Customised pediatric palliative care: Integrating oncological and palliative care priorities.

AIM: To describe the experience involving the early introduction of palliative care (PC) in oncological patients treated within the paediatric oncology unit of the Istituto Nazionale Tumori of Milan and compare this cohort with a cohort of patients resident in the same area treated before the introduction of early palliative care. METHODS: A virtual team was assembled in 2015. The PC providers operate outside the hospital. Conference calls were scheduled to discuss patients' problems. This sample was compared with the clinical records of patients residing in the same area who died between 2009 and 2014. RESULTS: Between January 2015 and April 2019, 41 patients residing in the Milan area mainly with CNS tumours or sarcomas were referred to the team. Comparing the results with the previous cohort, there was a rise in the number of patients dying at home or in a hospice and the duration of PC increased over time. From 2015, none of the patients died in an intensive care unit. CONCLUSION: Patients managed by the virtual team were able to continue their cancer treatments, take part in Phase I trials and receive PC. All patients with a poor prognosis should have PC at an early stage.

A novel glucuronoxylan hydrolase produced by fermentation is safe as feed additive: toxicology and tolerance in broiler chickens.

The current study presents a safety evaluation of a novel glucuronoxylan hydrolase (EC 3.2.1.136) from Bacillus subtilis produced in Bacillus licheniformis. The glucuronoxylan hydrolase preparation did not exhibit irritative potential to the eye and skin when applied in in vitro models. The glucuronoxylan hydrolase preparation was non-mutagenic and non-clastogenic in in vitro tests. Oral administration of the glucuronoxylan hydrolase preparation to rats did not cause any adverse effect in a 90-days subchronic toxicity study. A tolerance study was performed with broiler chickens and confirmed that this glucuronoxylan hydrolase is safe for broiler chickens when fed at the maximum recommended dose, as well as at the 10 times higher dose. In conclusion, there are no safety concerns with using this novel glucuronoxylan hydrolase as a feed additive as it is toxicologically inert and the glucuronoxylan hydrolase is well tolerated by broiler chickens. The beneficial safety evaluation of glucuronoxylan hydrolase is consistent with the fact that this type of enzyme is ubiquitous in nature.

Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion.

Ponatinib (Iclusig, ARIAD Pharmaceuticals-Incyte Co.) is a third-generation structure-guided tyrosine kinase inhibitor that is approved for treatment of Philadelphia chromosome-positive leukaemias resistant or intolerant to other inhibitors. The clinical use of ponatinib is complicated by the possible development of cardiovascular events, primarily hypertension and arterial or venous thrombotic events. The US Food and Drug Administration and the European Medicine Agency recommend that the cardiovascular profile of patients candidate for ponatinib should be carefully evaluated. For patients deemed to carry a high risk of cardiovascular events, other life-saving therapeutic options should be considered. When alternative options are not available, treatment with ponatinib is indicated but requires that haematologists and cardiologists collaborate and identify modalities of surveillance and risk mitigation in the best interest of the patient. This article reports on the expert opinion provided by a panel of Italian haematologists, cardiologists and clinical pharmacologists. It summarises suggestions that may help to improve the therapeutic index of ponatinib, primarily in the settings of chronic-phase chronic myeloid leukaemia.

Association between molecular lesions and specific B-cell receptor subsets in chronic lymphocytic leukemia.

Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome.

Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis.

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant.

Bendamustine salvage therapy for T cell neoplasms.

Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms.

Cancer-related fatigue in Italian cancer patients: validation of the Italian version of the Brief Fatigue Inventory (BFI).

PURPOSE: Cancer-related fatigue (CRF) is one of the most common symptoms experienced by cancer patients (CPs). The Brief Fatigue Inventory (BFI) is a reliable instrument to assess CRF in CPs. The aim of this study was to evaluate the psychometric properties of the Italian version of the BFI (BFI-I). METHODS: The BFI-I was developed by using the forward-backward translation approach. The psychometric properties of the BFI-I were assessed in terms of acceptability, internal consistency, and validity. Outpatient CPs filled in BFI-I along with the Medical Outcome Study Quality of Life Short Form 36 (SF36). Demographic and health data were collected. RESULTS: The BFI-I had an overall Cronbach alpha for the nine items of 0.94. The inter-item mean correlation was 0.64, and coefficients ranged from 0.47 to 0.81 for the nine items. The results of the factor analysis suggested a 1-factor solution explaining 68 % of the variance, supporting the hypothesis of unidimensionality of the BFI-I. The BFI-I score was compared to SF36 subscales score to evaluate concurrent validity. An expected inverse correlation between the BFI-I and the vitality subscale of the SF36 was observed (r = -0.67, 95 % confidence interval -0.73 to -0.59). The correlation with the other subscales of the SF36 ranged between -0.56 and -0.13. Discriminant validity analysis showed the BFI-I mean score significantly increased with increasing Eastern Cooperative Oncology Group values (p < 0.001). CONCLUSIONS: BFI-I is a clinical instrument with satisfactory psychometric properties to assess CRF in Italian CPs.

Relative age effects and the youth-to-senior transition in Italian soccer: the underdog hypothesis versus knock-on effects of relative age.

Relative Age Effects (RAEs) appear largely throughout youth soccer. However, little is known about how RAEs at youth levels can impact transition at senior levels. Accordingly, this study aimed to: (a) provide further test of RAEs by exploring the birth quarter (BQ) distribution of 2,030 Italian players born from 1975 to 2001 who have played in any of the Youth National Italian Soccer Teams; and (b) investigate how RAEs influence future career outcomes, by exploring the BQ distribution of players who completed the transition from youth squads to the Senior National Team (n = 182). Chi-square statistics revealed significantly skewed BQ distributions for all Youth squads (P values <0.0001), and for the cohort of players who completed the transition (P = 0.003). In contrast, results from the Odds Ratios highlighted how BQ4s were more likely to transition from youth-to-senior compared to BQ1s. Results showed BQ1s remained overrepresented at senior level due to a residual bias effect. Whereas BQ4s who were able to overcome selection processes at youth levels recorded the highest likelihood of competing at senior levels. Involving players' career trajectories in RAEs studies is needed to understand how RAEs impacts career outcomes of early selected players.

Relative age effect in Italian soccer: a cultural issue in talent management?

BACKGROUND: Relative age effect (RAE) is a well-known phenomenon among those involved in youth sports, especially when the sport being investigated is widespread and involves early selection for participation in national and international competitions. METHODS: The purpose of this study was to verify whether the Italian youth soccer ecosystem has adapted to this issue over the years, comparing players born in 1995 and in 2005 and been playing in Under 16 teams in the appropriate years. The sample included 13 professional Italian soccer teams. The number of players analysed was 260 (1995) and 344 boys (2005), respectively, making a total of 604 players enrolled in this study. RESULTS: Relative age effects were detected by χ2 goodness of fit tests both in players born in 1995 (P<0.000;V=0.40) and in 2005 (P<0.0001;V=0.39). χ2 test of independence showed no significant difference between the two groups of players (P=0.986;V=0.02), confirming a substantial parity of the phenomenon over the two investigated birth years. CONCLUSIONS: Ten years of research and dissemination of RAE did not change the selection policies adopted by coaches and/or scouts, who favor relatively older players during the selection processes. Therefore, RAE appears as the result of the Talent Identification and Development Structures, characterized by early selection and early specialization, and which consider performance as the pre-requisite for gaining access to the next developmental stages. Sport organizations should be aware of this issue and counteract accordingly, since it is important to mitigate the presence of RAE, as it causes inequality of opportunity.

Effects of the New COVID-19-Induced Rule on Substitutions and Performance in Italian Elite Soccer.

COVID-19 has resulted in widespread changes, including within the realm of sports. Professional soccer has adapted by allowing more substitutions, leading to tactical adjustments and potential physical benefits. Accordingly, this study analyzed the impact of the new rule in Italian top-level soccer, focusing on substitution patterns and performance differences between the pre-COVID (2017-2018, 2018-2019 seasons) and post COVID (2020-2021, 2021-2022 seasons) eras. As such, publicly available data from 1520 matches (760 matches per era) were recorded. The sample included matches played from 40 Italian top division teams in both the pre- and post-COVID eras. Analyses confirmed substitutions follow a consistent temporal pattern throughout the match in both eras, highlighting a slight difference in second-half management, and showed the new rule is still not used to its full potential, thus raising concerns about teams' financial strength, as not all managers possess "deep benches" (i.e., a large number of top-level players available to play). Further analyses revealed a statistically significant increment (p = 0.002) in the quantity of collectively produced sprints in the post-COVID era compared to the pre-COVID one. The results from this study emphasize the need to carefully address sprint preparation and repeated sprint abilities, also considering factors such as the number of substitutes and their skill level.

Temporal patterns of fatigue in repeated sprint ability testing in soccer players and acute effects of different IHRs: a comparison between genders.

BACKGROUND: Repeated sprint ability (RSA) in soccer is deemed fundamental to ensure high level of performance. The aim of this study was to investigate the acute effects of two different Initial Heart Rates (IHR) on fatigue when testing RSA in males and females' soccer players and to compare the respective patterns of fatigue. METHODS: Nineteen female soccer players (age: 22.5±3.3 years, height 163.9±7.3 cm, body weight 54.3±6.4 kg, BMI 20.6±1.5 kg·m-2) and 15 male soccer players (age: 17.9±1.5 years, height 175.9±5.8 cm, body weight 68.5±9.6 kg, BMI 22.3±1.5 kg·m-2) participated in this study. HRs reached at the end of two different warm-up protocols (~90 vs. ~ 60% HRmax), have been selected and the respective RSA performances were compared, within and between the groups of participants. Two sets of ten shuttle-sprints (15+15 m) with a 1:3 exercise to rest ratio with different IHR% were administered, in different days, in randomized order. To compare the different sprint performances, we employed the calculated Fatigue Index (FI%). Blood lactate concentration (BLa-) was also measured before and after testing, to compare metabolic energy. RESULTS: Significant differences among trials within each set (P<0.01) were found in both genders. Differences between sets were found in male players, (Factorial ANOVA 2x5; P<0.001), not in female. BLa- after warm-up was higher in 90% vs. 60% HRmax (P<0.05), in both genders but at the completion of RSA tests (after 3 minutes) the differences were not significant (P>0.05). CONCLUSIONS: difference between genders were found, suggesting specific approach in testing and training RSA in soccer players.

High pressure treatment of brine enhanced pork affects endopeptidase activity, protein solubility, and peptide formation.

In order to study the effect of high-pressure (HP) treatment and two different methods of brine addition (important for lysosomal membrane destabilisation) on lysosomal enzymes activity and protein degradation, pork semitendinosus muscle was brine enhanced by injection or tumbling, and HP treated at 600 MPa following storage at 2 °C for up to 8 weeks. In this report a novel protocol for SDS gelatin zymography was established, and an increase of cathepsin B and L activity after HP treatment was shown followed by a decrease during storage. No calpain activity was detected following HP treatment. HP treatment was shown to induce a decrease in protein solubility in both myofibrillar and sarcoplasmic fractions. LC-MS analysis of these fractions showed changes in the peptide pattern during storage. Western blot analysis showed that troponin-T was indeed degraded during storage after HP treatment. The results therefore suggest that HP treatment induced an increase in cathepsin activity, which subsequently affected the myofibrillar protein degradation pattern in pork meat.

Regulation of podosome dynamics by WASp phosphorylation: implication in matrix degradation and chemotaxis in macrophages.

Podosomes, adhesion structures capable of matrix degradation, have been linked with the ability of cells to perform chemotaxis and invade tissues. Wiskott-Aldrich Syndrome protein (WASp), an effector of the RhoGTPase Cdc42 and a Src family kinase substrate, regulates macrophage podosome formation. In this study, we demonstrate that WASp is active in podosomes by using TIRF-FRET microscopy. Pharmacological and RNA interference approaches suggested that continuous WASp activity is required for podosome formation and function. Rescue experiments using point mutations demonstrate an absolute requirement for Cdc42 binding to WASp in podosome formation. Although tyrosine phosphorylation was not absolutely required for podosome formation, phosphorylation did regulate the rate of podosome nucleation and actin filament stability. Importantly, WASp tyrosine phosphorylation does not alter WASp activation, instead phosphorylation appears to be important for the restriction of WASp activity to podosomes. In addition, the matrix-degrading ability of cells requires WASp phosphorylation. Chemotactic responses to CSF-1 were also attenuated in the absence of endogenous WASp, which could not be rescued with either tyrosine mutation. These results suggest a more complex role for tyrosine phosphorylation than simply in the regulation of WASp activity, and suggest a link between podosome dynamics and macrophage migration.

Mechanical stimuli on C2C12 myoblasts affect myoblast differentiation, focal adhesion kinase phosphorylation and galectin-1 expression: a proteomic approach.

Mechanical forces are crucial in the regulation of cell morphology and function. At the cellular level, these forces influence myoblast differentiation and fusion. In this study, we applied mechanical stimuli to embryonic muscle cells using magnetic microbeads, a method shown to apply stress to specific receptors on the cell surface. We showed that mechanical stimuli promote an increase in FAK (focal adhesion kinase) phosphorylation. In order to further shed light in the process of myoblast-induced differentiation by mechanical stimuli, we performed a proteomic analysis. Thirteen proteins were found to be affected by mechanical stimulation including galectin-1, annexin III and RhoGDI (Rho guanine-nucleotide-dissociation inhibitor). In this study, we demonstrate how the combination of this method of mechanical stimuli and proteomic analysis can be a powerful tool to detect proteins that are potentially interacting in biochemical pathways or complex cellular mechanisms during the process of myoblast differentiation. We determined an increase in expression and changes in cellular localization of galectin-1 in mechanically stimulated myoblasts. A potential involvement of galectin-1 in myoblast differentiation is presented.

Evidence for post-mortem m-calpain autolysis in porcine muscle.

The objective of the present work was to characterize changes in calpain activity in pork post-mortem. Samples from pig M. longissimus dorsi and M. semimembranosus were collected three days post-mortem from 75 animals and analyzed with casein zymography. The results indicated post-mortem autolysis of m-calpain as two m-calpain bands were observed on the zymogram gel. Use of M. longissimus dorsi from three pigs collected at different times during storage further confirmed post-mortem autolysis of m-calpain. The activity of the autolyzed form of m-calpain was detectable at day 3 and further increased at day 6. The results also showed a decrease in the non-autolyzed m-calpain activity during post-mortem storage. Collectively, these results suggest that m-calpain is active post-mortem in porcine muscles.

Term Amniotic membrane is a high throughput source for multipotent Mesenchymal Stem Cells with the ability to differentiate into endothelial cells in vitro.

BACKGROUND: Term Amniotic membrane (AM) is a very attractive source of Mesenchymal Stem Cells (MSCs) due to the fact that this fetal tissue is usually discarded without ethical conflicts, leading to high efficiency in MSC recovery with no intrusive procedures. Here we confirmed that term AM, as previously reported in the literature, is an abundant source of hMSCs; in particular we further investigated the AM differentiation potential by assessing whether these cells may also be committed to the angiogenic fate. In agreement with the recommendation of the International Society for Cellular Therapy, the mesenchymal cells herein investigated were named Amniotic Membrane-human Mesenchymal Stromal Cells (AM-hMSC). RESULTS: The recovery of hMSCs and their in vitro expansion potential were greater in amniotic membrane than in bone marrow stroma. At flow cytometry analysis AM-hMSCs showed an immunophenotypical profile, i.e., positive for CD105, CD73, CD29, CD44, CD166 and negative for CD14, CD34, CD45, consistent with that reported for bone marrow-derived MSCs. In addition, amniotic membrane-isolated cells underwent in vitro osteogenic (von Kossa stain), adipogenic (Oil Red-O stain), chondrogenic (collagen type II immunohistochemichal detection) and myogenic (RT-PCR MyoD and Myogenin expression as well as desmin immunohistochemical detection) differentiation. In angiogenic experiments, a spontaneous differentiation into endothelial cells was detected by in vitro matrigel assay and this behaviour has been enhanced through Vascular Endothelial Growth Factor (VEGF) induction. According to these findings, VEGF receptor 1 and 2 (FLT-1 and KDR) were basally expressed in AM-hMSCs and the expression of endothelial-specific markers like FLT-1 KDR, ICAM-1 increased after exposure to VEGF together with the occurrence of CD34 and von Willebrand Factor positive cells. CONCLUSION: The current study suggests that AM-hMSCs may emerge as a remarkable tool for the cell therapy of multiple diseased tissues. AM-hMSCs may potentially assist both bone and cartilage repair, nevertheless, due to their angiogenic potential, they may also pave the way for novel approaches in the development of tissue-engineered vascular grafts which are useful when vascularization of ischemic tissues is required.

Mechanical stimulation increases proliferation, differentiation and protein expression in culture: stimulation effects are substrate dependent.

Myogenesis is a complex sequence of events, including the irreversible transition from the proliferation-competent myoblast stage into fused, multinucleated myotubes. Myogenic differentiation is regulated by positive and negative signals from surrounding tissues. Stimulation due to stretch- or load-induced signaling is now beginning to be understood as a factor which affects various signal transduction pathways, gene sequences and protein synthesis. One indication of which cells are competent to undergo the fusion process is their expression of two proteins, Myo-D and myogenin. The mechanism by which the cells are able to to regulate Myo-D and myogenin is poorly understood. In the present work, we investigate the role of mechanical loading, through specific receptors to intracellular matrix proteins such as laminin and fibronectin, in both Myo-D and myogenin expression in C(2)C(12) cells. We propose to elucidate also the signaling pathway by which this mechanical stimulation can causes an increase in protein expression. When mechanically stimulated via laminin receptors on cell surface, C(2)C(12) cells showed an increase in cell proliferation and differentiation. Populations undergoing mechanical stimulation through laminin receptors show an increase in expression of Myo-D, myogenin and an increase in ERK1/2 phosphorylation. Cells stimulated via fibronectin receptors show no significant increases in fusion competence. We conclude that load induced signalling through integrin containing laminin recepotors plays a role in myoblast differentiation and fusion.

Multidrug reverting activity toward leukemia cells in a group of new verapamil analogues with low cardiovascular activity.

The development of refractory disease is often associated with the overexpression of multidrug resistance (MDR) proteins, especially in several hematological malignancies, such as acute myeloid leukemias (AML), multiple myeloma (MM) and non-Hodgkin's lymphomas (NHL). Since the recognition of these proteins, several attempts have been made to modulate their expression and activity (protein kinase C inhibitors, anti-MDR-1 oligonucleotides, pharmacological competitors and transcriptional inhibitors). Six new compounds (MM 36, CTS 4, CTS 9, CTS 12, CTS 27 and CTS 41), derived from verapamil (VRP), were designed and synthesized to improve their MDR-reverting activity and reduce cardiovascular effects. Cytotoxicity (WST-1 methods) and functional (calcein-acetoxymethyl (Calcein-AM)) assays were performed on a resistant cell line K-562/doxR and on the mononuclear cells (MNCs) of patients with AML. Furthermore, the six molecules were tested for their vasodilator, inotropic and chronotropic activity on guinea pig aortic strip and isolated atrium preparations, respectively. Comparison between survival plots and relative ID50, obtained from the K-562/doxR cells treated with Idarubicin (IDA), in the presence or absence of inhibitors, showed that these compounds function well. All the resistance modifying agents potentiated IDA activity inducing a significant reduction (P<0.01) in ID(50) values in comparison to VRP at each of the concentrations tested, but MM 36, CTS 27 and CTS 41 demonstrated the strongest activity. Results obtained from the MNCs were superimposible to K-562/doxR. Further studies on pump functional analysis confirmed the cytotoxic test results: MM 36, CTS 27 and CTS 41 showed a striking inhibition of P-glycoprotein (Pgp) efflux in K-562/doxR and MNCs. Cardiovascular activity of MM 36, CTS 27 and CTS 41, that are the most interesting compounds as MDR inhibitors, followed this course: MM 36>CTS 27>CTS 41, the last one presenting no cardiovascular activity. Chemosensivity to IDA in K-562/doxR cells and AML blasts could be enhanced in vitro by the adjuvant use of the six new VRP analogues. Compared to VRP, all the new compounds presented good MDR-reverting- and reduced cardiovascular activities along with no vasorelaxant effects. The particularly favourable results in some cases (MM 36, CTS 27 and CTS 41) suggests that anti-MDR activity should be further evaluated in clinical trials in patients with myeloid malignancies.

The effect of high pressure on the functional properties of pork myofibrillar proteins.

Complementary methodologies were used to analyse the pressure-induced modification and functionality of myofibrillar proteins from pork meat pressurised at 200, 400, 600, or 800 MPa (10 min, 5 or 20 °C). Pressure at 400 MPa was found to be the threshold for loss of solubility, and the structural proteins, myosin and actin, lost their native solubility due to aggregation. The results from the extraction of proteins with different reagents targeting the disruption of specific molecular interactions suggested that pressure-induced aggregation was caused mainly by hydrogen bonding during pressurisation and not hydrophobic interactions nor disulphide cross-links. Furthermore, the soluble proteins were exposed to remarkable structural changes already at 200 MPa and lost their native functionality. The modification of the proteins in pressurised meat affected the water binding sites of the myofibrillar proteins and, thereby, the interactions between proteins and water molecules, and distribution between myofibrillar and extra-myofibrillar compartments.

Management of homozygous familial hypercholesterolemia in real-world clinical practice: A report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis.

BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, genetically determined condition of highly elevated low-density lipoprotein cholesterol (LDLC) levels. If untreated, patients do not typically survive beyond the second decade of life. Traditional lipid-lowering therapies (statins and ezetimibe) are largely ineffective in HoFH patients, and extracorporeal lipoprotein apheresis (LA) forms the mainstay of treatment. Lomitapide is a microsomal triglyceride transfer protein inhibitor approved for the treatment of HoFH as an adjunct to LA. We undertook to examine the efficacy and safety of lomitapide in 7 HoFH patients treated with LA in the Lipid Clinic and Therapeutic Apheresis Unit in Rome, Italy outside a clinical trial setting. METHODS: Seven patients with genetically determined HoFH were treated with lomitapide in the normal course of their therapy. All patients received LA either weekly or biweekly. Lomitapide was administered according to the approved European Union prescribing information. LDLC levels, liver enzymes, and hepatic fat were monitored. Length of follow-up varied between 12 and 50 weeks. RESULTS: After titration, lomitapide doses ranged from 10 to 30 mg/d for most (5/7) patients. One patient received lomitapide 60 mg/d and another 5 mg/d. Three patients achieved LDLC reductions of >50%. The patient on the lowest lomitapide dose did not gain significant benefit. Gastrointestinal adverse events (AEs) were managed via alterations to dietary fat intake. CONCLUSION: Lomitapide is an effective adjunct to LA in patients with HoFH. AEs are manageable; gastrointestinal AEs can be managed with a low-fat eating plan.