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Diabetes Study of Children of Diverse Ethnicity and Race: Study design.
Redondo, MJ, Harrall, KK, Glueck, DH, Tosur, M, Uysal, S, Muir, A, Atkinson, EG, Shapiro, MR, Yu, L, Winter, WE, et al
Diabetes/metabolism research and reviews. 2024;(3):e3744
Abstract
AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. MATERIALS AND METHODS The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.
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Genetic landscape of pediatric acute liver failure of indeterminate origin.
Lenz, D, Schlieben, LD, Shimura, M, Bianzano, A, Smirnov, D, Kopajtich, R, Berutti, R, Adam, R, Aldrian, D, Baric, I, et al
Hepatology (Baltimore, Md.). 2024;(5):1075-1087
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BACKGROUND AND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. APPROACH AND RESULTS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation. CONCLUSIONS This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.
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Hyperparathyroidism, Serum Phosphorus and Dietary Intake in Hemodialysis Patients: Is There a Novel Relationship?
Garagarza, C, Valente, A, Queirós, C, Neto, IP, Sebastião, J, Gomes, M, Ferreira, A
International journal of molecular sciences. 2024;(4)
Abstract
The management of hyperparathyroidism (intact parathyroid hormone (iPTH) serum levels > 585 pg/mL), frequently focuses on the appropriate control of mineral and bone markers, with the decrease in serum and dietary phosphorus as two of the targets. We aimed to investigate the association between iPTH, serum phosphorus levels and dietary intake. This was a cross-sectional, multicenter, observational study with 561 patients on hemodialysis treatment. Clinical parameters, body composition and dietary intake were assessed. For the analysis, patients were divided into three groups: (a) iPTH < 130, (b) iPTH between 130 and 585 and (c) iPTH > 585 pg/mL. The association between PTH, serum phosphorus and dietary intake was analyzed using linear regression models. In the whole sample, 23.2% of patients presented an iPTH > 585 pg/mL. Patients with higher iPTH levels were those with longer HD vintage and lower ages, higher serum phosphorus, serum calcium, Ca/P product, albumin and caffeine intake, and a lower dietary intake of phosphorus, fiber, riboflavin and folate. Higher serum phosphorus predicted higher iPTH levels, even in the adjusted model. However, lower dietary phosphorus and fiber intake were predictors of higher iPTH levels, including in the adjusted model. Our results bring new data to the relationship between dietary intake and iPTH values. Despite higher serum phosphorus being observed in patients with HPTH, an opposite association was noted regarding dietary phosphate and fiber.
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A prospective comparison study utilizing patient-reported outcomes of taxane-related peripheral neuropathy between nab-paclitaxel and standard paclitaxel in patients with breast cancer.
Kida, K, Yamada, A, Shimada, K, Narui, K, Sugae, S, Shimizu, D, Doi, T, Oba, M, Endo, I, Ishikawa, T
Breast cancer (Tokyo, Japan). 2024;(3):409-416
Abstract
UNLABELLED BACKGROUND Characteristics of taxane-induced peripheral neuropathy (PN) could be different between paclitaxel and nab-paclitaxel. The purpose of this prospective observational multicenter cohort study was to compare tri-weekly nab-paclitaxel to weekly standard paclitaxel regarding the severity, onset and recovery of sensory and motor PN in patients with breast cancer. METHODS Patients with histologically confirmed breast cancer who were scheduled to receive standard weekly paclitaxel (80 mg/m2) or tri-weekly nab-paclitaxel (260 mg/m2) at institutions in our multicenter group were eligible for this study. Sensory and motor PN were evaluated every 3 weeks until PN improved for up to one year using patient-reported outcome. RESULTS Between February 2011 and April 2013, 115 patients were enrolled, including 57 and 58 in the paclitaxel and nab-paclitaxel groups, respectively. The incidence of moderate or severe sensory PN was not significantly different between the two groups (p = 0.40). The incidence of moderate or higher motor PN was more frequent in the nab-paclitaxel group than in the paclitaxel group (p = 0.048). The median period for demonstrating PN were shorter in the nab-paclitaxel group than in the paclitaxel group (sensory, p = 0.003; motor, p = 0.001). The recovery of motor PN was slower in the nab-paclitaxel group than in the paclitaxel group (p = 0.035), while the recovery period of sensory PN was not statistically different. CONCLUSION Nab-paclitaxel induced sensory PN sooner than paclitaxel, and no difference was observed in the severity and recovery duration between the two agents. Motor PN was more severe, started sooner, and improved over a longer period in the nab-paclitaxel-treated patients than in the paclitaxel-treated patients.
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Fluorouracil, Leucovorin, and Irinotecan Plus Cetuximab Versus Cetuximab as Maintenance Therapy in First-Line Therapy for RAS and BRAF Wild-Type Metastatic Colorectal Cancer: Phase III ERMES Study.
Pinto, C, Orlandi, A, Normanno, N, Maiello, E, Calegari, MA, Antonuzzo, L, Bordonaro, R, Zampino, MG, Pini, S, Bergamo, F, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2024;(11):1278-1287
Abstract
PURPOSE The intensity of anti-EGFR-based first-line therapy for RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC), once disease control is achieved, is controversial. A de-escalation strategy with anti-EGFR monotherapy represents a potential option to maintain efficacy while reducing cytotoxicity. METHODS In this multicenter, open-label, phase III trial, patients with untreated RAS/BRAF wt mCRC were randomly assigned to receive either fluorouracil, leucovorin, and irinotecan/cetuximab (FOLFIRI/Cet) until disease progression (arm A) or FOLFIRI/Cet for eight cycles followed by Cet alone (arm B). The coprimary end points were a noninferior progression-free survival (PFS) in the modified per-protocol (mPP) population (>eight cycles) and a lower incidence of grade (G) 3-4 adverse events (AEs) for arm B compared with arm A. RESULTS Overall, 606 patients were randomly assigned, with 300 assigned to arm A and 306 to arm B. The median follow-up was 22.3 months. In the mPP population, 291 events occurred with a PFS of 10 versus 12.2 months for arms B and A, respectively (P of noninferiority = .43). In the intention-to-treatment (ITT, ≥one cycle) population, 503 events occurred with a PFS of 9 versus 10.7 months (P = .39). The overall survival was 35.7 versus 30.7 months (P = .119) and 31.0 versus 25.2 months (P = .32) in the mPP and ITT population, respectively. Arm B had lower G3-4 AEs during the maintenance period than arm A (20.2% v 35.1%). CONCLUSION The ERMES study did not demonstrate noninferiority of maintenance with Cet alone. Despite a more favorable safety profile, maintenance with single-agent Cet after induction with FOLFIRI/Cet cannot be recommended for all patients but could represent an option in selected cases.
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Gender-related differences in patients with carcinoid syndrome: new insights from an Italian multicenter cohort study.
Ruggeri, RM, Altieri, B, Razzore, P, Retta, F, Sperti, E, Scotto, G, Brizzi, MP, Zumstein, L, Pia, A, Lania, A, et al
Journal of endocrinological investigation. 2024;(4):959-971
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BACKGROUND The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking. PURPOSE To evaluate gender differences in clinical presentation and outcome of CaS. METHODS Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender. RESULTS Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender. CONCLUSIONS In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable.
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A Phase II Study of FOLFIRI Plus Ziv-Aflibercept After Trifluridine/Tipiracil Plus Bevacizumab in Patients with Metastatic Colorectal Cancer: WJOG 11018G.
Matsumoto, T, Yamamoto, Y, Kotaka, M, Masuishi, T, Tsuji, Y, Shoji, H, Hirata, K, Tsuduki, T, Makiyama, A, Izawa, N, et al
Targeted oncology. 2024;(2):181-190
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BACKGROUND Non-inferiority of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) to irinotecan/fluoropyrimidine plus BEV in metastatic colorectal cancer was investigated in the phase III TRUSTY study, and we conducted a phase II study of FOLFIRI (5-FU+leucovorin+irinotecan) plus zib-aflibercept (AFL) after FTD/TPI plus BEV. However, the TRUSTY study failed during the recruitment of our patients. OBJECTIVE We present the findings of a phase II study on the efficacy of FOLFIRI plus zib-aflibercept (AFL) after FTD/TPI plus BEV, including clinical results with plasma biomarker analyses. METHODS This was a multicenter, single-arm, phase II study in patients with metastatic colorectal cancer refractory or intolerant to oxaliplatin, fluoropyrimidine, BEV, and FTD/TPI. The primary endpoint was progression-free survival. Fifteen plasma angiogenesis-associated biomarkers were analyzed using a Luminex® multiplex assay U-kit. RESULTS Between January 2020 and May 2022, 26 patients (median age, 68 years) from 15 sites were enrolled. The median progression-free survival was 4.9 months (85% confidence interval, 3.4 month-not estimated). The overall response and disease control rates were 8% and 62%, respectively. The median levels of vascular endothelial growth factor-A and placental growth factor, both targets of AFL, were below the measurable limit of 30 pg/mL and 16 pg/mL, respectively. Patients were divided into two groups at the median levels of baseline biomarkers. The progression-free survival did not differ between high and low expressers of placental growth factor (p = 0.7), while it tended to be shorter in those with high levels of osteopontin (p = 0.05), angiopoietin-2 (p = 0.07), and tissue inhibitor of matrix metalloproteinases-1 (p = 0.1). CONCLUSIONS This study did not meet the primary endpoint. Hence, FOLFIRI plus AFL should not be used after FTD/TPI plus BEV for metastatic colorectal cancer. Further studies are needed to determine factors not targeted by AFL that may affect the efficacy of the treatment. CLINICAL TRIAL REGISTRATION jRCTs041190100.
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Glucometrics and device satisfaction in children and adolescents with type 1 diabetes using different treatment modalities: A multicenter real-world observational study.
Cherubini, V, Fargalli, A, Arnaldi, C, Bassi, M, Bonfanti, R, Patrizia Bracciolini, G, Cardella, F, Dal Bo, S, Delvecchio, M, Di Candia, F, et al
Diabetes research and clinical practice. 2024;:111621
Abstract
AIMS: To analyze metabolic outcomes, diabetes impact and device satisfaction in children and adolescents with type 1 diabetes in Italy who used different treatment modalities for diabetes care in a real-life context. METHODS In this multicenter, nationwide, cross-sectional study, 1464 participants were enrolled at a routine visit. The following treatment modalities were considered MDI + SMBG; MDI + CGM; Sensor Augmented Pump Therapy; predictive management of low glucose; Hybrid Closed Loop (HCL); Advanced Hybrid Closed Loop (AHCL). Health related quality of life was evaluated by the Italian version of the Diabetes Impact and Device Satisfaction Scale (DIDS) questionnaire. RESULTS Patients treated with AID systems were more likely to have HbA1c ≤ 6.5 %, higher percentage of time with glucose levels between 70 and 180 mg/dL, lower percentage of time with glucose levels above 180 mg/dL, higher device satisfaction, and reduced impact of diabetes. All the therapeutic modalities with respect to MDI + CGM, except for MDI + SMBG, contributed to increase the device satisfaction. HCL and AHCL respect to MDI + CGM were associated with lower diabetes impact. CONCLUSION Real-life use of automated insulin delivery systems is associated with reduced type 1 diabetes impact, increased device satisfaction, and achievement of glycemic goals.
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The Brazilian Cardioprotective Nutritional (BALANCE) Program improves diet quality in patients with established cardiovascular disease: Results from a multicenter randomized controlled trial.
da Conceição, AR, da Silva, A, Juvanhol, LL, Marcadenti, A, Bersch-Ferreira, ÂC, Weber, B, Shivappa, N, Bressan, J
Nutrition research (New York, N.Y.). 2024;:82-94
Abstract
Dietary modifications are essential strategies for cardiovascular disease prevention. However, studies are needed to investigate the diet quality of individuals undergoing secondary prevention in cardiology and who received dietary intervention based on cardiovascular disease management. We prospectively evaluated the diet quality in the Brazilian Cardioprotective Nutritional Program Trial (BALANCE Program Trial). We hypothesized that the BALANCE Program could improve patients' dietary pattern according to different indices of diet quality such as the Dietary Inflammatory Index (DII); the dietary total antioxidant capacity; overall, healthful, and unhealthful Plant-Based Diet Index (PDI, hPDI, and uPDI, respectively); and modified Alternative Healthy Eating Index (mAHEI). This multicenter randomized, controlled trial included patients aged ≥45 years randomly assigned to either the experimental or control group. Data from 2185 participants at baseline and after 12, 24, 36, and 48 months showed that the intervention group (n = 1077) had lower mean values of DII and higher dietary total antioxidant capacity, PDI, hPDI, and mAHEI than the control group. The results also showed differences between the follow-up times for DII, hPDI, and uPDI (48 months vs baseline) and for PDI and mAHEI (24 months vs baseline), regardless of group. The interaction analysis demonstrated that the intervention group showed better results than the control group at 12, 24, 36, and 48 months for the DII and at months 12, 36, and 48 for the mAHEI. Our results provide prospective evidence that the BALANCE Program improved the diet quality in those in secondary cardiovascular prevention according to different indices, with the intervention group showing better results than the control group.
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Protein and Exercise to Reverse Frailty in Older Men and Women Undergoing Transcatheter Aortic Valve Replacement: Design of the PERFORM-TAVR Trial.
Fountotos, R, Lauck, S, Piazza, N, Martucci, G, Arora, R, Asgar, A, Forcillo, J, Kouz, R, Labinaz, M, Lamy, A, et al
The Canadian journal of cardiology. 2024;(2):267-274
Abstract
Despite the high procedural success of transcatheter aortic valve replacement (TAVR), 2 out of 5 older adults report poor physical performance and health-related quality of life (HRQOL) in the ensuing months, particularly those with frailty. There has yet to be a trial examining the synergistic effects of exercise and protein supplementation to counteract frailty and improve patient-centred outcomes following TAVR. The PERFORM-TAVR trial is a multicentre parallel-group randomised clinical trial that is enrolling 200 frail older adults ≥ 70 years of age undergoing TAVR. Patients will be randomly allocated to 1 of 2 treatment groups: standard-of-care lifestyle education (control group) or protein-rich oral nutritional supplement for 4 weeks before TAVR with the addition of home-based supervised exercise sessions for 12 weeks after TAVR (intervention group). The primary outcome will be physical performance as measured by a blinded observer using the Short Physical Performance Battery at 3 months. Secondary outcomes at 3, 6, and 12 months will include HRQOL, as measured by the Short-Form 36 Physical and Mental Component summary scores, and a composite safety end point. The PERFORM-TAVR trial is testing a novel frailty intervention in older adults undergoing TAVR to optimise recovery and downstream HRQOL. This represents a potential paradigm shift that highlights the value of assessing and treating patients' frailty in parallel with their underlying heart valve disease. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT03522454.