RESUMEN
Epilepsy is a central nervous system (CNS) disorder causing repeated seizures due to a transient excessive or synchronous alteration in the electrical activity of the brain. Several neurological disorders have been associated to gluten-related diseases (GRD), including epilepsy. However, the molecular mechanisms that associate GRD and epileptogenesis are still unknown. Our previous data have shown that the gliadin peptide 31-43 (p31-43) enhanced number and duration of seizures induced by kainate in mice and exacerbated CA3-kainate-induced neurotoxicity in organotypic hippocampal slices. Here, we investigated whether another important gliadin peptide p57-68 may exerts effects similar to p31-43 on kainate-induced neurotoxicity. We find that both peptides exacerbate kainate-induced damage in the CA3 region once simultaneously challenged. However, after pre-incubation, p31-43 additionally exacerbates neurotoxicity in the CA1 region, while p57-68 does not. These data suggested differential intracellular mechanisms activated by the peptides. Indeed, analysing intracellular signalling pathways we discover that p31-43 induces significant intracellular changes, including increased phosphorylation of Akt, Erk1/2, and p65, decreased p38 phosphorylation, and deacetylation of nuclear histone-3. Based on these observations, we demonstrate that p31-43 likely activates specific intracellular signaling pathways involved in neuronal excitability, inflammation, and epigenetic regulation, which may contribute to its exacerbation of kainate-induced neurotoxicity. In contrast, p57-68 appears to exert its effects through different mechanisms. Further research is necessary to elucidate the precise mechanisms by which these peptides influence neurotoxicity and understand their implications for neurological disorders.
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Epilepsia , Gliadina , Animales , Epilepsia/metabolismo , Epilepsia/inducido químicamente , Gliadina/toxicidad , Gliadina/metabolismo , Fragmentos de Péptidos/toxicidad , Fragmentos de Péptidos/metabolismo , Ácido Kaínico/toxicidad , Ratones , Hipocampo/metabolismo , Hipocampo/efectos de los fármacosRESUMEN
BACKGROUND: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24âGy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.
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Linfoma Folicular , Neoplasia Residual , Humanos , Linfoma Folicular/radioterapia , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/terapia , Linfoma Folicular/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Adulto , Inmunoterapia/métodos , Estadificación de Neoplasias , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano de 80 o más AñosRESUMEN
Data about biosimilar Peg-filgrastim (bioPEG) in autologous stem cell transplant (ASCT) are still scarce. The aim of this study has been to assess efficacy and safety of bioPEG among lymphoma and myeloma patients undergoing ASCT, comparing these data with historical controls receiving other G-CSFs. Furthermore, an economic evaluation has been included to estimate the savings by using bioPEG. This is a prospective cohort study comparing lymphoma and myeloma patients undergoing ASCT and receiving bioPEG (n = 73) with three historical consecutive cohorts collected retrospectively who received other G-CSFs (Lenograstim - Leno - n = 101, biosimilar Filgrastim - bioFIL n = 392, and originator Peg-filgrastim - oriPEG n = 60). We observed a significantly shorter time to neutrophils and platelet engraftment (p < 0.001) in patients treated with bioPEG and oriPEG. Moreover, patients who received bioPEG showed a shorter hospitalization time (p < 0.001) and a lower transfusion need (p < 0.001). We did not observe any significant difference in terms of transplant-related mortality, mucositis, and diarrhea among the four groups. No serious adverse events were associated with bioPEG. Similar data were obtained after running a stratified analysis for lymphomas and myeloma separately conducted by using a propensity score matching. The average total cost per patient of bioPEG was 18218.9 compared to 23707.8, 20677.3 and 19754.9 of Leno, oriPEG, and bioFIL, respectively. In conclusion, bioPEG seems to be as effective as the originator and more effective than short-acting G-CSFs in terms of post-transplant engraftment in myeloma and lymphoma patients undergoing ASCT. Moreover, bioPEG was cost-effective when compared with the other G-CSFs.
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Biosimilares Farmacéuticos , Linfoma , Mieloma Múltiple , Humanos , Filgrastim/efectos adversos , Lenograstim , Mieloma Múltiple/tratamiento farmacológico , Biosimilares Farmacéuticos/efectos adversos , Estudios Retrospectivos , Estudios Prospectivos , Linfoma/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos , Trasplante de Células Madre , Proteínas Recombinantes , Movilización de Célula Madre HematopoyéticaRESUMEN
[This corrects the article DOI: 10.3389/fmicb.2022.886008.].
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BACKGROUND: Patients with relapsed or refractory classical Hodgkin lymphoma (R/R cHL) have limited opportunities for curative therapy. High-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) produces cure rates of 50% to 60%. Patients relapsing after, or ineligible for HDT-ASCT have limited therapeutic options and long-term remission is uncommon. Furthermore, few patients are candidate to allogeneic stem cell transplantation (AlSCT), a potentially curative approach. The combination of brentuximab vedotin and bendamustine (BVB) is a promising treatment for patients with R/R cHL, regardless of SCT eligibility. PATIENTS AND METHODS: We conducted a real-life study of BVB in 41 patients with R/R cHL after failure of ≥ 1 therapy including ASCT, AlSCT, or BV. RESULTS: Among 40 patients evaluable for efficacy, the overall response rate and complete response (CR) rate were 75% and 50%, respectively. No significant differences were observed between patients with primary refractory and relapsed disease, previously treated with ≤ 2 and ≥ 3 lines of therapy, or BV-exposed and BV-naïve. After a median follow-up of 38 months, the median progression free survival (PFS) for the entire population is 26 months; PFS is not reached, 10.5 months, and 4 months for patients achieving CR, partial response and no response, respectively (P < .0001). BVB was well tolerated and no grade 4 toxicity or new safety signals were observed. The most common treatment-emergent adverse events were infections. CONCLUSION: Our experience supports the efficacy and tolerability of the BVB combination in R/R cHL as a bridge to SCT, or as a definitive therapy for SCT-ineligible patients. Larger comparative studies testing BVB against standards of care are warranted in both settings.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Inmunoconjugados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina , Brentuximab Vedotina , Enfermedad de Hodgkin/patología , Humanos , Inmunoconjugados/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Trasplante Autólogo , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales , Antígenos CD20 , Vacuna BNT162 , COVID-19 , Linfoma de Células B , Linfoma no Hodgkin , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD20/inmunología , Vacuna BNT162/administración & dosificación , COVID-19/inmunología , COVID-19/prevención & control , Estudios de Seguimiento , Linfoma de Células B/sangre , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/virología , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/virología , PronósticoRESUMEN
The reason why only few coeliac patients develop the cutaneous manifestation of the disease, named dermatitis herpetiformis (DH), is still unknown. Epidermal transglutaminase (TG3) has been described as the main autoantigen of humoral immunity in DH but the mechanisms leading to this autoimmune response remain obscure. Here we characterized T cells from skin, gut and peripheral blood of DH and coeliac disease (CD) patients, evaluated the impact of the gluten-free diet on circulating T lymphocytes' phenotype and investigated antigen specific T cell response toward epidermal and tissue transglutaminase (TG2). DH patients showed an increased frequency of skin-derived T cells producing TNFα when compared to CD patients. Moreover, circulating T cells producing TNFα and IL-17A positively correlated with clinical score of skin disease activity and decreased after gluten-free diet. Finally, TG2 and TG3-specific T cells resulted more reactive to antigens stimulation in DH patients and showed cross reactivity toward the two autoantigens in both the group of patients. Our data suggest a role of TNFα and IL-17A producing cells in the development of DH and, for the first time, show the existence of a crossed T cell response toward the two transglutaminases isoforms, thus suggesting new insights on T cells role in skin damage.
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Enfermedad Celíaca/inmunología , Dermatitis Herpetiforme/inmunología , Proteínas de Unión al GTP/inmunología , Linfocitos T/inmunología , Transglutaminasas/inmunología , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Interleucina-17/inmunología , Masculino , Persona de Mediana Edad , Proteína Glutamina Gamma Glutamiltransferasa 2 , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Altered circulating levels of free fatty acids (FFAs), namely short chain fatty acids (SCFAs), medium chain fatty acids (MCFAs), and long chain fatty acids (LCFAs), are associated with metabolic, gastrointestinal, and malignant diseases. Hence, we compared the serum FFA profile of patients with celiac disease (CD), adenomatous polyposis (AP), and colorectal cancer (CRC) to healthy controls (HC). We enrolled 44 patients (19 CRC, 9 AP, 16 CD) and 16 HC. We performed a quantitative FFA evaluation with the gas chromatography-mass spectrometry method (GC-MS), and we performed Dirichlet-multinomial regression in order to highlight disease-specific FFA signature. HC showed a different composition of FFAs than CRC, AP, and CD patients. Furthermore, the partial least squares discriminant analysis (PLS-DA) confirmed perfect overlap between the CRC and AP patients and separation of HC from the diseased groups. The Dirichlet-multinomial regression identified only strong positive association between CD and butyric acid. Moreover, CD patients showed significant interactions with age, BMI, and gender. In addition, among patients with the same age and BMI, being male compared to being female implies a decrease of the CD effect on the (log) prevalence of butyric acid in FFA composition. Our data support GC-MS as a suitable method for the concurrent analysis of circulating SCFAs, MCFAs, and LCFAs in different gastrointestinal diseases. Furthermore, and notably, we suggest for the first time that butyric acid could represent a potential biomarker for CD screening.
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Poliposis Adenomatosa del Colon/sangre , Ácido Butírico/sangre , Enfermedad Celíaca/sangre , Neoplasias Colorrectales/sangre , Ácidos Grasos no Esterificados/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Factores SexualesRESUMEN
Granular deposits of IgA represent the specific cutaneous marker of dermatitis herpetiformis. The prevalence of IgA deposits in the skin of patients with coeliac disease without dermatitis herpetiformis remains unknown. In this prospective case-control study, skin biopsies from newly diagnosed coeliac patients without dermatitis herpetiformis were analysed by direct immunofluorescence. Controls included healthy volunteers and patients with both bowel symptoms and skin eruptions unrelated to coeliac disease. Clinical data and serum level of anti-tissue transglutaminase and anti-epidermal transglutaminase IgA antibodies were collected from patients and controls. Granular deposits of IgA or IgA1 in the skin were found in 29 out of 45 patients with coeliac disease (64.4%), and in none of the included controls (specificity 100%; sensitivity 64.4%). Positive direct immunofluorescence correlated significantly with an increased serum level of anti-epidermal transglutaminase IgA antibodies (p < 0.005). This study shows that granular deposits of IgA represent a low sensitive, but highly specific, cutaneous marker of coeliac disease independent of dermatitis herpetiformis.
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Enfermedad Celíaca , Dermatitis Herpetiforme , Estudios de Casos y Controles , Enfermedad Celíaca/diagnóstico , Dermatitis Herpetiforme/diagnóstico , Humanos , Inmunoglobulina A , Estudios ProspectivosRESUMEN
Previous studies investigated the efficacy and the safety of bendamustine (B) vs. chlorambucil (Chl) associated with rituximab (R) in fludarabine-ineligible patients with treated and untreated chronic lymphocytic leukemia (CLL). We conducted a retrospective multicenter study in the Lazio region to further evaluate and compare the efficacy and the toxicity of Chl-R and B-R regimen in CLL patients over the age of 65. We enrolled 192 untreated CLL patients: 111 treated with B-R and 81 with Chl-R. The overall response rates (ORR; 93.6% in B-R and 86.5% in Chl-R) were not statistically different between the two groups, such as progression-free survival (PFS), time to retreatment (TTR), and overall survival (OS). The B-R group showed a higher hematological (p = 0.007) and extra-hematological (p = 0.008) toxicity. When comparing the toxicities according to age, we noted that the extra-hematological toxicity was higher in patients over the age of 75 who were treated with B-R than those treated with Chl-R (p = 0.03). This retrospective study confirms the feasibility of B-R and Chl-R in elderly untreated CLL patients. Currently, patients who are over 75 and unfit are usually treated with Chl-R. This scheme allows achieving the same ORR, PFS, TTR, and OS when compared with B-R because of hematological and extra-hematological toxicities due to B, in which a greater dose reduction has been shown in comparison to Chl.
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OBJECTIVE: To describe a population of patients referred for fertility preservation (FP), how to efficiently provide FP care, and how FP care changed over time. METHODS: This longitudinal observational study enrolled 281 female cancer patients referred between 2013 and 2016 to the non-profit organisation Gemme Dormienti ONLUS (GD) for FP care. All patients underwent the same battery of instrumental and laboratory diagnostic tests. GnRHa therapy was started at least seven days before CTh treatment. RESULTS: From 2013 to 2016, we observed a progressive increase in the number of patients referred for FP care. Out of 251 eligible patients, 135 patients were treated with GnRHa only, and 72 patients underwent GnRHa therapy and cryopreservation. The median time from GD referral to oocyte and ovarian tissue cryopreservation was 11 and 5 days respectively. Tissue cryopreservation requests increased during our study period (from four cases in 2013 to 17 cases in 2016). During follow-up, 17ß-estradiol and FSH levels were significantly increased (p < .0001), and AMH levels were significantly decreased (p < .0001). CONCLUSION: The rapid increase in the number of patients who requested FP care and in the complexity of FP procedures overtime reflects the need to improve quality of life for cancer patients.
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Antineoplásicos/efectos adversos , Preservación de la Fertilidad/métodos , Hormona Liberadora de Gonadotropina/agonistas , Infertilidad Femenina/prevención & control , Insuficiencia Ovárica Primaria/prevención & control , Adolescente , Adulto , Hormona Antimülleriana/sangre , Consejo , Criopreservación , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Infertilidad Femenina/inducido químicamente , Estudios Longitudinales , Hormona Luteinizante/sangre , Recuperación del Oocito , Oocitos , Folículo Ovárico , Reserva Ovárica , Ovario , Inducción de la Ovulación , Prioridad del Paciente , Insuficiencia Ovárica Primaria/inducido químicamente , Progesterona/sangre , Derivación y Consulta , Adulto JovenRESUMEN
Background and Aims: In cancer patients, a common complication during chemotherapy is chemotherapy-induced peripheral neuropathy (CIPN). For this reason, we decided to conduct a phase II prospective study on 33 patients with multiple myeloma at first diagnosis, to evaluate whether a nutraceutical compound given for 6 months during bortezomib (BTZ) treatment succeeded in preventing the onset of neurotoxicity. Methods: Neurological evaluation, electroneurography, and functional and quality of life (QoL) scales were performed at baseline and after 6 months. We administered a tablet containing docosahexaenoic acid 400 mg, α-lipoic acid 600 mg, vitamin C 60 mg, and vitamin E 10 mg bid for 6 months. Results: Concerning the 25 patients who completed the study, at 6-month follow-up, 10 patients had no neurotoxicity (NCI-CTCAE [National Cancer Institute-Common Terminology Criteria for Adverse Events] = 0), while 13 progressed to NCI-CTCAE grade 1, 1 had NCI-CTCAE grade 1 with pain, and 1 experienced a NCI-CTCAE grade 2. Painful symptoms were reported only in 2 patients, and we observed stability on functional and QoL scales in all patients. None of the 25 patients stopped chemotherapy due to neurotoxicity. Conclusions: Our data seem to indicate that the co-administration of a neuroprotective agent during BTZ treatment can prevent the appearance/worsening of symptoms related to CIPN, avoiding the interruption of BTZ and maintaining valuable functional autonomy to allow normal daily activities. We believe that prevention remains the mainstay to preserve QoL in this particular patient population, and that future studies with a larger patient population are needed.
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Bortezomib/efectos adversos , Bortezomib/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Síndromes de Neurotoxicidad/prevención & control , Ácido Tióctico/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dolor/inducido químicamente , Estudios Prospectivos , Calidad de VidaAsunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Piridazinas/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Imidazoles/sangre , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Piridazinas/sangreRESUMEN
OBJECTIVES: Polyneuropathy (PN) is a frequent and significant clinical manifestation of multiple myeloma that may be observed at onset of disease or induced during treatment as a therapy-related complication. Polyneuropathy may be a relevant issue in myeloma patients owing to its significant impact on the quality of life, considering that it may lead to dose reduction or treatment discontinuation. The present retrospective study intended to evaluate efficacy of pregabalin (PGB) in treatment of PN in multiple myeloma patients. MATERIALS AND METHODS: Medical charts of 108 consecutive PN myeloma patients were reviewed. Data regarding the tumor history and therapy as well as the clinical and neurophysiological examinations 6 months before and after initiation of PGB therapy were collected. RESULTS: Thirty-eight medical charts had all the requested information. All patients (n = 38) underwent bortezomib-based treatment; 19 were previously treated and 19 were treatment naive. At first neurologic visit, all patients had PN symptoms (grade 2 of National Cancer Institute-Common Toxicity Criteria) without relevant pain. Neurophysiological evaluation showed a significant decrease in sensory nerve action potential amplitude (P = 0.006), conduction velocity (P = 0.006), and distal latency (P = 0.03) of sensory nerves between the first and the last neurological examination, in all patient population. Similar results were observed in treatment-naive patients, when the study cohort was stratified according to previous treatment. On the contrary, no significant differences were found between the first and the last neurophysiological follow-up evaluation in previously treated patients. Six months after PGB treatment, all patients reported disappearance of neurological symptoms (grade 0 National Cancer Institute-Common Toxicity Criteria). CONCLUSIONS: In this retrospective study, improvement in neurological symptoms during PGB therapy was observed in the total population, despite the presence of a distal, sensory axonal neuropathy, as evidenced by neurophysiological examination.
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Polineuropatías/tratamiento farmacológico , Pregabalina/uso terapéutico , Adulto , Anciano , Bortezomib/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Polineuropatías/etiología , Estudios RetrospectivosRESUMEN
Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC < 500/mm³) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.
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Infecciones por Citomegalovirus/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones Fúngicas Invasoras/complicaciones , Trastornos Linfoproliferativos/microbiología , Trastornos Linfoproliferativos/virología , Infecciones Oportunistas/complicaciones , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Trasplante Autólogo/efectos adversos , Adulto JovenRESUMEN
Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by ongoing inflammatory destruction of the interlobular bile ducts, eventually leading to chronic cholestasis and biliary cirrhosis. This study primarily aims to define the metabolomic signature of PBC after comparison with healthy controls (HC). Second, it aims to evaluate the possible metabolic association between PBC and celiac disease (CD), an immune-mediated disorder frequently associated with PBC. Serum and urine samples from 20 PBC, 21 CD, and 19 sex-matched HC subjects were collected. 1H nuclear magnetic resonance (NMR) spectra for all samples were acquired, and multivariate statistics were used to evaluate the differences among the three groups and to provide information about the involved metabolites. The classification accuracies to discriminate PBC and HC groups were 78.9-84.6% for serum and 76.9% for urine. In comparison to HC, PBC patient sera were characterized by altered levels ( p value <0.05) of pyruvate, citrate, glutamate, glutamine, serine, tyrosine, phenylalanine, and lactate. PBC patient urine showed lower levels ( p value <0.05) of trigonelline and hippurate with respect to HC. Furthermore, the NMR metabolomic fingerprint was able to cluster PBC with respect to CD patients, and the classification accuracies in the discriminations between these groups were 81.9-91.7% for serum and 77.7% for urine. Our results show that PBC displays a unique metabolomic fingerprint, which led to speculation about an impaired energy metabolism, probably associated with an altered gut microbiota. PBC and CD showed two distinct metabolic fingerprints. These data could provide clues for the comprehension of the PBC pathogenetic mechanisms and the detection of novel therapeutic targets.
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Enfermedad Celíaca/genética , Cirrosis Hepática Biliar/genética , Metaboloma/genética , Metabolómica , Adulto , Anciano , Enfermedad Celíaca/sangre , Enfermedad Celíaca/patología , Enfermedad Celíaca/orina , Femenino , Microbioma Gastrointestinal/genética , Voluntarios Sanos , Humanos , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/patología , Cirrosis Hepática Biliar/orina , Espectroscopía de Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To retrospectively evaluate the value of whole-lesion histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating between lymphoma and metastatic squamous cell carcinoma (SCC) of unknown clinical primary in neck nodes. METHODS: A total of 39 patients, 20 affected by lymphoma and 19 affected by metastatic non-nasopharyngeal SCC, were included in this retrospective study. All patients underwent MR imaging with a 1.5 T scanner system, including diffusion-weighted imaging (DWI) with three different b values (b = 0, 500 and 800 s/mm2). The entire tumor volume was manually delineated on the ADC maps, using the T2-weighted images and DWIs with b = 800 s/mm2 as a guide to the lesion location. The Mann-Whitney rank-sum test for independent samples was performed to compare the histogram parameters of patients with lymphoma and SCC. RESULTS: The SCCs showed significantly higher median ADC (ADCmedian) and mean ADC (ADCmean) values, compared to lymphomas (p < 0.001), while they exhibited lower kurtosis and skewness without reaching significance (p = 0.066 and 0.148, respectively). The ADCmean and ADCmedian had the best discriminative powers for differentiating lymphoma and SCC, with an area under the curve of 87% and 85%, respectively. The optimal cutoff values for ADCmean and ADCmedian as predictors for lymphoma were ≤ 0.83 × 10-3 mm2/s and ≤ 0.73 × 10-3 mm2/s, respectively. CONCLUSIONS: The whole-lesion ADC histogram analysis of cervical lymphadenopathy may help to discriminate lymphomas from non-nasopharyngeal SCC in patients with unknown clinical primary tumor.
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Imagen de Difusión por Resonancia Magnética/métodos , Linfadenopatía/diagnóstico por imagen , Linfoma/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Linfadenopatía/patología , Linfoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carga TumoralRESUMEN
BACKGROUND AND AIMS: Peripheral neuropathy is a common complication of chemotherapy that can induce marked disability that negatively affects the quality of life in patients with multiple myeloma (MM). The aim of this study was to prevent the onset or the worsening of peripheral neuropathy in MM patients treated with bortezomib (BTZ), using a new nutritional neuroprotective compound. We report preliminary results of 18 out of 33 patients who completed the study. METHODS: We administered a tablet of Neuronorm to patients, containing docosahexaenoic acid 400 mg, α-lipoic acid 600 mg, vitamin C 60 mg, and vitamin E 10 mg bid for the whole follow-up period. Neurological visit assessment, electroneurography, and evaluation scales were performed at baseline and after 6 months. RESULTS: At 6 months, 8 patients had no chemotherapy-induced peripheral neuropathy, while 10 patients experienced chemotherapy-induced peripheral neuropathy of grade 1 according to the Common Terminology Criteria for Adverse Events, one of them with pain. Seventeen patients did not report painful symptoms; no limitation of functional autonomy and stability in quality of life domains explored was observed. CONCLUSIONS: Our results seem to indicate that early introduction of a neuroprotective agent in our patients with MM treated with BTZ could prevent the onset or the worsening of neuropathic pain, avoiding the interruption of the therapy with BTZ, and maintaining a good functional autonomy to allow normal daily activities. Despite the limitations due to the fact that this is a preliminary study, in a small population, with short follow-up, our data seem to indicate that the nutraceutical may have some potential to be considered for a future trial.
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Bortezomib/efectos adversos , Bortezomib/uso terapéutico , Ácidos Docosahexaenoicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Ácido Tióctico/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Resultado del TratamientoRESUMEN
BACKGROUND: Rett syndrome (RTT) is a neurological disorder mainly caused by mutations in MeCP2 gene. It has been shown that MeCP2 impairments can lead to cytokine dysregulation due to MeCP2 regulatory role in T-helper and T-reg mediated responses, thus contributing to the pro-inflammatory status associated with RTT. Furthermore, RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. Therefore, we asked whether the intestinal fungal population of RTT subjects might contribute the sub-inflammatory status triggered by MeCP2 deficiency. METHODS: We evaluated the cultivable gut mycobiota from a cohort of 50 RTT patients and 29 healthy controls characterizing the faecal fungal isolates for their virulence-related traits, antifungal resistance and immune reactivity in order to elucidate the role of fungi in RTT's intestinal dysbiosis and gastrointestinal physiology. RESULTS: Candida parapsilosis, the most abundant yeast species in RTT subjects, showed distinct genotypic profiles if compared to healthy controls' isolates as measured by hierarchical clustering analysis from RAPD genotyping. Their phenotypical analysis revealed that RTT's isolates produced more biofilm and were significantly more resistant to azole antifungals compared to the isolates from the healthy controls. In addition, the high levels of IL-1ß and IL-10 produced by peripheral blood mononuclear cells and the mixed Th1/Th17 cells population induced by RTT C. parapsilosis isolates suggest the capacity of these intestinal fungi to persist within the host, being potentially involved in chronic, pro-inflammatory responses. CONCLUSIONS: Here we demonstrated that intestinal C. parapsilosis isolates from RTT subjects hold phenotypic traits that might favour the previously observed low-grade intestinal inflammatory status associated with RTT. Therefore, the presence of putative virulent, pro-inflammatory C. parapsilosis strains in RTT could represent an additional factor in RTT's gastrointestinal pathophysiology, whose mechanisms are not yet clearly understood.
Asunto(s)
Candida parapsilosis/aislamiento & purificación , Candida parapsilosis/patogenicidad , Candidiasis/microbiología , Gastroenteritis/microbiología , Síndrome de Rett/microbiología , Antifúngicos/uso terapéutico , Candida albicans/genética , Candida albicans/aislamiento & purificación , Candida parapsilosis/efectos de los fármacos , Candida parapsilosis/genética , Candidiasis/tratamiento farmacológico , Candidiasis/inmunología , Citocinas/sangre , Farmacorresistencia Fúngica , Gastroenteritis/tratamiento farmacológico , Gastroenteritis/inmunología , Microbioma Gastrointestinal , Variación Genética , Genotipo , Humanos , Interleucina-10/sangre , Leucocitos Mononucleares/metabolismo , Proteína 2 de Unión a Metil-CpG/deficiencia , Proteína 2 de Unión a Metil-CpG/genética , Mutación , Síndrome de Rett/genética , Síndrome de Rett/inmunología , VirulenciaRESUMEN
BACKGROUND: Randomized trials comparing chemomobilization efficiency between lenograstim and biosimilar filgrastim are lacking. Our previous retrospective study suggested that lenograstim could be more effective than biosimilar filgrastim when used at the same conventional dosage (5 µg/kg) only in lymphoma patients undergoing peripheral blood stem cell mobilization. We planned a prospective randomized study comparing lenograstim 5 µg/kg with biosimilar filgrastim 10 µg/kg to verify the hypothesis of lenograstim superiority even at half the dosage (stress test). Herein we report data after enrolling 60% of planned patients. STUDY DESIGN AND METHODS: From October 2014 to November 2017, a total of 42 of 70 planned patients with lymphoma were randomly assigned to receive lenograstim 5 µg/kg (21) or biosimilar filgrastim 10 µg/kg (21). Patients were stratified according to treatment line at the time of mobilization (1 or ≥2). Primary endpoint was the rate of achievement of the CD34+ cell collection target dose (≥ 4 × 106 /kg). An improvement by 23% was expected to validate the hypothesis of lenograstim superiority. RESULTS: The two cohorts were balanced for all the baseline features. We observed an identical rate of patients able to reach the targeted CD34+ cell dose and of mobilization failures (90.4 and 4.8% in both cohorts) and a perfect equivalence in any of the secondary collection outcomes. The hypothesis of lenograstim superiority was not corroborated at interim analysis. CONCLUSION: Lenograstim at conventional dosage has failed to demonstrate its superiority over biosimilar filgrastim at double the dosage at interim analysis in their first head-to-head trial.