We reported about AYA cancer burden in Europe and between 28 EU member states. We described incidence and mortality for all cancers and for the 13 cancers most relevant to the AYA population. RESULTS: Incidence and mortality varied widely between countries with the highest mortality observed in Eastern EU countries. Cancers of the female breast, thyroid and male testis were the most common cancers across countries followed by melanoma of skin and cancers of the cervix. Variations in cancer incidence rates across different populations may reflect different distribution of risk factors, variations in the implementation or uptake of screening as well as overdiagnosis. AYA cancer mortality disparities may be due to variation in early-stage diagnoses, different public education and awareness of cancer symptoms, different degrees of access or availability of treatment. CONCLUSIONS: Our results highlight the future health care needs and requirements for AYA-specialised services to ensure a homogeneous treatment across different countries as well as the urgency for preventive initiatives that can mitigate the increasing burden.

Immunometabolic Status of COVID-19 Cancer Patients.

Cancer patients appear to be more likely to be diagnosed with coronavirus disease 2019 (COVID-19). This is supported by the understanding of immunometabolic pathways that intersect patients with infection and cancer. However, data derived by case series and retrospective studies do not offer a coherent interpretation, since data from China suggest an increased risk of COVID-19, while data from the United States and Italy show a prevalence of COVID-19 in cancer patients comparable with the general population. Noteworthy, cancer and COVID-19 exploit distinct patterns of macrophage activation that promote disease progression in the most severe forms. In particular, the alternative activation of M2-polarized macrophages plays a crucial role in cancer progression. In contrast, the macrophage-activation syndrome appears as the source of M1-related cytokine storm in severe COVID-19 disease, thus indicating macrophages as a source of distinct inflammatory states in the two diseases, nonetheless as a common therapeutic target. New evidence indicates that NAMPT/NAD metabolism can direct both innate immune cell effector functions and the homeostatic robustness, in both cancer and infection. Moreover, a bidirectional relationship exists between the metabolism of NAD and the protective role that angiotensin converting enzyme 2, the COVID-19 receptor, can play against hyperinflammation. Within this immunometabolic framework, the review considers possible interference mechanisms that viral infections and tumors elicit on therapies and provides an overview for the management of patients with cancer affected by COVID-19, particularly for the balance of risk and benefit when planning normally routine cancer treatments and follow-up appointments.

The European study on centralisation of childhood cancer treatment.

BACKGROUND: It is generally agreed to centralise treatment of childhood cancers (CCs). We analysed (1) the degree of centralisation of CCs in European countries and 2) the relations between centralisation and survival. PATIENTS AND METHODS: The analysis comprised 4415 CCs, diagnosed between 2000 and 2007 and followed up to the end of 2013, from Belgium, Bulgaria, Finland, Ireland, the Netherlands and Slovenia. All these countries had national population-based cancer registries and were able to provide information on diagnosis, treatment, treatment hospitals, and survival. Each case was then classified according to whether the patient was treated in a high- or a low-volume hospital among those providing CC treatment. A Cox proportional hazard model was used to calculate the relation between volume category and five-year survival, adjusting by age, sex and diagnostic group. RESULTS: The number of hospitals providing treatment for CCs ranged from six (Slovenia) to slightly more than 40 (the Netherlands and Belgium). We identified a single higher volume hospital in Ireland and in Slovenia, treating 80% and 97% of cases, respectively, and three to five major hospitals in the other countries, treating between 65% and 93% of cases. Outcome was significantly better when primary treatment was given in high-volume hospitals compared to low-volume hospitals for central nervous system tumours (relative risk [RR] = 0.71), haematologic tumours (RR = 0.74) and for all CC combined (RR = 0.83). CONCLUSION: Treatment centralisation is associated with survival benefits and should be further strengthened in these countries. New plans for centralisation should include ongoing evaluation.

Epidemiology of rare cancers and inequalities in oncologic outcomes.

Rare cancers epidemiology is better known compared to the other rare diseases. Thanks to the long history of the European population-based cancer registries and to the EUROCARE huge database, the burden of rare cancers has been estimated the European (EU28) population. A considerable fraction of all cancers is represented by rare cancers (24%). They are a heterogeneous group of diseases, but they share similar problems: uncertainty of diagnosis, lack of therapies, poor research opportunities, difficulties in clinical trials, lack of expertise and of centres of reference. This paper analyses the major epidemiological indicators of frequency (incidence and prevalence) and outcome (5-year survival) of all rare cancers combined and of selected rare cancers that will be in depth treated in this monographic issue. Source of the results is the RARECAREnet search tool, a database publicly available. Disparities both in incidence and survival, and consequently in prevalence of rare cancers were reported across European countries. Major differences were shown in outcome: 5-year relative survival for all rare cancers together, adjusted by age and case-mix, varied from 55% or more (Italy, Germany, Belgium and Iceland) and less than 40% (Bulgaria, Lithuania and Slovakia). Similarly, for all the analyzed rare cancers, a large survival gap was observed between the Eastern and the Nordic and Central European regions. Dramatic geographical variations were assessed for curable cancers like testicular and non epithelial ovarian cancers. Geographical difference in the annual age-adjusted incidence rates for all rare cancers together varied between >140 per 100,000 (Italy, Scotland, France, Germany, and Switzerland) and <100 (Finland, Portugal, Malta, and Poland). Prevalence, the major indicator of public health resources needs, was about 7-8 times larger than incidence. Most of rare cancers require complex surgical treatment, thus a multidisciplinary approach is essential and treatment should be provided in centres of expertise and/or in networks including expert centres. Networking is the most appropriate answer to the issues pertaining to rare cancers. Actually, in Europe, an opportunity to improve outcome and reduce disparities is provided by the creation of the European Reference Networks for rare diseases (ERNs). The Joint Action of rare cancers (JARC) is a major European initiative aimed to support the mission of the ERNs. The role of population based cancer registries still remains crucial to describe rare cancers management and outcome in the real word and to evaluate progresses made at the country and at the European level.

The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells.

Despite the risk of transmitting HIV-1, mothers in resource-poor areas are encouraged to breastfeed their infants because of beneficial immunologic and nutritional factors in milk. Interestingly, in the absence of antiretroviral prophylaxis, the overwhelming majority of HIV-1-exposed, breastfeeding infants are naturally protected from infection. To understand the role of HIV-1 envelope (Env)-specific antibodies in breast milk in natural protection against infant virus transmission, we produced 19 HIV-1 Env-specific monoclonal antibodies (mAbs) isolated from colostrum B cells of HIV-1-infected mothers and investigated their specificity, evolution, and anti-HIV-1 functions. Despite the previously reported genetic compartmentalization and gp120-specific bias of colostrum HIV Env-specific B cells, the colostrum Env-specific mAbs described here demonstrated a broad range of gp120 epitope specificities and functions, including inhibition of epithelial cell binding and dendritic cell-mediated virus transfer, neutralization, and antibody-dependent cellular cytotoxicity. We also identified divergent patterns of colostrum Env-specific B-cell lineage evolution with respect to crossreactivity to gastrointestinal commensal bacteria, indicating that commensal bacterial antigens play a role in shaping the local breast milk immunoglobulin G (IgG) repertoire. Maternal vaccine strategies to specifically target this breast milk B-cell population may be necessary to achieve safe breastfeeding for all HIV-1-exposed infants.

Available evidence and new biological perspectives on medical treatment of advanced thymic epithelial tumors.

Thymic epithelial tumors (TETs) are rare primary mediastinal tumors arising from thymic epithelium. Their rarity and complexity hinder investigations of their causes and therapy development. Here, we summarize the existing knowledge regarding medical treatment of these tumors, and thoroughly review the known genetic aberrations associated with TETs and the present status of potential biological treatments. Epidermal growth factor receptor (EGFR), stem-cell factor receptor, insulin-like growth factor-1 receptor (IGF1R), and vascular endothelial growth factors (VEGF-A, VEGF-B, and VEGF-2) are overexpressed in TETs. EGFR overexpression in TETs is associated with higher stage, and IGF1R overexpression has poor prognostic value. Data indicate that anti-IGF1R monoclonal antibodies, and inhibitors of angiogenesis, somatostatin receptors, histone deacetylase, mammalian target of rapamycin, and cyclin-dependent kinases may be active against TETs. Continued investigations in this field could lead to advancement of targeted and biological therapies for TETs.

Descriptive epidemiology of Kaposi sarcoma in Europe. Report from the RARECARE project.

Kaposi sarcoma (KS) is a virus-related malignancy which most frequently arises in skin, though visceral sites can also be involved. Infection with Kaposi sarcoma herpes virus (KSHV or HHV-8) is required for development of KS. Nowadays, most cases worldwide occur in persons who are immunosuppressed, usually because of HIV infection or as a result of therapy to combat rejection of a transplanted organ, but classic Kaposi sarcoma is predominantly a disease of the elderly without apparent immunosuppression. We analyzed 2667 KS incident cases diagnosed during 1995-2002 and registered by 75 population-based European cancer registries contributing to the RARECARE project. Total crude and age-standardized incidence rate was 0.3 per 100,000 per year with an estimated 1642 new cases per year in the EU27 countries. Age-standardized incidence rate was 0.8 per 100,000 in Southern Europe but below 0.3 per 100,000 in all other regions. The elevated rate in southern Europe was attributable to a combination of classic Kaposi sarcoma in some Mediterranean countries and the relatively high incidence of AIDS in several countries. Five-year relative survival for 2000-2002 by the period method was 75%. More than 10,000 persons were estimated to be alive in Europe at the beginning of 2008 with a past diagnosis of KS. The aetiological link with suppressed immunity means that many people alive following diagnosis of KS suffer comorbidity from a pre-existing condition. While KS is a rare cancer, it has a relatively good prognosis and so the number of people affected by it is quite large. Thus it provides a notable example of the importance of networking in diagnosis, therapy and research for rare cancers.

Cancer prevalence estimates in Europe at the beginning of 2000.

BACKGROUND: Complete cancer prevalence data in Europe have never been updated after the first estimates provided by the EUROPREVAL project and referred to the year 1993. This paper provides prevalence estimates for 16 major cancers in Europe at the beginning of the year 2003. PATIENTS AND METHODS: We estimated complete prevalence by the completeness index method. We used information on cancer patients diagnosed in 1978-2002 with vital status information available up to 31 December 2003, from 76 European cancer registries. RESULTS: About 11.6 millions of Europeans with a history of one of the major considered cancers were alive on 1 January 2003. For breast and prostate cancers, about 1 out of 73 women and 1 out of 160 men were living with a previous diagnosis of breast and prostate cancers, respectively. The demographic variations alone will increase the number of prevalent cases to nearly 13 millions in 2010. CONCLUSIONS: Several factors (early detection, population aging and better treatment) contribute to increase cancer prevalence and push for the need of a continuous monitoring of prevalence indicators to properly plan needs, resource allocation to cancer and for improving health care programs for cancer survivors. Cancer prevalence should be included within the EU official health statistics.

Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.

Sarcomas are a heterogeneous group of malignant neoplasms arising from mesenchymal cells which encompass dozens of histological types and can occur in virtually any anatomic site. They form one of the principal groups of rare cancers in Europe as defined in the RARECARE project. We analysed 45,568 incident cases diagnosed during 1995-2002 and registered by 76 population-based cancer registries. Total crude incidence was 5.6 per 100,000 per year with an estimated 27,908 new cases per year in the EU27 countries, of which 84% were soft tissue sarcomas and 14% were bone sarcomas. Gastrointestinal stromal tumours (GIST) were only widely recognised as an entity in the late 1990s and consequently were under-registered. Their true incidence is believed to be about 1.5 per 100,000. Age-standardised incidence of soft tissue sarcomas ranged from 3.3 per 100,000 in Eastern Europe to 4.7 per 100,000 in Northern Europe. About 280,000 persons were estimated to be alive at the beginning of 2003 with a past diagnosis of sarcoma, of which 83% were soft tissue sarcomas and 16% were bone sarcomas. Five-year relative survival for 2000-2002 by the period was 58% for soft tissue sarcomas and 62% for bone sarcomas. The diversity and rarity of sarcomas combined with the quite large number of people affected by them mean that they provide a classic example of the importance of networking in diagnosis, therapy and research for rare cancers.

Incidence, survival and prevalence of myeloid malignancies in Europe.

BACKGROUND: The Surveillance of Rare Cancers in Europe (RARECARE) project aims at increasing knowledge of rare cancers in Europe. This manuscript describes the epidemiology of myeloid malignancies (MMs), taking into account the morphological characterisation of these tumours. METHODS: We used data gathered by RARECARE on cancer patients diagnosed from 1995 to 2002 and archived in 64 European population-based cancer registries, followed up to 31st December 2003 or later. RESULTS: The overall annual crude incidence of MMs was 8.6 per 100,000. Acute myeloid leukaemia (AML) and myeloproliferative neoplasms (MPN) were most common, with incidence rates of 3.7 and 3.1 per 100,000 year respectively, followed by 1.8 for myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MD/MPN) and 0.1 for histiocytic and dendritic cell neoplasms (HDCN). The 5-year relative survival rate ranged from 18% for chronic myelomonocytic leukaemia, 19% for AML, 29% for MDS and 44% for chronic myeloid leukaemia to relatively favourable rates for MPN (62%) and HDCN (83%). Total number of new cases of MMs in the EU27 is estimated at 43,000 annually, total number of prevalent cases (1st January 2008) at 189,000 cases. CONCLUSION: MMs form a large variety of rare entities with specific characteristics. Collection of detailed information (immunophenotype, genetic abnormalities, molecular data and clinical data) and an up-to-date classification system is essential for their surveillance, especially now that more and more targeted therapies are being introduced.

Incidence, prevalence and survival of patients with rare epithelial digestive cancers diagnosed in Europe in 1995-2002.

BACKGROUND AND AIMS: Little is known about the epidemiology of rare epithelial digestive cancers. The aim of this study was to report on their incidence, prevalence and survival across Europe. METHODS: The analysis was carried out on 50,646 cases diagnosed from 1995 to 2002 within a population of 162,000,000 in 21 European countries. Age-standardised incidence rates were computed using the European standard population. Prevalence rates, relative survival and period survival indicators for the years 2000-2002 were calculated. The expected number of new cases per year and of prevalent cases in Europe was estimated. RESULTS: There were large variations in gallbladder epithelial cancer incidence rates: the incidence in Eastern Europe was 7 times higher than in the UK & Ireland. Differences between incidence rates were smaller for the other sites. The estimated number of new epithelial cancers arising in the EU each year was estimated to be 11,050 for extrahepatic bile duct cancer, 10,713 for gallbladder cancer, 5427 for anal cancer and 3595 for small intestine cancer. The corresponding estimated number of total prevalent cases was 18,483, 15,620, 40,589 and 13,276. There was also a large variation in the 5-year relative survival rate. For epithelial cancer of the anal canal, this varied between 66% (Central Europe) and 44% (Eastern Europe). The corresponding rates for small intestine cancers were 33% and 20%, for extrahepatic bile duct cancers, 17% and 12% and for gallbladder cancer 13% and 10%. CONCLUSION: There are large variations within Europe in the incidence and survival of rare digestive cancers according to geographic area.

Burden of testicular, paratesticular and extragonadal germ cell tumours in Europe.

We provide updated estimates of survival, incidence, complete prevalence, and proportion cured for patients with testicular/paratesticular and extragonadal germ cell cancers in Europe, grouped according to the new list of cancer types developed by RARECARE. We collected data, archived in European cancer registries, with vital status information available to 31st December 2003. We analysed 26,000 cases of testicular, paratesticular and extragonadal germ cell cancers diagnosed 1995-2002, estimating that about 15,600 new testicular/paratesticular and 630 new extragonadal cancer cases occurred per year in EU27, with annual incidence rates of 31.5/1,000,000 and 1.27/1,000,000, respectively. Slightly more than 436,000 persons were alive at the beginning of 2008 with a diagnosis of testicular/paratesticular cancer, and about 17,000 with a diagnosis of extragonadal germ cell cancer. Five-year relative survival was 96% for testicular/paratesticular cancer and 71% for extragonadal germ cell cancer; the proportions cured were 95% and 69%, respectively. We found limited variation in survival between European regions except for non-seminomatous testicular cancer, for which five-year relative survival ranged from 86% in Eastern Europe to 96% in Northern Europe. Survival for all cancer types considered decreased with increasing age at diagnosis. Further investigation is required to establish the real reasons for the lower survival in Eastern Europe. Considering the high prevalence of these highly curable cancers, it is important to monitor patients long-term, so as to quantify treatment-related risks and develop treatments having limited impact on quality of life.