Italian Patient Research Articles

A West Nile Virus infection expressed as unilateral limb paralysis and complicated by Parsonage–Turner syndrome: a case report

BackgroundWest Nile Virus is a single-stranded Ribonucleic Acid arbovirus of the Flaviviridae family that is transmitted to humans by Culex species mosquitoes. West Nile Virus infection is asymptomatic in the majority of affected people. Of those who develop symptoms, the usual manifestation is a febrile syndrome, while only 1% develop neurological symptoms due to a neuroinvasive form of infection, including encephalitis, meningitis, asymmetrical flaccid paralysis, or a combination of all these features. Parsonage–Turner syndrome is a rare disorder characterized by sudden painful symptoms and subsequent paralysis, involving a shoulder or one of the upper limbs due to post-infective brachial plexopathy. The etiology is unknown, although it can be considered a multifactorial process: a predisposing factor, such as viral infection or strenuous upper-extremity exercise, can trigger an immune-mediated process localized in the brachial plexus.Clinical presentationIn late summer, a 79-year-old male Italian patient was admitted to the emergency department for acute right upper limb weakness and high fever, without any mental status impairment, pain, sensory alterations, or signs of meningeal irritation. Laboratory tests confirmed acute West Nile Virus infection, expressed as a unilateral upper limb flaccid paralysis. After a few days, the patient reported an acute pain in the right upper limb scarcely responsive to nonsteroidal anti-inflammatory drug therapy and a subsequent wider distribution of flaccid paralysis. After multiple examinations, Parsonage–Turner syndrome could be suspected. Patient was treated with steroids and reported an improvement of clinical condition after 2 months, with complete pain remission but partial strength recovery in the affected limb.ConclusionsWest Nile Virus disease has a broad spectrum of neurological manifestations, among which the most common are signs of meningeal irritation or cognitive impairment. We report an unusual presentation of neuroinvasive West Nile Virus infection with arm weakness as expression of unilateral viral neuritis, followed by a post-infective brachial plexopathy consistent with Parsonage–Turner syndrome diagnosis. We diagnosed Parsonage–Turner syndrome after excluding the most common causes of atraumatic acute upper limb pain, through a challenging differential diagnosis in a patient with several comorbidities.

Sporadic and MEN1-related gastrinoma and Zollinger–Ellison syndrome: differences in clinical characteristics and survival outcomes

PurposeGastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features.MethodsConsecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort.ResultsOf 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively.ConclusionMEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia.

Background and ObjectivesTo date, approximately 20 heterozygous mainly loss-of-function variants in KCND3 have been associated with spinocerebellar ataxia (SCA) type 19 and 22, a clinically heterogeneous group of neurodegenerative disorders. We aimed at reporting the second patients with the V374A KCND3 mutation from an independent family, confirming its pathogenic role.MethodsWe describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing.ResultsThis male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121T>C [p.V374A] mutation in KCND3.DiscussionThis report consolidates the pathogenicity of the V374A KCND3 mutation and suggests that the ataxic paroxysmal exacerbations are not a key phenotypic feature of this mutation.

Expanding the Phenotypic Spectrum of Vocal Cord and Pharyngeal Weakness With Distal Myopathy due to the p.S85C MATR3 Mutation.

ObjectivesThe c.254C>G (p.S85C) MATR3 variant causes vocal cord and pharyngeal weakness with distal myopathy (VCPDM), which is characterized by progressive, asymmetric, predominantly distal muscle weakness, dysphonia, dysphagia, and respiratory impairment. Herein, we describe an Italian patient who harbored the p.S85C MATR3 variant and showed a composite phenotype of VCPDM and sensorimotor polyneuropathy.MethodsThe proband underwent neurologic evaluation, muscular MRI of the lower limbs, neurophysiologic assessment, muscle biopsy, and spirometry. After excluding common acquired and genetic causes of sensorimotor polyneuropathy, a larger group of genes involved in inherited forms of neuropathy, distal myopathy, and motor neuron disorders were analyzed by next-generation sequencing targeted panels.ResultsThe patient, affected by progressive distal muscle weakness and hypotrophy, myalgias, dysphonia, dysphagia, respiratory impairment, and sensory abnormalities, harbored the heterozygous c.254C>G (p.S85C) MATR3 substitution. Neurophysiologic assessment revealed a severe sensorimotor polyneuropathy. Variation of fiber size, central nuclei, and nonrimmed vacuoles were evident at muscle biopsy.DiscussionThis finding extends the MATR3-associated VCPDM phenotypic spectrum and suggests considering MATR3 analysis in suspected congenital polyneuropathies with odd features, including dysphonia, dysphagia, and respiratory insufficiency.

P-498 Psychological care during ART treatments In Italy: the patients’ point of view

Abstract Study question What are the characteristics of the psychological care and the emotional needs of couples undergoing ART treatment in Italy? Summary answer The presence of psychological support services in ART centers is poorly communicated to patients, with less than half being advised to take a pathway. What is known already Couples who decide to undergo ART treatment show significantly higher depression and shame scores, lower acceptance and self-compassion scores, greater reliance and avoidant coping strategies. Couples experience the procedure as source of stress, anxiety and pain, fluctuating between hope and despair, and all of this seem to negatively impact on treatment continuation and outcomes. A review of 25 studies using different psychological interventions (counseling, focused educational interventions and integrated educational programs) found positive effects on anxiety (61.5%), depression (38.4%) and infertility-related stress (100%) reduction. Several studies showed the effectiveness of psychological intervention in promoting pregnancy rates. Study design, size, duration The ART Italian National Register (National Health Institute) with the Department of Dynamic and Clinical Psychology and Health Studies (Sapienza University) proposed a national survey to 195 Italian ART centres and patient associations. Patient associations and the Medical Director of each centre were invited by e-mail to participate and to encourage all patients to fill a questionnaire made available on an on-line platform. Data collection was between March to October 2021. Participants/materials, setting, methods 324 ART patients completed an online questionnaire consisting of 19 closed-ended and 8 open-ended questions. In this abstract we focus on the closed-ended questions. The questionnaire was created ad hoc for the survey starting from a previous study on the characteristics of the services offered in Italian ART centres. Main results and the role of chance In 90% of cases women responded to the questionnaire, only 10% of responses were from men. On average, participants are 38 years old, married (60%), and have a bachelor's degree or post-graduate degree (59%). In half of the cases respondents are employed. In 68% of cases, participants performed ART treatment in centers with public service. Most of the respondents are facing their first or second ART cycle. They share their infertility condition with family and friends, and in 60% of cases they have been informed of the presence of the psychological service, mainly from gynecologists and through informed consent. Only in 31% of cases patients were invited to undertake psychological counseling, strongly recommended to only 8% of them. In fact, 65% of respondents never had a meeting with the psychologist during ART treatment. Those who resorted to counseling had mainly couple (45%) and individual (31.3%) meetings. Participants did not know the cost of counseling, would prefer it to be included in the cost of ART treatment, and would like it to be available throughout treatment The main emotions felt during ART treatment are sadness, fear and anger, those attributed to the partner are the same but joy also appears. Limitations, reasons for caution Firstly the limited sample size, mainly related to the ability of ART center staff to spread the initiative among patients. The low response from male partners, that could be related to their rare presence in ART centers, as the medical treatment is mainly targeted to women. Wider implications of the findings In conclusion, the results show that psychological services in Italian ART centers are not yet fully operational and integrated in the ART procedure. All this highlights the importance of further investigations with the aim of sharing information to establish common protocols for psychological interventions in ART centres. Trial registration number Not applicable

P-304 Sexual function in women with endometriosis: an online survey

Abstract Study question What factors are associated with sexual function in women with endometriosis? Summary answer In this study, the most important variables associated with sexual function were dyspareunia (especially deep and introital dyspareunia combined), infertility, fatigue, and psychological comorbidities. What is known already Endometriosis is a chronic gynaecologic disease that affects women of reproductive age, with negative consequences on multiple life domains, including sexuality. Although it has been demonstrated that endometriosis-related sexual issues may negatively affect women’s intimate relationships, their subjective experience remains overlooked, either in research or clinical practice. In this regard, the impact of dyspareunia (especially deep dyspareunia) has been highlighted in several studies, but the role of symptoms other than pain, such as fatigue, infertility, and psychological comorbidities, has not been yet clarified. Moreover, little is known about how women deal with dyspareunia and the quality of doctor-patient communication. Study design, size, duration This observational study was conducted between 8 November and 21 December 2021 in collaboration with the largest Italian patient association, Associazione Progetto Endometriosi (APE [Endometriosis Project Association]). Data were collected through a self-administered online survey hosted on Qualtrics (Qualtrics Ltd.). Women were invited to participate in the study via APE’s Facebook page and newsletters. The online survey was anonymous, and women were allowed to complete it only after providing their electronic consent. Participants/materials, setting, methods Participants were 612 women (age: 36.41 ± 6.72 years) with a surgical or clinical diagnosis of endometriosis and a sexual partner. They completed the Female Sexual Function Index (FSFI), the Hospital Anxiety and Depression Scale (HADS), and the Rosenberg Self-Esteem Scale (RSES). Demographic and gynaecologic data – including endometriosis stage, type of lesions, symptoms (e.g., pelvic pain, fatigue, infertility), treatment –, and information regarding women’s subjective experience of dyspareunia were collected using a researcher-made questionnaire. Main results and the role of chance Dyspareunia was experienced by 524 (86%) women. Sexual dysfunction (FSFI total score < 26.55) was reported by 479 (78%) participants. Multiple regression analyses revealed that sexual function (FSFI total score) was associated with dyspareunia (β = −.108, P = .008), infertility (β = −.082, P = .040), fatigue (β = −.108, P = .021), and symptoms of anxiety and depression (HADS total score; β = −.127, P = .021). Women with sexual dysfunction were more likely to report rectovaginal endometriotic lesions (59% vs. 47%, P = .016) and stage 4 endometriosis (43% vs. 32%, P = .002), to experience deep and introital dyspareunia combined (50% vs. 21%, P < .001), with greater symptoms of anxiety and depression (F [2,595] = 21.812, P < .001, Wilk’s Λ = .932, η2p = .068) and lower self-esteem (t [589] = 5.111, P < .001). Women with dyspareunia and sexual dysfunction reported greater fear of pain and consequent inability to relax during intercourse, avoidance of sex, worries about their sexual life, sexual dissatisfaction, and feelings of guilt towards the partner (Ps < .001), along with poorer support and understanding from doctors (P = .006) than women with dyspareunia who did not report sexual dysfunction. Limitations, reasons for caution This is one of the largest studies on sexual function in women with endometriosis. However, there are reasons for caution when interpreting our results due to the self-reported nature of all the data (including medical information) and the risk of selection bias due to our recruitment strategy. Wider implications of the findings Our results clearly indicate that the majority of women with endometriosis experience sexual problems that are mostly (but not solely) due to dyspareunia. The assessment of sexual function should be included in routine clinical practice with these patients, also considering its association with psychological symptoms and self-esteem. Trial registration number Not applicable

Improving Keyword-Based Topic Classification in Cancer Patient Forums with Multilingual Transformers.

Online forums play an important role in connecting people who have crossed paths with cancer. These communities create networks of mutual support that cover different cancer-related topics, containing an extensive amount of heterogeneous information that can be mined to get useful insights. This work presents a case study where users' posts from an Italian cancer patient community have been classified combining both count-based and prediction-based representations to identify discussion topics, with the aim of improving message reviewing and filtering. We demonstrate that pairing simple bag-of-words representations based on keywords matching with pre-trained contextual embeddings significantly improves the overall quality of the predictions and allows the model to handle ambiguities and misspellings. By using non-English real-world data, we also investigated the reusability of pretrained multilingual models like BERT in lower data regimes like many local medical institutions.

The novel I213S mutation in PSEN1 gene is located in a hotspot codon associated with familial early-onset Alzheimer's disease

Mutations in presenilin 1 gene (PSEN1) are the most common causes of autosomal dominant early-onset Alzheimer's disease (EOAD). We report a novel PSEN1 mutation (I213S) that was discovered in an Italian patient with a family history of early-onset dementia, who developed a slowly progressive cognitive decline since the age of 40 years. Clinical investigations, including neuropsychological assessment, brain MRI and 18-fluorodeoxyglucose PET, as well as cerebrospinal fluid biomarkers, supported the diagnosis of EOAD. Genetic studies identified a novel missense mutation at codon 213 (I213S). Three other mutations at the same codon have been described in association with EOAD. Previous in silico, in vitro and in vivo studies indicated that these mutations affect the functional properties of γ-secretase and are most likely pathogenic. In silico algorithms suggested that even the I213S mutation has similar deleterious effects on PSEN1 structure and function. Overall, these data strongly support a role of hotspot site for the codon 213 of PSEN1, and provide evidence that the genetic variants located on this site cause EOAD.

Clinical validation of a combinatorial PharmAcogeNomic approach in major Depressive disorder: an Observational prospective RAndomized, participant and rater-blinded, controlled trial (PANDORA trial)

BackgroundMajor depressive disorder (MDD) is a common, chronic, debilitating mood disorder that causes serious functional impairment and significantly decreased quality of life. Pharmacotherapy represents the first-line treatment option; however, only approximately one third of patients respond to the first treatment because of the ineffectiveness or side effects of antidepressants. Precision medicine in psychiatry might offer clinicians the possibility to tailor treatment according to the best possible evidence of efficacy and tolerability for each subject. In this context, our study aims to carry out a clinical validation of a combinatorial pharmacogenomics (PGx) test in an Italian MDD patient cohort with advocacy license independence.MethodsOur study is a prospective participant- and rater-blinded, randomized, controlled clinical observational trial enrolling 300 MDD patients who are referred to psychiatric services to receive a new antidepressant due to the failure of their current treatment and/or the onset of adverse effects. Eligible participants are randomized to the TGTG group (Treated with Genetic Test Guide) or TAU group (Treated as Usual). For all subjects, DNA is collected with a buccal brush. The primary outcome is the reduction in depressive symptomatology. The secondary outcomes involve a range of scales that assess MDD symptoms and social functioning outcomes. The assessment is performed at four timepoints: baseline and 4, 8, and 12 weeks.DiscussionThis project represents the first randomized controlled clinical trial to investigate whether a non-commercial PGx test improves outcomes in an MDD naturalistic cohort. Moreover, the identification of new genetic variants associated with non-response or side effects will improve the efficacy of the test, leading to further cost-saving.Trial registration numberClinicalTrials.gov NCT04615234. Registered on November 4, 2020.

NEUROD1 mutation in an Italian patient with maturity onset diabetes of the young 6: a case report

BackgroundMaturity Onset Diabetes of the Young (MODY) is a monogenic, autosomal, dominant disease that results in beta-cells dysfunction with consequent hyperglycaemia. It represents a rare form of diabetes (1–2% of all the cases).Sulphonylureas (SUs) represent the first-line treatment for this form of diabetes mellitus.NEUROD1 is expressed by the nervous and the pancreatic tissues, and it is necessary for the proper development of beta cells. A neurogenic differentiation factor 1 (NEUROD1) gene mutation causes beta-cells dysfunction, inadequate insulin secretion, and hyperglycaemia (MODY 6).Case presentationWe have documented a new missense mutation (p.Met114Leu c.340A > C) of the NEUROD1 gene, pathogenetic for diabetes mellitus, in a 48 years-old man affected by diabetes since the age of 25 and treated with insulin basal-bolus therapy. Unfortunately, an attempt to replace rapid insulin with dapagliflozin has failed. However, after the genetic diagnosis of MODY6 and treatment with SUs, he was otherwise able to suspend rapid insulin and close glucose monitoring. Interestingly, our patient had an early onset dilated cardiomyopathy, though no data about cardiac diseases in patients with MODY 6 are available.ConclusionsDiagnostic criteria for MODY can overlap with other kinds of diabetes and most cases of genetic diabetes are still misdiagnosed as diabetes type 1 or 2. We encourage to suspect this disease in patients with a strong family history of diabetes, normal BMI, early-onset, and no autoimmunity. The appropriate therapy simplifies disease management and improves the quality of the patient’s life.

The Primary Failure of Eruption in Orthodontics: knowledge to prevent overtreatment

Aim: The aim of this paper is to report a rare clinical case of Primary Failure of Eruption (PFE) in a young Italian patient. Materials and methods: A 19-year-old patient presented a bilateral posterior dental open bite with lingual interposition during swallowing that was not resolved with a previous four-years orthodontic treatment with fixed appliance. … Continued

Linac-based STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia: a treatment planning study.

To analyze geometrical approaches, prescription modalities, and delivery efficiency for linear accelerator (Linac)-based STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia. The anatomy and planning target volume (PTV) of the first Italian STAR patient were used. To assess geometrical approaches, 3 plans prescribed to 75% isodose-line, differing for number, length of arcs, and couch rotations, were generated and compared (Plans#1-3). Volumetric-arc with 6-MV flattening-filter-free (FFF) was employed. To evaluate prescription modality and delivery, the best geometrical plan was compared with other plans prescribed on 70%, 65%, and 60% isodose-line and with another one using 10MV-FFF beams (Plans#4-7). For Plans#1-3, PTV coverage, mean cardiac dose, monitor units (MUs), and beam-delivery-time (BDT) were 96-98.5%, 4.9-5.2Gy, 7047-7790, and 5-6min, respectively. Plans#4-7 were similar in terms of mean cardiac dose, MUs and BDT to Plans#1-3, except in maximum dose and lower time for 10MV-FFF plan. Linac-based STAR is safe and efficient in terms of BDT and MUs. To ensure high dose to PTV, different dose prescription modalities should be evaluated. The 10FFF approach was the faster but not suitable in patient with cardiac implantable electronic devices.

COVID-19 in Italy: Reloading of Life Standards

For more than a year and a half, the world has been living in the grips of Covid-19, which has had a serious impact on the lifestyle of the people of all countries. From March 2020, the population of most European countries has been forced to revise the existing rules of everyday life and go into a state of siege. This was due to a poor understanding of power and danger of viral infection that most likely came first from China to Europe in the fall of 2019. Italy was one of the first states, which faced all the negative consequences of the pandemia. The first Italian patient was identified in December 2019. The new disease did not cause any particular alarm among doctors, patients, media, and most importantly, the Italian government. As a result in March 2020 Italian medical system, which was not ready for a massive increase of Covid-19 patients, literally collapsed. Article is based on an analysis of the results of the various research, including materials of Rome Institute for Economic and Social Research (Eurispes), forecasts by consulting companies and world statistics. An attempt has been undertaken to show the changes in consumer behavior in Italy and its impact on the daily life of Italians.

Individualized Prophylaxis with BAY 81-8973: Clinical Experience in an Italian Patient with Severe Hemophilia A

Introduction: Prophylaxis with a factor VIII (FVIII) product is the standard of care for patients with severe hemophilia A to prevent bleeding episodes and development of target joints and hemophilic arthropathy. In patients with established joint disease, prophylaxis can slow progression of joint damage, which can improve health-related quality of life. Adherence to prophylaxis is critical to its success. Missing or skipping a prophylaxis infusion can cause FVIII levels to fall below the desired target level, which can increase the risk of breakthrough bleeding episodes. To promote adherence to prophylaxis, healthcare providers and patients must work together to ensure that the prophylaxis regimen is manageable for each patient. In this case report, we describe the strategy we used to improve adherence, including changes to the prophylaxis dosing regimen, in a patient with severe hemophilia A.Demographics and medical history: A 54-year-old patient was diagnosed with severe hemophilia A in early childhood and treated on demand with a plasma-derived FVIII product, despite meeting criteria for use of prophylaxis. In 2000, he began tertiary prophylaxis with a standard-acting recombinant FVIII (rFVIII) product given twice weekly. At that time, he had target joints in both knees and both elbows and a Hemophilia Joint Health Score (HJHS) of 16. In 2007, he underwent surgical replacement of the left knee. In 2010, prophylaxis with a rFVIII was started at 3000 IU (32 IU/kg) 3 times per week. The patient's job as a vendor in outdoor markets affected his ability to adhere to this prophylaxis regimen. To facilitate adherence, prophylaxis dosing was decreased to twice weekly. The patient's comorbidities included obesity and hepatitis C infection, which did not respond to combined treatment with interferon and ribavirin.Current prophylaxis treatment: In 2015, because of weight gain (to 110 kg), joint bleeding episodes (2-3 per year), repeated occurrence of left ankle pain, and further joint deterioration (HJHS score, 25), prophylaxis dosing was increased to 4000 IU (40 IU/kg) 3 times per week. Adherence to this regimen was again difficult for the patient. In March 2017, based on pharmacokinetic results obtained in this patient with BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA; Table 1), he was transitioned to BAY 81-8973 5000 IU (45 IU/kg) twice weekly (every 84 hours, on Monday morning and Wednesday evening). This prophylaxis regimen accommodated his work schedule, and no bleeding episodes occurred after the patient started BAY 81-8973 prophylaxis.Conclusion: This case illustrates that the prophylaxis dose and dosing interval can be individually tailored, keeping in mind the clinical goal of treatment and the patient's bleeding phenotype and daily activities. In this patient, tailored prophylaxis dosing with BAY 81-8973 was key to improved adherence, outcomes, and health-related quality of life. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Identification of the novel HLA-DRB1*03:01:32 in an Italian patient.

The novel HLA-DRB1*03:01:32 allele differs from HLA-DRB1*03:01:01:01 by one nucleotide substitution in exon 4.

A rare mutation of thyroid hormone receptor beta gene in thyroid hormone resistance syndrome.

SummaryResistance to thyroid hormone (RTH) is a rare hereditary syndrome with impaired sensitivity to thyroid hormones (TH) and reduced intracellular action of triiodothyronine (T3) caused by genetic variants of TH receptor beta (TRB) or alpha (TRA). RTH type beta (RTHβ) due to dominant negative variants in the TRB gene usually occurs with persistent elevation of circulating free TH, non-suppressed serum TSH levels responding to a thyrotropin-releasing hormone (TRH) test, an absence of typical symptoms of hyperthyroidism and goiter. Here, we present a rare variant in the TRB gene reported for the first time in an Italian patient with generalized RTHβ syndrome. The patient showed elevated TH, with non-suppressed TSH levels and underwent thyroid surgery two different times for multinodular goiter. The genetic test showed a heterozygous mutation in exon 9 of the TRB gene resulting in the replacement of threonine (ACG) with methionine (ATG) at codon 310 (p.M310T). RTHβ syndrome should be considered in patients with elevated TH, non-suppressed TSH levels and goiter.Learning pointsResistance to thyroid hormone (RTH) is a rare autosomal dominant hereditary syndrome with impaired tissue responsiveness to thyroid hormones (TH).Diagnosis of RTH is usually based on the clinical finding of discrepant thyroid function tests and confirmed by a genetic test.RTH is a rare condition that must be considered for the management of patients with goiter, elevation of TH and non-suppressed serum TSH levels in order to avoid unnecessary treatments.

A Novel Multidrug-Resistant Cell Line from an Italian Intrahepatic Cholangiocarcinoma Patient.

Simple SummaryIntrahepatic cholangiocarcinoma (ICC) has limited prognosis and therapies. The first-line gemcitabine-based therapy provided poor benefits in terms of survival due to the development of resistance. Gemcitabine-resistance mechanisms were studied on pancreatic cancer models or cell lines derived from ICC patients of Eastern countries. Since ICC has different etiology and genetic/molecular characteristics depending on the ethnicity, appropriate preclinical models that recapitulate their biology are required. Thus, we aimed to establish and characterize an Italian ICC cell line, named 82.3. Cells were isolated from a patient-derived xenograft. After one year, immunophenotypical, biological, genetic, molecular features, and in vivo tumorigenicity in NOD/SCID mice were investigated. Furthermore, 82.3 cells displayed resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin. This model could be exploited either to investigate drug resistance mechanisms or to test alternative drugs through the identification of suitable targets to overcome drug resistance.Chemotherapy resistance is a relevant clinical issue in tumor treatment, in particular in biliary tract carcinoma (BTC), for which there are no effective therapies, neither in the first nor in the second line. The development of chemoresistant cell lines as experimental models to investigate the mechanisms of resistance and identify alternative druggable pathways is mandatory. In BTC, in which genetics and biological behavior depend on the etiology, ethnicity, and anatomical site of origin, the creation of models that better recapitulate these characteristics is even more crucial. Here we have established and characterized an intrahepatic cholangiocarcinoma (iCCA) cell line derived from an Italian patient, called 82.3. Cells were isolated from a patient-derived xenograft (PDX) and, after establishment, immunophenotypic, biological, genetic, molecular characteristics, and tumorigenicity in vivo in NOD/SCID mice were investigated. 82.3 cells exhibited epithelial morphology and cell markers (EPCAM, CK7, and CK19); they also expressed different cancer stem markers (CD44, CD133, CD49b, CD24, Stro1, PAX6, FOXA2, OCT3/4), α–fetoprotein and under anchorage-independent and serum-free conditions were capable of originating cholangiospheres. The population doubling time was approximately 53 h. In vitro, they demonstrated a poor ability to migrate; in vivo, 82.3 cells retained their tumorigenicity, with a long latency period (16 weeks). Genetic identity using DNA fingerprinting analysis revealed 16 different loci, and the cell line was characterized by a complex hyperdiploid karyotype. Furthermore, 82.3 cells showed cross-resistance to gemcitabine, 5-fluorouracil, carboplatin, and oxaliplatin; in fact, their genetic profile showed that 60% of genes (n = 168), specific for drug resistance and related to the epithelial-mesenchymal transition, were deregulated in 82.3 cells compared to a control iCCA cell line sensitive to chemotherapeutics. RNA sequencing analysis revealed the enrichment for genes associated with epithelial to mesenchymal transition (EMT), vasculature development, and extracellular matrix (ECM) remodeling, underlining an aggressive phenotype. In conclusion, we have created a new iCCA cell line of Caucasian origin: this could be exploited as a preclinical model to study drug resistance mechanisms and to identify alternative therapies to improve the prognosis of this tumor type.

Hypocalcemia in COVID-19: Prevalence, clinical significance and therapeutic implications.

COVID-19 extra-pulmonary features include several endocrine manifestations and these are becoming strongly clinically relevant in patients affected influencing disease severity and outcomes.At the beginning of COVID-19 pandemic no population data on calcium levels in patients affected were available and in April 2020 a first case of severe acute hypocalcemia in an Italian patient with SARS-CoV-2 infection was reported. Subsequently, several studies reported hypocalcemia as a highly prevalent biochemical abnormality in COVID-19 patients with a marked negative influence on disease severity, biochemical inflammation and thrombotic markers, and mortality. Also a high prevalence of vertebral fractures with worse respiratory impairment in patients affected and a widespread vitamin D deficiency have been frequently observed, suggesting an emerging “Osteo-Metabolic Phenotype” in COVID-19.To date, several potential pathophysiological factors have been hypothesized to play a role in determining hypocalcemia in COVID-19 including calcium dependent viral mechanisms of action, high prevalence of hypovitaminosis D in general population, chronic and acute malnutrition during critical illness and high levels of unbound and unsaturated fatty acids in inflammatory responses.Since hypocalcemia is a frequent biochemical finding in hospitalized COVID-19 patients possibly predicting worse outcomes and leading to acute cardiovascular and neurological complications if severe, it is reasonable to assess, monitor and, if indicated, replace calcium at first patient hospital evaluation and during hospitalization.

Utilization of Healthcare Resources in Osteoarthritis: A Cost of Illness Analysis Based on Real-World Data in Italy.

PurposeUnderstand the demographics and clinical features of patients with osteoarthritis (OA), quantify healthcare resource utilization by OA patients, and estimate the annual direct medical costs per OA patient from a National Health Service (NHS) perspective in Italy.Patients and MethodsRetrospective observational cohort analysis using data from electronic medical records captured by the Italian IQVIA Longitudinal Patient Database (LPD). Only direct medical costs reimbursed by the NHS were considered. Patients were included if they received at least one diagnosis of OA during the period from January 1 to December 31, 2018. Each patient was observed for 3 years: a 24-month baseline period preceding the index date, and a 12-month follow-up period starting at the index date.ResultsA total of 71,467 patients met inclusion criteria: 43.98% had not been prescribed NSAIDs/opioids, 40.76% had been prescribed NSAIDs, and 15.26% an opioid. Mean age was 71.36 years, and 68.2% of the patients were women. At least one comorbidity was present in 91.34% of the patients; 38.05% were newly diagnosed with OA. During 1-year of follow-up, 173,884 prescriptions with an associated diagnosis of OA were found: 47.36% had been prescribed an NSAID, 9.11% diclofenac, 8.30% codeine+paracetamol, and 7.32% ketoprofen. Nearly 15% of the patients had at least 1 request for a specialist visit and 23.82% had at least 1 request for exams. Orthopedic visits accounted for 60% of all specialist visits. Yearly mean costs per patient were €622, for approximately €2.5 billion per year in direct costs, considering 3.9 million patients with OA in Italy. Protheses were a major driver in annual costs: €143.45 in patients without a prosthesis and €10,090.91 in those with a joint prosthesis.ConclusionThis real-world analysis of direct costs of care of patients with OA in Italy confirms the substantial economic burden. Direct costs dramatically increased when joint replacement was needed.

The future of Funds for Innovative Medicines: results from a Delphi Study

Introduction: Dedicated Funds for Innovative Medicines were introduced in 2017 for cancer and non-cancer drugs in Italy. After three years, their impact on patient access to the relevant treatments and critical issues about their management has been poorly investigated.
 Aims and scope. This paper aims at bridging the literature gap and providing possible reforms scenarios.
 Methods: Our analysis relied on a qualitative approach. The personal opinions of twelve Italian experts coming from the Ministry of Economy and Finance, the Scientific Committee of the Italian Medicines Agency, the Regions and Patient Associations, the Oncologists’ Scientific Societies and Hospital Pharmacists were elicited through a Delphi approach. A consensus on final recommendations was reached in two rounds.
 Results: Experts were in favour of maintaining dedicated Funds for Innovative Medicines and had a distinct preference for a single Fund. Most of them suggested to extend access to Funds to more than three years, if, for the relevant indication, there are no alternatives to the innovative drug and provided that this does not represent a barrier to new entries. Responders advocated for Funds being covered by on top resources and the production of more evidence on their impact. They finally claimed a speeder flow of information to the regions on expenditure for innovative treatments and an enhancement of controls on prescribing behaviour, to avoid prescriptions be dependent on Funds capacity.
 Conclusions: The consensus document provides for eight recommendations that could be taken into account for possible reforms and future research on this topic.