Targeted therapies and adverse drug reactions in oncology: the role of clinical pharmacist in pharmacovigilance.

Background The majority of adverse drug reactions (ADRs) reported in the summary of product characteristics (SPCs) are based on pivotal clinical trials, performed under controlled conditions and with selected patients. Objectives (1) to observe ADRs in the real-world setting and to evaluate if the supervision of the pharmacist impacts on the management of ADRs and on the satisfaction of patients; (2) to sensitise health professionals and patients on the need to increase the reporting of ADRs, in compliance with Pharmacovigilance. Setting CRO Aviano, Italian National Cancer Institute. Method From February 2013 to April 2015, we conducted an observational study enrolling 154 patients (≥ 18 years) undergoing treatment with at least one of ten targeted-therapies included in the study. Main outcome ADR reporting in the real-world setting. Patient satisfaction with clinical pharmacist support. Results Reported ADRs in the real setting do not always correspond with data described in the respective SPCs. Unknown ADRs were also identified such as hyperglycaemia with lenalidomide and sorafenib; and hypomagnesaemia with bevacizumab. We also observed a 124.3% increase in spontaneous reports. Conclusion This study shows the high value of active pharmacovigilance programs, and our results might be a starting point for developing a randomised trial which should aim to demonstrate the impact of the pharmacist on improving patient's adherence and in measuring the difference in ADRs reports in the different arms followed or not by the pharmacist.

The persistent problem of late HIV diagnosis in people with AIDS: a population-based study in Italy, 1999-2013.

OBJECTIVES: Despite the wide accessibility to free human immunodeficiency virus (HIV) testing and combined antiretroviral therapy (cART), late HIV diagnosis remains common with severe consequences at individual and population level. This study aimed to describe trends of late HIV testing and to identify their determinants in the late cART era in Italy. STUDY DESIGN: We conducted a population-based, nationwide analysis of the Italian National AIDS Registry data (AIDS - acquired immune deficiency syndrome) for the years 1999-2013. METHODS: Late testers (LTs) were defined as people with AIDS (PWA) whose first HIV-positive test preceded AIDS diagnosis by 3 months or less. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were estimated to examine factors associated with being LTs. Joinpoint analysis was used to estimate annual percent changes (APCs) of LTs' proportion over time. RESULTS: Among 20,753 adult PWA, 50.8% were LTs. Italian PWA showed a lower proportion of LTs than non-Italian PWA (46.5% vs 68.2%). Among Italian PWA, the odds of being LTs was higher in men than in women (OR = 2.62, 95% CI: 2.38-2.90); in the age groups below 35 years and over 49 years at diagnosis (OR = 1.24, 95% CI: 1.12-1.37 and OR = 1.51, 95% CI: 1.38-1.67, respectively) vs PWA aged 35-49 years; and in those infected through sexual contact as compared with injecting drug use (OR = 13.34, 95% CI: 12.06-14.76 for heterosexual contact and OR = 8.13, 95% CI: 7.30-9.06 for male-to-male sexual contact). The proportion of LTs increased over time among Italians, especially in the latest period (APC2006-2013 = 5.3, 95% CI: 3.8-6.9). The LTs' proportion resulted higher, though stable, among PWA aged ≥50 years. Conversely, an increasing trend was observed among PWA aged 18-34 years (APC = 5.3, 95% CI: 4.5-6.1). The LTs' proportion was persistently higher among PWA who acquired HIV infection through sexual contact, even if a marked increase among injecting drug users was observed after 2005 (APC = 11.4, 95% CI: 5.7-17.5). CONCLUSIONS: The increasing trend of LTs' proportion in the late cART era highlights the need of new strategies tailored to groups who may not consider themselves to be at a high risk of infection. Active promotion of early testing and continuous education of infection, especially among young people, need to be implemented.

Kaposi's Sarcoma Herpesvirus: twenty years after its discovery.

Twenty years after the discovery of Kaposi's Sarcoma Herpes Virus (KSHV), many aspects of the pathogenesis have been discovered and innovative approaches are presently applied to the diagnosis and treatment of KSHV associated diseases. The virus is coupled to different types of cancers, as well as to syndromes combined with increased inflammatory response or with immunoreconstitution in immunocompromised hosts. The etiopathological diagnosis of KSHV associated cancers relies on the demonstration of the virus in tumor samples, as well as in the peripheral blood of infected subjects. Novel treatment strategies related to the pathogenetic events of KSHV associated diseases have been recently studied, that are based on drugs able to induce oncolysis by promoting a viral lytic phase or on the blockade of v-IL6, a cytokine with tumor promoting activities. In addition, antiangiogenetic strategies have also been applied to treat KSHV associated cancers. Despite these important discoveries, some aspects of KSHV associated diseases are presently not completely clear and, consequently, response to treatment strategies is still suboptimal.

Clinical presentation and outcome of non-AIDS defining cancers, in HIV-infected patients in the ART-era: the Italian Cooperative Group on AIDS and tumors activity.

The advent of antiretroviral therapy (ART) has markedly extended the survival rates of patients with human immunodeficiency virus (HIV), leading to suppression even though not eradication of HIV. In HIV infected patients, cancer has become a growing problem, representing the first cause of death. A large number of worldwide studies have shown that HIV infection raises the risk of many non-AIDS defining cancers (NADCs), including squamous cell carcinoma of the anus (SCCA), testis cancer, lung cancer, cancer of the colon and rectum (CRC), skin (basal cell skin carcinoma and melanoma), Hodgkin disease (HD) and hepatocellular carcinoma (HCC). Generally in HIV positive patients NADCs are more aggressive and in advanced stage disease than in the general population. In the ART era, however, the outcome of HIV positive patients is more similar as in the general population. Only about lung cancer the outcome seems different between HIV positive and HIV negative patients. The aim of this article is to provide an up-date on NADCs within the activity of the Italian Cooperative Group on AIDS and Tumors (GICAT) to identify clinical prognostic and predicting factors in patients with HIV infection included in the GICAT.

Making patient centered care a reality: a survey of patient educational programs in Italian Cancer Research and Care Institutes.

BACKGROUND: Educational intervention represents an essential element of care for cancer patients; while several single institutions develop their own patient education (PE) programs on cancer, little information is available on the effective existence of PE programs at the level of research and care institutes. In Italy such institutes--Istituti di Ricovero e Cura a Carattere Scientifico--are appointed by the Ministry of Health, and 11 (Cancer Research & Care Istitute-CRCI) of the 48 are specific for cancer on the basis of specific requirements regarding cancer care, research and education. Therefore, they represent an ideal and homogeneous model through which to investigate PE policies and activities throughout the country. The objective of this study was to assess PE activities in Italian CRCI. METHODS: We carried out a survey on PE strategies and services through a questionnaire. Four key points were investigated: a) PE as a cancer care priority, b) activities that are routinely part of PE, c) real involvement of the patients, and d) involvement of healthcare workers in PE activities. RESULTS: Most CRCI (85%) completed the survey. All reported having ongoing PE activities, and 4 of the 11 considered PE an institutional activity. More than 90% of CRCI organize classes and prepare PE handouts, while other PE activities (e.g., Cancer Information Services, mutual support groups) are less frequently part of institutional PE programs. Patients are frequently involved in the organization and preparation of educational activities on the basis of their own needs. Various PE activities are carried out for caregivers in 8 (73%) out of 11 institutes. Finally, health care workers have an active role in the organization of PE programs, although nurses take part in these activities in only half of CRCI and pharmacists are seldom included. CONCLUSIONS: The information arising from our research constitutes a necessary framework to identify areas of development and to design new strategies and standards to disseminate the culture of PE. This may ultimately help and stimulate the establishment of institutional integrated PE programs, including policies and interventions that can benefit a significant proportion of cancer patients.

Head and neck cancer survivors patients and late effects related to oncologic treatment: update of literature.

Cancer survivorship represents a new challenge in the third Millennium. In Europe the number of cancer survivors was estimated to be 17,8 million in 2008 and this number is growing. Recent improvements in cancer survival are largely due to earlier diagnosis and advancements in treatment. Despite having favorable effects on cancer survival, radiation therapy, surgery treatment and combination chemotherapy regimens can also cause long-term organ damage and functional disabilities. In this paper we review the most important aspects of long-term toxicities in otolaryngology cancer survivors patients.

Report from the OECI Oncology Days 2014.

The 2014 OECI Oncology Days was held at the 'Prof. Dr. Ion Chiricuta' Oncology Institute in Cluj, Romania, from 12 to 13 June. The focus of this year's gathering was on developments in personalised medicine and other treatment advances which have made the cost of cancer care too high for many regions throughout Europe.

Kaposi' s sarcoma in HIV-positive patients: the state of art in the HAART-era.

Kaposi's sarcoma (KS) is a multicentric angioproliferative cancer of endothelial origin typically occurring in the context of immunodeficiency, i.e. coinfection with Human Immonodeficiency Virus (HIV) or transplantation. The incidence of KS has dramatically decreased in both US and Europe in the Highly Active Antiretroviral Therapy (HAART) era. However, KS remains the second most frequent tumor in HIV-infected patients worldwide and it has become the most common cancer in Sub-Saharan Africa. In 1994, Yuan Chang et al discovered a novel γ-herpesvirus in biopsy specimens of human KS. Epidemiologic studies showed that KS-associated herpesvirus (KSHV) or human herpesvirus-8 (HHV-8) was the etiological agent associated with all subtypes of KS. KS has a variable clinical course ranging from very indolent forms to a rapidly progressive disease. HAART represents the first treatment step for slowly progressive disease. Chemotherapy (CT) plus HAART is indicated for visceral and/or rapidly progressive disease. The current understanding of KS as a convergence of immune evasion, oncogenesis, inflammation and angiogenesis has prompted investigators to develop target therapy, based on anti-angiogenic agents as well as metalloproteinase and cytokine signaling pathway inhibitors. These drugs may represent effective strategies for patients with AIDS-associated KS, which progress despite chemotherapy and/or HAART. In this review, we focus on the current state of knowledge on KSHV epidemiology, pathogenesis and therapeutic options.

De novo malignancies after organ transplantation: focus on viral infections.

Organ transplantation is an increasingly used medical procedure for treating otherwise fatal end stage organ diseases with 107,000 transplants performed worldwide in 2010. Newly developed anti-rejection drugs greatly helped to prolong long-term survival of both the individual and the transplanted organ, and they facilitate the diffusion of organ transplantation. Presently, 5-year patient survival rates are around 90% after kidney transplant and 70% after liver transplant. However, the prolonged chronic use of immunosuppressive drugs is well known to increase the risks of opportunistic diseases, particularly infections and virus-related malignancies. Although transplant recipients experience a nearly 2-fold elevated risk for all types of de-novo cancers, persistent infections with oncogenic viruses - such as Kaposi sarcoma herpes virus, high-risk human papillomaviruses, and Epstein-Barr virus - are associated with up to 100-fold increased cancer risks. This review, focusing on kidney and liver transplants, highlights updated evidences linking iatrogenic immunosuppression, persistent infections with oncogenic viruses and cancer risk. The implicit capacity of oncogenic viruses to immortalise infected cells by disrupting the cell-cycle control can lead, in a setting of induced lowered immune surveillance, to tumorigenesis and this ability is thought to closely correlate with cumulative exposure to immunosuppressive drugs. Mechanisms underlying the relationship between viral infections, immunosuppressive drugs and the risk of skin cancers, post-transplant lymphoproliferative disorders, Kaposi sarcoma, cervical and other ano-genital cancers are reviewed in details.

Antiblastic treatment, for solid tumors, during pregnancy: a crucial decision.

Cancer is the second leading cause of death during the reproductive years complicating between 0.02 percent and 0.1 percent of pregnancies. The incidence is expected to rise with the increase in age of childbearing. The most common types of pregnancy-associated cancers are: cervical cancer, breast cancer, malignant melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. The treatment of pregnancy-associated cancer is complex since it may be associated with adverse fatal effects. In pregnant patients diagnosed with cancer during the first trimester, treatment with multidrug anti-cancer chemotherapy is associated with an increased risk of congenital malformations, spontaneous abortions or fetal death, and therefore, should follow a strong recommendation for pregnancy termination. Second and third trimester exposure is not associated with teratogenic effect but increases the risk of intrauterine growth retardation and low birth weight. There are no sufficient data regarding the teratogenicity of most cytotoxic drugs. Almost all chemotherapeutic agents were found to be teratogenic in animals and for some drugs only experimental data exist. Moreover, no pharmacokinetic studies have been conducted in pregnant women receiving chemotherapy in order to understand whether pregnant women should be treated with different doses of chemotherapy. This article reviews the available data regarding the different aspects of the treatment of cancer during pregnancy.

Hepatocellular carcinoma in HIV positive patients.

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV-1-infected patients leading to increased survival and a better quality of life. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are common among HIV-1-infected subjects and represent the most important risk factors for hepatocellular carcinoma (HCC). Whether HIV plays a direct role in hepatocellular carcinoma (HCC) pathogenesis remains to be established.HCC clinical course depends on stage of cancer disease, performance status and comorbidities. Therapeutic options include liver transplantation, local antiblastic chemotherapy and biological drugs. In the HIV setting few data are available about treatment options. The increased longevity of patients with HIV imposes new strategies for prevention and therapeutic management of patients. The aim of this article is to provide an up-to-date review of HIV-related HCC in the HAART era.

Exposure to animals and increased risk of marginal zone B-cell lymphomas of the ocular adnexae.

BACKGROUND: Ocular adnexal marginal zone B-cell lymphoma (OAMZL) has been associated with Chlamydophila psittaci, an infection that may be transmitted by carrier animals. However, it is still unclear whether exposure to animals affects the risk of OAMZL in comparison with other lymphoma histotypes. We therefore investigated the role of professional and/or domestic exposures to animals in the occurrence of OAMZL, as compared with other types of lymphoma. METHODS: A hospital-based case-control study was carried out on 43 consecutive OAMZL patients (cases) and 87 consecutive patients with nodal non-Hodgkin's lymphomas (NHLs; controls). Multiple logistic regression (MLR) odds ratios (ORs), and 95% confidence intervals (CIs) were used to estimate the association between exposures to animals and OAMZL risk. RESULTS: A higher proportion of cases reported a lifetime exposure to household animals (79.1% vs 64.4% among controls), with a non-statistical significant MLR-OR of 2.18 (95% CI: 0.85-5.62). The OAMZL cases more frequently reported a history of occupation in breeding and/or slaughtering than controls (34.9% vs 6.9%), with an overall increased risk of 7.69 (95%CI: 2.65-22.34). CONCLUSION: These results indicate that, compared with nodal NHLs, the risk of OAMZL is markedly increased by contact with animals, particularly by occupational exposures.

MTHFR polymorphisms in gastric cancer and in first-degree relatives of patients with gastric cancer.

Two common mutations, 677 C-->T and a1298 A-->C, in the methylenetetrahydrofolate reductase gene (MTHFR) reduce the activity of MTHFR and folate metabolism. Familial aggregation in a variable but significant proportion of gastric cancer (GC) cases suggests the importance of genetic predisposition in determining risk. In this study, we evaluate MTHFR polymorphisms in 57 patients with a diagnosis of GC, in 37 with a history of GC in first-degree relatives (GC-relatives), and in 454 blood donors. Helicobacter pylori (HP) infection was also determined. An increased risk was found for 677TT in GC patients with respect to blood donors (odds ratio (OR) = 1.98), and statistical significance was sustained when we compared sex-age-matched GC patients and donors (OR = 2.37). The 677TT genotype association with GC was found in women (OR = 3.10), while a reduction in the 667C allele frequency was present in both the sex. No statistically significant association was detected when 677-1298 genotype was stratified by sex and age. Men of GC-relatives showed a higher 1298C allele frequency than donors (OR = 4.38). Between GC and GC-relatives, HP infection frequency was similar. In conclusion, overall findings support the hypothesis that folate plays a role in GC risk. GC-relatives evidence a similar 677TT frequency to that found in the general population.

Plasma HHV-8 viral load in HHV-8-related lymphoproliferative disorders associated with HIV infection.

This is a mono-institutional analysis of the clinical features, immunological and virological findings, and prognostic factors of patients with HIV infection and HHV-8-lymphoproliferative disorders. Patients with Multicentric Castleman Disease and HHV-8-related lymphoma diagnosed and treated from April 1987 to June 2004 were included in the study. HHV-8 and HIV plasma viral load, CD4+ count, hematologic parameters, and general wellbeing (performance status) were assessed at the onset of the diseases and analyzed in order to identify possible prognostic factors. Nine patients with Multicentric Castleman disease, and 16 with HHV-8-related lymphomas (13 primary effusion lymphomas and 3 solid lymphomas), were diagnosed and treated out of 327 HIV-related non-Hodgkin's lymphomas. Four patients with Multicentric Castleman disease received only antiretroviral drugs; 5 HAART plus oral etoposide. Nine patients with primary effusion lymphoma were treated with a CHOP-like regimen (Cyclophosphamide, Prednisone anthracyclines, Vinca alkaloids, Bleomycin, Etoposide) and HAART; 1 with etoposide and HAART, 1 with HAART alone. The patients with solid lymphoma underwent CHOP-like chemotherapy. Patients with Multicentric Castleman disease showed lower median values of HHV-8 viral load and longer overall survival compared with HHV-8-related lymphomas. Patients with viral load of HHV-8, >40,000 cp/ml had a significant shorter overall survival. In the univariate analysis, HHV-8-related lymphoma, HHV-8 viral load >40,000 cp/ml and performance status >2 were associated with an increased risk of death. Multivariate analysis confirmed the diagnosis of lymphoma as an independent predictor of shorter survival.

Future of biobanking in microbiology for medical research.

Biobanks are actively contributing to advances in biomedical research by offering opportunities to link laboratory research with clinical applications and by accelerating developments in personalized medicine. Microbiologists have a long tradition of storing microorganisms as part of projects focused on microbial genetics or phenotypic investigations. However, the impressive recent advances of biomedical translational research demand the integration of biobanks with high-level technological infrastructures in genomics, proteomics, bioinformatics, patient information systems and disease registries, where data originating from microorganisms are linked with human clinical information with the ultimate aim of improving healthcare by increasing the quality of biomedical research.

Recent thymic emigrants in lymphoma patients with and without human immunodeficiency virus infection candidates for autologous peripheral stem cell transplantation.

Signal joint T cell receptor excision circles (sjTRECs) have been reported as a clinical marker to measure the potential for recovery of the immune system after immunosuppressive treatments. The aim of this study was to investigate the thymic regenerative potential in 55 human immunodeficiency virus (HIV)-1 infected (HIV(+)) and non-infected (HIV(-)) lymphoma patients, candidates for autologous stem cell transplantation (ASCT). Moreover, the possible associations between sjTRECs and other immunological and clinical parameters were examined. SjTRECs levels in peripheral blood mononuclear cells (PBMCs) were quantified by real-time polymerase chain reaction and T lymphocyte subsets were analysed by flow cytometry. Our data showed that sjTRECs were reduced in lymphoma patients compared to healthy controls, although a weak significant association between low sjTRECs levels and increasing age was maintained [odds ratio (OR) = 4.00; 95% confidence interval (CI) 1.09-17.17]. We found that different chemotherapeutic treatments seem to induce similar effects on the thymic reservoir, independently from their intensity (type and number of cycles of previous chemotherapy). Results from multivariate models including adjustment for patients' sex, type of lymphoma and type of chemotherapy showed that thymic output was independent from HIV infection (OR, 0.95; 95% CI 0.20-4.48). SjTRECs levels correlated with naive T cell subsets in overall lymphoma patients and after stratification by HIV infection (r > 0.37). HIV replication should be maximally suppressed to properly evaluate thymic output by sjTREC markers. Our results suggested that de novo T cell generation is maintained partially in pretreated recurrent lymphoma patients, candidates for ASCT, and could contribute to restore the immune function after transplantation.

Joint Nordic prospective study on human herpesvirus 8 and multiple myeloma risk.

An association between human herpesvirus 8 (HHV8) and multiple myeloma (MM) has been reported, though most studies have not confirmed such association. To follow-up on a previous prospective seroepidemiological study, where HHV8 tended to associate with MM risk, we linked five large serum banks in the Nordic countries with the Nordic cancer registries and 329 prospectively occurring cases of MM were identified, together with 1631 control subjects matched by age and gender. The HHV8 seroprevalences among cases and controls were similar (12 and 15%, respectively) and HHV8 seropositivity did not associate with the risk of MM, neither when considering positivity for lytic antibodies (relative risk (RR) = 0.8, 95% confidence interval (CI) = 0.5-1.1) nor for latent antibodies (RR = 0.6, 95% CI = 0.1-2.7). Similar risks were seen when analysis was restricted to case-control sets with at least 2 years lag before diagnosis (RR = 0.8, 95% CI = 0.5-1.2 and RR = 0.9, 95% CI = 0.1-4.2). In conclusion, the data indicate that HHV8 infection is not associated with MM.

Catheter-related bacteremia due to Kocuria kristinae in a patient with ovarian cancer.

We report on the first case of a catheter-related recurrent bacteremia caused by Kocuria kristinae, a gram-positive microorganism belonging to the family Micrococcaceae, in a 51-year-old woman with ovarian cancer. This unusual pathogen may cause opportunistic infections in patients with severe underlying diseases.