Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Health literacy of informal caregivers of older adults with dementia: results from a cross-sectional study conducted in Florence (Italy)

AIM: The aim of this study was to measure the prevalence of inadequate health literacy (HL) in a sample of family caregivers of older adults with dementia, and to assess the relationship of HL with characteristics of caregiver and persons with dementia. METHODS: The study followed a cross-sectional design. Persons with dementia and their family caregivers were enrolled in an outpatients’ geriatric memory clinic. For the caregivers, the following information was collected: socio-demographic data, level of HL, cognitive impairment (using the Mini-Cog). For persons with dementia, the following data were collected: socio-demographic data, functional status (using the Basic and Instrumental Activities of Daily Living), cognitive impairment (using the Mini Mental State Evaluation, and the Global Deterioration Scale) behavioral and psychological symptoms associated with dementia (assessed using the Neuropsychiatric Inventory). RESULTS: A total of 174 person with dementia/caregiver dyads were enrolled. About 45% of the caregivers presented a possibility or a high likelihood of inadequate HL. The percentage of caregivers with inadequate HL was higher among spousal caregivers than in offspring. Female gender, higher age and lower education were independent predictors of low HL. On multiple logistic regression analysis, persons with dementia assisted by caregivers with a high likelihood of limited HL presented higher risk of a more severe disease. CONCLUSION: The results of this study suggest that the HL of dementia caregivers has to be included in the comprehensive geriatric assessment, to develop an appropriate individualized care plan. Moreover, public health interventions are needed to increase the HL of dementia caregivers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40520-022-02271-0

VEGF GENE POLYMORPHISMS IN THE PREDICTION OF BENEFIT FROM FIRST-LINE FOLFIRI PLUS BEVACIZUMAB (BV) IN METASTATIC COLORECTAL CANCER (MCRC) PATIENTS (PTS)

Introduction: Addition of BV to first-line irinotecan plus 5FU improves PFS and OS of mCRC pts. Meanwhile, the anti-VEGF causes specific toxicities and increases costs of treatment. At the same time, not all pts derive an equal benefit from the VEGF inhibitor. Molecular predictors of BV efficacy have not yet been identified. Specific VEGF polymorphisms may affect gene transcription, thus indirectly influencing BV efficacy. Methods: Peripheral blood samples for genomic DNA extraction were collected from consecutive mCRC pts receiving FOLFIRI plus BV as first-line treatment (BV-group). VEGF -2578A/C, -460C/T, +405C/G, +936C/T polymorphisms were analysed by means of PCRRFLP. One-hundred-seven pts, treatedwith FOLFIRI alone, served as historical control group. Results: One-hundred-eleven pts were included in the BV-group. M/F=57/54, median age=63 (34-82), Ko¨hne score (low/intermediate/high/data missing)=57/39/12/3. Sixtynine out of 111 pts achieved response (RR=62%). Median PFS (mPFS) and median OS (mOS) were 10.2 and 22.2 months, respectively. -460C/C, C/T and T/T allelic variants were found in 20%, 54% and 26% of pts, respectively. -460 T allele demonstrated shorter PFS and OS with an additive effect of each T allele (PFS:HR=2.65[1.49- 6.62],p=0.003; OS:2.47[0.91-7.66],p=0.074). -460C/C pts achieved longer PFS and OS in comparison to pts carrying at least one T allele (mPFS:12.8 vs 9.8 months;HR=0.48[0.28-0.85],p=0.012; mOS:27.3 vs 20.5 months; HR=0.38[0.19- 0.94],p=0.034). In the control group mPFS and mOS were 8.2 and 20.6 months; -460C/ C, C/T and T/T variants were found in 23%, 52% and 25% of pts; there was no significant association with PFS or OS. Other polymorphisms did not affect outcome neither in BV-group nor in the control group. Conclusions: At our knowledge this is the first report of a pharmacogenetic determinant of improved PFS and OS for mCRC pts treated with first-line BVcontaining therapy. The observation that VEGF -460C/T variants did not influence the outcome in the control group led to hypothesize a predictive other than a prognostic role for such genetic signature. These preliminary data deserve investigation in prospective, randomized, validating trials

Prospective validation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab.

Purpose:The potential impact of different SNPs ofVEGF/VEGFRpathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association ofVEGFArs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with firstline FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs ofVEGF/VEGFRpathway genes was included. Experimental design:To detect a HR for PFS of 1.7 forVEGFArs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sideda= 0.05 andb= 0.20, 199 events were required. VEGFA rs699946 A/G, rs699947 A/C, VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and EPAS1 rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing. Results:Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to VEGFA rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only VEGFR2rs12505758 Cvariants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14). Conclusion:This prospective experience failed to validate the hypothesized predictive impact ofVEGFArs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizuma

Human Respiratory Syncytial Virus Epidemiological Burden in Pediatric Outpatients in Italy: A Systematic Review

Background: Human respiratory syncytial virus (hRSV) is a key contributor to lower respiratory tract infections (LRTIs), affecting children aged 0–5 years and often leading to outpatient visits, emergency department utilization, and hospitalization. With the development of hRSV vaccines for mitigation, understanding the epidemiological impact of hRSV infections among 0–5-year-old pediatric outpatients in Italy is crucial. Methods: This systematic review conducted searches on PubMed, Embase, Scopus, and the International HTA Database, yielding 20,845 English and Italian records from January 2000 to July 2022. Results: Six eligible articles were identified following inclusion and exclusion criteria. These studies demonstrated hRSV-positivity proportions ranging from 18% to 41% in pediatric outpatients with respiratory infections. However, data comparability was hindered by diverse diagnostic approaches, data sources, sample populations, and study designs. Notably, hRSV-positivity showed temporal variability, rising from 23.8% (2001–2002) to 40.6% (2019–2020). This trend could stem from evolving epidemiological factors, heightened clinician awareness in hRSV diagnosis, or more sensitive molecular techniques. Conclusion: As the first review of its kind, this study underscores the need for more comprehensive data to inform effective preventive strategies against hRSV-related burdens in pediatric outpatients