The relevance of citizen involvement in Health Technology Assessment. A concrete application in the assessment of HPV co-testing in the Autonomous Province of Trento

Background Specific programs have been developed in the latest decades to involve patients in Health Technology Assessments (HTAs). However, there are no structured practises in Italy and citizen’ perspective is rarely included in HTA reports. Aim of this study is to explore citizen’ opinions about cervical cancer screening with Human Papillomavirus (HPV) co-testing in the Autonomous Province of Trento (PAT). Methods Two focus groups were conducted: one with representatives of patients’ associations, the other one with women between 31 and 64 years and their family members. Following aspects were investigated: the importance of cervical cancer screening programs; the impact of HPV test on women’ and their partners’ life; needs, expectations, and critical aspects of the new screening method. Results Organised screening programs are very important for all participants. HPV co-testing screening is preferred to cytology for its higher sensitivity, but different opinions came out regarding the longer screening interval after normal HPV and Pap test results. Citizen stressed that correct, clear, and unambiguous information have to be provided to the whole population (men included). A cardinal role plays the patient-doctor relationship in informing and taking care, also emotionally, of women, their partners and relatives in case of positive HPV test. Conclusion In order to facilitate the introduction of the new screening method, various media must be used to spread clear and unambiguous information, as well as informative and educational meetings with doctors and caregivers. Citizen perspective was included in the report for the Health Trust and played an important role in the decision process

Impact of ABCG2 and ABCB1 Polymorphisms on Imatinib Plasmatic Exposure: An Original Work and Meta-Analysis

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (Ctrough) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma Ctrough with respect to the CC/CA carriers (Ctrough, 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib Ctrough, neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma Ctrough in GIST and CML patients

Economic analysis of remote monitoring in patients with implantable cardioverter defibrillators or cardiac resynchronization therapy defibrillators in the Trento area, Italy

IntroductionRemote monitoring (RM) technologies have the potential to improve patient care by increasing compliance, providing early indications of heart failure (HF), and potentially allowing for therapy optimization to prevent HF admissions. The aim of this retrospective study was to assess the clinical and economic consequences of RM vs. standard monitoring (SM) through in-office cardiology visits, in patients carrying a cardiac implantable electronic device (CIED).MethodsClinical and resource consumption data were extracted from the Electrophysiology Registry of the Trento Cardiology Unit, which has been systemically collecting patient information from January 2011 to February 2022. From a clinical standpoint, survival analysis was conducted, and incidence of cardiovascular (CV) related hospitalizations was measured. From an economic standpoint, direct costs of RM and SM were collected to compare the cost per treated patient over a 2-year time horizon. Propensity score matching (PSM) was used to reduce the effect of confounding biases and the unbalance of patient characteristics at baseline.ResultsIn the enrollment period, N = 402 CIED patients met the inclusion criteria and were included in the analysis (N = 189 patients followed through SM; N = 213 patients followed through RM). After PSM, comparison was limited to N = 191 patients in each arm. After 2-years follow-up since CIED implantation, mortality rate for any cause was 1.6% in the RM group and 19.9% in the SM group (log-rank test, p < 0.0001). Also, a lower proportion of patients in the RM group (25.1%) were hospitalized for CV-related reasons, compared to the SM group (51.3%; p < 0.0001, two-sample test for proportions). Overall, the implementation of the RM program in the Trento territory was cost-saving in both payer and hospital perspectives. The investment required to fund RM (a fee for service in the payer perspective, and staffing costs for hospitals), was more than offset by the lower rate of hospitalizations for CV-related disease. RM adoption generated savings of −€4,771 and −€6,752 per patient in 2 years, in the payer and hospital perspective, respectively.ConclusionRM of patients carrying CIED improves short-term (2-years) morbidity and mortality risks, compared to SM and reduces direct management costs for both hospitals and healthcare services

Shedding light on typical species : implications for habitat monitoring

Habitat monitoring in Europe is regulated by Article 17 of the Habitats Directive, which suggests the use of typical species to assess habitat conservation status. Yet, the Directive uses the term “typical” species but does not provide a definition, either for its use in reporting or for its use in impact assessments. To address the issue, an online workshop was organized by the Italian Society for Vegetation Science (SISV) to shed light on the diversity of perspectives regarding the different concepts of typical species, and to discuss the possible implications for habitat monitoring. To this aim, we inquired 73 people with a very different degree of expertise in the field of vegetation science by means of a tailored survey composed of six questions. We analysed the data using Pearson's Chi-squared test to verify that the answers diverged from a random distribution and checked the effect of the degree of experience of the surveyees on the results. We found that most of the surveyees agreed on the use of the phytosociological method for habitat monitoring and of the diagnostic and characteristic species to evaluate the structural and functional conservation status of habitats. With this contribution, we shed light on the meaning of “typical” species in the context of habitat monitoring

Plant–environment interactions through a functional traits perspective: a review of Italian studies

Italy is among the European countries with the greatest plant diversity due to both a great environmental heterogeneity and a long history of man–environment interactions. Trait-based approaches to ecological studies have developed greatly over recent decades worldwide, although several issues concerning the relationships between plant functional traits and the environment still lack sufficient empirical evaluation. To draw insights on the association between plant functional traits and direct and indirect human and natural pressures on the environmental drivers, this article summarizes the existing knowledge on this topic by reviewing the results of studies performed in Italy adopting a functional trait approach on vascular plants, bryophytes and lichens. Although we recorded trait measurements for 1418 taxa, our review highlighted some major gaps in plant traits knowledge: Mediterranean ecosystems are poorly represented; traits related to belowground organs are still overlooked; traits measurements for bryophytes and lichens are lacking. Finally, intraspecific variation has been little studied at community level so far. We conclude by highlighting the need for approaches evaluating trait–environment relationship at large spatial and temporal scales and the need of a more effective contribution to online databases to tie more firmly Italian researchers to international scientific networks on plant traits

Circulating Tumor DNA Monitoring and Pharmacogenetics Patients\u2019 Profiling: Pharmacological Implications in Locally Advanced Rectal Cancer and Gastrointestinal Stromal Tumor

Background The standard of care for the management of locally advanced rectal cancer (LARC) relies on chemoradiotherapy (nCRT), followed by surgery. The achievement of a pathological complete response (pCR) after nCRT is observed in up to 30% of patients and is positively associated with a lower risk of local and distant recurrence. The need to discriminate good from poor responder in the early steps of nCRT is urgently required to optimize the therapeutic strategies and improve prognosis. In gastrointestinal stromal tumor (GIST), the development of resistance to first line imatinib treatment represents the leading cause of disease progression and is determined by pharmacodynamics and pharmacokinetics alterations. The chance of interrogating circulating tumor DNA (ctDNA) represents an appealing tool for the real-time monitoring of treatment response in a low-invasive manner and to sustain the decision making for treatment\u2019s personalization in gastrointestinal malignancies. Aims The aims can be summarized as follow: i) Assess whether the presence of copy number aberrations (CNAs) in the cell-free DNA (cfDNA) of LARC patients receiving nCRT might represent an early biomarker of treatment efficacy. ii) Test whether the detection of ctDNA in GIST might help in the identification of disease progression. iii) Assess whether the presence of specific pharmacogenetic variants, as well as the administration of imatinib interacting drug, might explain the pharmacokinetics variability of imatinib. Materials and Methods 84 blood samples were collected from 40 consent LARC patients with available clinical data at the Clinical Pharmacology Unit of IRCCS CRO Aviano. cfDNA was extracted and the presence of CNAs was assessed by means of shallow whole genome sequencing (sWGS) in a tumor-informed manner. The response to nCRT was assessed using the Mandard\u2019s tumor regression grade (TRG) scale. 188 blood samples were collected from 39 consent GIST patients. cfDNA was extracted and the presence of ctDNA was assessed by means of targeted deep sequencing in a panel of GIST relevant genes. Imatinib trough levels were quantified by means of LC-MM/MS validated method and the presence of genetic variants in cytochromes and transporters was assessed on genomic DNA by means of target allele discrimination assays and NGS. Intake of co-administrated drugs was retrieved from clinical records and patients\u2019 interview. Response to imatinib was assessed according to RECIST criteria. Results For all LARC patients the plasma sample collected at the time of diagnosis (T1, n = 40) was available. Further longitudinal plasma samples were collected in the course of nCRT (T2, n = 24) and after nCRT (T3, n = 15). The presence of CNAs was detected in the cfDNA of 6/40 patients (15.0%) at the T1, with a median tumor fraction (TFx) of 10.41% (range 5.89\u201327.34). When comparing the variation of TFx between T2 and T1, 7/24 evaluable patients (29.2%) showed an increase of the TFx, which was associated with an increased rate of pCR (RR: 3.75; 95% CI 1.47 \u2013 9.56). For GIST patients, ctDNA was detected in 2/9 (22.2%) patients with progressive disease and was informative on the mechanisms of imatinib resistance. Pharmacogenetic profiling was performed on 33 GIST patients and the genotype of CYP2D6 was shown to influence the imatinib plasma exposure, while the concomitant intake of strong CYP3A4 inducers (carbamazepine) and CYP1A2 inhibitors (smoking) were associated with a faster imatinib clearance and risk of under-dosage. Conclusions The identification of CNAs and their quantification by means of TFx estimation is feasible in the cfDNA of LARC patients and preliminary data suggests that an increased TFx in course of nCRT is associated with a higher probability of achieving a pCR. The identification of ctDNA in GIST shows a low sensitivity (22.2%) and a high specificity (100%) in identifying patients with progressive disease and might represent a valuable too

The use of pharmacogenetics to increase the safety of colorectal cancer patients treated with fluoropyrimidines

Fluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways, TYMS and MTHFR, but no additional clinically validated genetic markers of toxicity are available to date. The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients

Circulating-Free DNA Analysis in Hepatocellular Carcinoma: A Promising Strategy to Improve Patients’ Management and Therapy Outcomes

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide, representing the third leading cause of cancer-related deaths. HCC genetic characterization at the tumor level has been recently completed, highlighting how a number of genes are frequently mutated in this pathology. Actionable somatic mutations found in a HCC tumor may represent targets for innovative drugs as well as prognostic/predictive markers. Nonetheless, surgical or bioptic tissue is hardly accessible in HCC and a single tumor sample is poorly representative of the tumor genetic heterogeneity. In this context, analyzing the circulating cell-free DNA (ccfDNA) and its tumor-derived fraction (ctDNA) could represent a promising strategy of liquid biopsy. Recent data suggested that the fluctuation of the ccfDNA quantity in the plasma of HCC patients could anticipate the detection of tumor progression. The presence of somatic mutations in p53 signaling, Wnt/β-catenin, chromatin remodeling, response to oxidative stress and telomerase maintenance pathways can also be studied in ccfDNA bypassing the need to perform a tumor biopsy. The profiling of ccfDNA fragmentation and the methylation pattern could further improve the clinical management of HCC patients. Performing a dynamic monitoring in the course of systemic treatment with sorafenib or regorafenib is a possible way to provide insights into the resistance mechanism, and to identify predictive and prognostic genetic alterations, helping the clinicians in terms of treatment decision making. This review will discuss the most recent literature data about the use of ccfDNA to monitor and improve the treatment of HCC