Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity. Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype−phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype−phenotype association data is needed to enable the clinical use of sequencing data

Risk of latent tuberculosis infection among healthcare workers in Italy: a retrospective study with Quantiferon Test

OBJECTIVE. The latent tuberculosis infection (LTBI) is a state of persistent immune response to stimulation by Mycobacterium Tuberculosis antigens without clinical manifestation: the healthcare workers (HCWs) have a higher exposure risk so prevention is an important challenge for occupational medicine. The aim of our study is to evaluate the prevalence of LTBI among HCWs of the Foundation Policlinic “Tor Vergata”. METHODS. This is a retrospective study conducted by analyzing the clinical records of 825 HCWs of the PTV, from January 1st to December 31th 2016. To evaluate the TB infection we used the Quantiferon TB Gold interferon-gamma release assay. RESULTS. Our study underline the low prevalence of LTBI in the Italian healthcare workers. CONCLUSION. Although the LTBI status is not contagious, the diagnosis and the safety strategies require specific clinical and preventive considerations

DRD2, DRD3, and HTR2A Single-Nucleotide Polymorphisms Involvement in High Treatment Resistance to Atypical Antipsychotic Drugs

Background: The objective of this study was to investigate the DRD2 rs1800497, rs1799732, rs1801028, DRD3 rs6280, and HTR2A rs6314, rs7997012, and rs6311 single-nucleotide polymorphism (SNP) correlations with resistance to second-generation antipsychotics (SGAs) in a real-world sample of patients with treatment-resistant mental disorders. Methods: We divided 129 participants into a high treatment resistance (HTR) group (current treatment with two SGAs, or clozapine, or classic neuroleptics for a failure of previous SGAs trials) and a low treatment resistance (LTR) group (current treatment with one atypical antipsychotic). We used Next-Generation Sequencing on DNA isolated from peripheral blood samples to analyze the polymorphisms. We performed logistic regression to search for predictors of HTR membership. Results: A diagnosis of schizophrenia significantly predicted the HTR membership compared to other diagnoses. Other predictors were the DRD3 rs6280 C|T (OR = 22.195) and T|T (OR = 18.47) vs. C|C, HTR2A rs7997012 A|G vs. A|A (OR = 6.859) and vs. G|G (OR = 2.879), and DRD2 rs1799732 I|I vs. D|I (OR = 12.079) genotypes. Conclusions: A diagnosis of schizophrenia and the DRD2 rs1799732, DRD3 rs6280, and HTR2A rs7997012 genotypes can predict high treatment resistance to SGAs

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Practice patterns and 90-day treatment-related morbidity in early-stage cervical cancer

To evaluate the impact of the Laparoscopic Approach to Cervical Cancer (LACC) Trial on patterns of care and surgery-related morbidity in early-stage cervical cancer

Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype–phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype–phenotype association data is needed to enable the clinical use of sequencing data

Domenico Maccarano: le vicissitudini di uno stampatore napoletano

This paper aims to show how censorship represented a facet of the jurisdictional tug of war between the Kingdom of Naples and the Holy See by relating the hardships of a Neapolitan printer, Ferdinando Maccarano, at the hands of the Archiepiscopal Court. Maccarano was prosecuted trice in less than two years, while the first two prosecutions came to nothing, the last led to a trial that dragged on for nearly seven years. Maccarano’s case(s) might not have been pivotal in resolving the jurisdictional issue, yet it shows how the problem permeated all social strata and could shed light on how the Neapolitan political power handled it

Recensione di: Messinetti M., Diritto e schiavitù. Il paradigma dell'uomo merce nel secolo XVIII tra Regno di Napoli e colonie spagnole

La recensione riporta i punti salienti dell'opera di Messinetti, nella quale l'autore approfondisce, in quattro capitoli riccamente documentati e rinfrancati da una scrittura tanto solida quanto limpida, il tema della schiavitù mediterranea e atlantica nel Settecento