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1.
Front Public Health ; 12: 1401662, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39185124

RESUMEN

People experiencing homelessness have historically had high mortality rates compared to housed individuals in Canada, a trend believed to have become exacerbated during the COVID-19 pandemic. In this matched cohort study conducted in Toronto, Canada, we investigated all-cause mortality over a one-year period by following a random sample of people experiencing homelessness (n = 640) alongside matched housed (n = 6,400) and low-income housed (n = 6,400) individuals. Matching criteria included age, sex-assigned-at-birth, and Charlson comorbidity index. Data were sourced from the Ku-gaa-gii pimitizi-win cohort study and administrative databases from ICES. People experiencing homelessness had 2.7 deaths/100 person-years, compared to 0.7/100 person-years in both matched unexposed groups, representing an all-cause mortality unadjusted hazard ratio (uHR) of 3.7 (95% CI, 2.1-6.5). Younger homeless individuals had much higher uHRs than older groups (ages 25-44 years uHR 16.8 [95% CI 4.0-70.2]; ages 45-64 uHR 6.8 [95% CI 3.0-15.1]; ages 65+ uHR 0.35 [95% CI 0.1-2.6]). Homeless participants who died were, on average, 17 years younger than unexposed individuals. After adjusting for number of comorbidities and presence of mental health or substance use disorder, people experiencing homelessness still had more than twice the hazard of death (aHR 2.2 [95% CI 1.2-4.0]). Homelessness is an important risk factor for mortality; interventions to address this health disparity, such as increased focus on homelessness prevention, are urgently needed.


Asunto(s)
COVID-19 , Personas con Mala Vivienda , Humanos , Personas con Mala Vivienda/estadística & datos numéricos , COVID-19/mortalidad , COVID-19/epidemiología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Estudios de Cohortes , Ontario/epidemiología , Disparidades en el Estado de Salud , Mortalidad/tendencias , Canadá/epidemiología , Causas de Muerte , Anciano
3.
JAMA Oncol ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39023864

RESUMEN

Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated. Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction. Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status. Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46). Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups. Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death. Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

4.
Microbiol Spectr ; 12(7): e0041024, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38809005

RESUMEN

The Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic bacteria often associated with fatal pulmonary infections in patients with impaired immunity, particularly those with cystic fibrosis (CF) and chronic granulomatous disease (CGD). Some Bcc strains are known to naturally produce pyomelanin, a brown melanin-like pigment known for scavenging free radicals; pigment production has been reported to enable Bcc strains to overcome the host cell oxidative burst. In this work, we investigated the role of pyomelanin in resistance to oxidative stress and virulence in strains J2315 and K56-2, two epidemic CF isolates belonging to the Burkholderia cenocepacia ET-12 lineage. We previously reported that a single amino acid change from glycine to arginine at residue 378 in homogentisate 1,2-dioxygenase (HmgA) affects the pigment production phenotype: pigmented J2315 has an arginine at position 378, while non-pigmented K56-2 has a glycine at this position. Herein, we performed allelic exchange to generate isogenic non-pigmented and pigmented strains of J2315 and K56-2, respectively, and tested these to determine whether pyomelanin contributes to the protection against oxidative stress in vitro as well as in a respiratory infection in CGD mice in vivo. Our results indicate that the altered pigment phenotype does not significantly impact these strains' ability to resist oxidative stress with H2O2 and NO in vitro and did not change the virulence and infection outcome in CGD mice in vivo suggesting that other factors besides pyomelanin are contributing to the pathophysiology of these strains.IMPORTANCEThe Burkholderia cepacia complex (Bcc) is a group of Gram-negative opportunistic bacteria that are often associated with fatal pulmonary infections in patients with impaired immunity, particularly those with cystic fibrosis and chronic granulomatous disease (CGD). Some Bcc strains are known to naturally produce pyomelanin, a brown melanin-like pigment known for scavenging free radicals and overcoming the host cell oxidative burst. We investigated the role of pyomelanin in Burkholderia cenocepacia strains J2315 (pigmented) and K56-2 (non-pigmented) and performed allelic exchange to generate isogenic non-pigmented and pigmented strains, respectively. Our results indicate that the altered pigment phenotype does not significantly impact these strains' ability to resist H2O2 or NO in vitro and did not alter the outcome of a respiratory infection in CGD mice in vivo. These results suggest that pyomelanin may not always constitute a virulence factor and suggest that other features are contributing to the pathophysiology of these strains.


Asunto(s)
Infecciones por Burkholderia , Burkholderia cenocepacia , Enfermedad Granulomatosa Crónica , Homogentisato 1,2-Dioxigenasa , Melaninas , Animales , Femenino , Humanos , Ratones , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Burkholderia cenocepacia/genética , Burkholderia cenocepacia/patogenicidad , Burkholderia cenocepacia/metabolismo , Infecciones por Burkholderia/microbiología , Fibrosis Quística/microbiología , Modelos Animales de Enfermedad , Enfermedad Granulomatosa Crónica/microbiología , Enfermedad Granulomatosa Crónica/genética , Homogentisato 1,2-Dioxigenasa/genética , Homogentisato 1,2-Dioxigenasa/metabolismo , Pulmón/microbiología , Pulmón/patología , Melaninas/metabolismo , Mutación , Estrés Oxidativo , Virulencia/genética
5.
JHEP Rep ; 6(2): 100982, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38274490

RESUMEN

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

6.
Future Oncol ; 20(1): 39-53, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37476983

RESUMEN

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.


Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.


Asunto(s)
Adenina/análogos & derivados , Leucemia Linfocítica Crónica de Células B , Pirazinas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Piperidinas , Benzamidas/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos
7.
J Clin Endocrinol Metab ; 109(5): 1301-1307, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-37997380

RESUMEN

OBJECTIVE: To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM). RESEARCH DESIGN AND METHODS: Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison. RESULTS: All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis. CONCLUSION: Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative.

8.
Hepatol Commun ; 7(11)2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37889520

RESUMEN

BACKGROUND: Since the introduction of the combination treatment of anti-programmed death-ligand 1 antibody atezolizumab and anti-VEGF antibody bevacizumab (AB), median overall survival in HCC has drastically improved. However, evidence on the efficacy and safety of the novel treatment standard in patients with prior exposure to systemic treatment is scarce. The aim of this global, multicenter, observational study was to evaluate the efficacy and safety of AB in patients after previous systemic therapy. METHODS: We screened our global, multicenter, prospectively maintained registry database for patients who received any systemic therapy before AB. The primary end point was overall survival; secondary end points were time-to-progression, progression-free survival, objective response rate, and safety (rate and severity of adverse events). RESULTS: Among 493 patients who received AB for unresectable HCC, 61 patients received prior systemic therapy and were included in this analysis. The median age of the study population was 66 years, with 91.8% males. Predominant risk factors for HCC were viral hepatitis (59%) and alcohol (23%). Overall survival for AB was 16.2 (95% CI, 14.5-17.9) months, time-to-progression and progression-free survival were 4.1 (95% CI, 1.5-6.6) and 3.1 (95% CI, 1.1-5.1) months, respectively. The objective response rate was 38.2% (7.3% with complete and 30.9% with partial response). Overall survival was not influenced by treatment line (2nd vs. >2nd) or previous systemic treatment modality (tyrosine kinase inhibitors vs. immune checkpoint inhibitors). Treatment-related adverse events of all grades according to Common Terminology Criteria for Adverse Events were documented in 42.6% of patients, with only 13.1% of grade ≥3, including one death. CONCLUSION: In this observational study, AB emerges as a safe and efficacious treatment option in patients with HCC previously treated with other systemic therapy.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Anciano , Femenino , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inducido químicamente , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos
9.
Patient Prefer Adherence ; 17: 2073-2084, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37641660

RESUMEN

Purpose: Increased dosing frequency adversely affects treatment adherence and outcomes in chronic diseases; however, such data related to treatment adherence is lacking in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This study compared adherence between patients treated with ibrutinib (once-daily) versus acalabrutinib (twice-daily) as first-line (1L) therapy for CLL/SLL. Patients and Methods: Specialty pharmacy electronic medical records were used to identify adults with CLL/SLL initiating 1L ibrutinib or acalabrutinib between 01/01/2018 and 11/30/2020. Adherence was measured by the proportion of days covered (PDC) and medication possession ratio (MPR) and was compared between cohorts using odds ratios (ORs) obtained from logistic regression models adjusted for baseline characteristics. Results: Between 01/01/2018 and 11/30/2020, 1374 and 140 patients initiated ibrutinib and acalabrutinib, respectively. Based on PDC/MPR ≥80%, patients treated with once-daily ibrutinib were more likely to be adherent than those treated with twice-daily acalabrutinib (OR ranges: PDC: 1.04-1.76; MPR: 1.03-1.58). At 6 months, patients on ibrutinib had a 58-76% higher likelihood of staying adherent compared to patients on acalabrutinib (PDC: 75.9% for ibrutinib vs 63.6% for acalabrutinib, OR: 1.76, P=0.008; MPR: 76.8% vs 66.9%, OR: 1.58, P=0.036) with a similar trend noted for the entire line of treatment (LOT) (PDC: 53.0% vs 41.4%, OR: 1.53, P=0.021; MPR: 58.7% vs 47.1%, OR: 1.50, P=0.027). Conclusion: In this real-world analysis, CLL/SLL patients initiating 1L once-daily ibrutinib had >50% higher treatment adherence than those initiating twice-daily acalabrutinib during their LOT. Given the importance of sustained adherence for disease control in CLL/SLL, dosing frequency may be an important consideration for patients and physicians.

10.
Curr Med Res Opin ; 39(9): 1227-1235, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37530387

RESUMEN

OBJECTIVE: To evaluate the time to discontinuation (TTD) and baseline characteristics among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treated with first-line (1L) venetoclax + obinutuzumab (VO) in the United States. METHODS: A nationwide electronic health record-derived database was used to select adults with CLL/SLL initiating a 1L venetoclax-based regimen between April 11, 2016-July 31, 2020. Study measures included TTD (defined as >120-day treatment gap or switching therapy) and baseline characteristics by discontinuation status. RESULTS: A total of 113 patients receiving 1L VO on/before July 31, 2020 were eligible for analysis (mean age: 65.9 years; 31.9% women). During the first 60 days post-treatment initiation, 3.5% had tumor lysis syndrome (TLS). The proportion of patients using corticosteroids, anti-hyperuricemics, and anti-emetics was higher during the first 60 days post-treatment initiation (100.0%, 78.8%, and 52.2%, respectively) than the period from day 61 onward (67.0%, 45.5%, and 33.9%, respectively). Mean (median) duration of active treatment was 11.6 (12.1) months; 16.8% discontinued treatment before completing 12 cycles, 68.1% completed ≥12 cycles (among which 29.9% completed ≥15 cycles), and 15.0% who did not discontinue treatment were censored before completing 12 cycles. Kaplan-Meier analysis showed that median TTD was 13.8 months. Relative to those completing ≥12 cycles, patients discontinuing treatment before completing the prescribed 12 cycles were older (70.4 vs. 65.1 years) and had poorer renal function (36.8% vs. 13.0% with creatinine clearance <60 mL/min). CONCLUSION: A small proportion of CLL/SLL patients who were older and had poorer baseline renal function discontinued 1L VO prior to completing 12 treatment cycles. Additionally, treatment utilization, including medications related to TLS mitigation and management, was more intense during the initiation phase of VO. Further research with longer follow-up to assess long-term outcomes of VO treatment after early discontinuation is warranted.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Adulto , Humanos , Femenino , Anciano , Masculino , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico
11.
Diabetes Care ; 46(6): 1292-1299, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-37220262

RESUMEN

BACKGROUND: Checkpoint inhibitor-associated autoimmune diabetes mellitus (CIADM) is a distinct form of autoimmune diabetes that is a rare complication of immune checkpoint inhibitor therapy. Data regarding CIADM are limited. PURPOSE: To systematically review available evidence to identify presentation characteristics and risk factors for early or severe presentations of adult patients with CIADM. DATA SOURCES: MEDLINE and PubMed databases were reviewed. STUDY SELECTION: English full text articles from 2014 to April 2022 were identified with a predefined search strategy. Patients meeting diagnostic criteria for CIADM with evidence of hyperglycemia (blood glucose level >11 mmol/L or HbA1c ≥6.5%) and insulin deficiency (C-peptide <0.4 nmol/L and/or diabetic ketoacidosis [DKA]) were included for analysis. DATA EXTRACTION: With the search strategy we identified 1,206 articles. From 146 articles, 278 patients were labeled with "CIADM," with 192 patients meeting our diagnostic criteria and included in analysis. DATA SYNTHESIS: Mean ± SD age was 63.4 ± 12.4 years. All but one patient (99.5%) had prior exposure to either anti-PD1 or anti-PD-L1 therapy. Of the 91 patients tested (47.3%), 59.3% had susceptibility haplotypes for type 1 diabetes (T1D). Median time to CIADM onset was 12 weeks (interquartile range 6-24). DKA occurred in 69.7%, and initial C-peptide was low in 91.6%. T1D autoantibodies were present in 40.4% (73 of 179) and were significantly associated with DKA (P = 0.0009) and earlier time to CIADM onset (P = 0.02). LIMITATIONS: Reporting of follow-up data, lipase, and HLA haplotyping was limited. CONCLUSIONS: CIADM commonly presents in DKA. While T1D autoantibodies are only positive in 40.4%, they associate with earlier, more severe presentations.


Asunto(s)
Diabetes Mellitus Tipo 1 , Cetoacidosis Diabética , Adulto , Humanos , Persona de Mediana Edad , Anciano , Péptido C , Factores de Riesgo , Insulina Regular Humana , Autoanticuerpos
12.
Hepatol Int ; 17(4): 904-914, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37005953

RESUMEN

BACKGROUND: Atezolizumab plus bevacizumab (Atezo/Bev) is first line-treatment for unresectable hepatocellular carcinoma (HCC). Body mass index (BMI) has demonstrated predictive value for response to immunotherapy in non-HCC cancer types. Our study investigated the effect of BMI on safety and efficacy of real-life use of Atezo/Bev for unresectable HCC. METHODS: 191 consecutive patients from seven centres receiving Atezo/Bev were included in the retrospective study. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in overweight (BMI ≥ 25) and non-overweight (BMI < 25) patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: Patients in the overweight cohort (n = 94) had higher rates of non-alcoholic fatty liver disease (NAFLD) and lower rates of Hepatitis B compared to non-overweight cohort (n = 97). Baseline Child-Pugh class and Barcelona Clinic Liver Cancer stage were similar between cohorts, with lower rates of extrahepatic spread in the overweight group. Overweight patients had similar OS compared to non-overweight (median OS 15.1 vs. 14.9 months; p = 0.99). BMI did not influence median PFS (7.1 vs. 6.1 months; p = 0.42), ORR (27.2% vs. 22.0%; p = 0.44) and DCR (74.1% vs. 71.9%; p = 0.46). There were higher rates of atezolizumab-related fatigue (22.3% vs. 10.3%; p = 0.02) and bevacizumab-related thrombosis (8.5% vs. 2.1%; p = 0.045) in the overweight patients, but overall trAEs and treatment discontinuation were comparable between cohorts. CONCLUSION: Atezo/Bev has comparable efficacy in overweight HCC patients, with an increase in treatment-related fatigue and thrombosis. Combination therapy is safe and efficacious to use in overweight patients, including those with underlying NAFLD.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Índice de Masa Corporal , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Estudios Retrospectivos , Neoplasias Hepáticas/tratamiento farmacológico , Fatiga , Ubiquitina-Proteína Ligasas
14.
Eur J Cancer ; 175: 204-213, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36148739

RESUMEN

BACKGROUND: IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). METHODS: We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported. RESULTS: Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4-10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1-8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS. CONCLUSION: This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.


Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombosis de la Vena , Albúminas/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Bevacizumab/efectos adversos , Bilirrubina , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Sorafenib/uso terapéutico , alfa-Fetoproteínas
15.
Liver Int ; 42(11): 2538-2547, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35986902

RESUMEN

BACKGROUND AND AIMS: Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. METHODS: 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age < 65 years) age patients. Treatment-related adverse events (trAEs) were evaluated. RESULTS: The elderly (n = 116) had higher rates of non-alcoholic fatty liver disease (19.8% vs. 2.7%; p < .001), presenting with smaller tumours (6.2 cm vs 7.9 cm, p = .02) with less portal vein thrombosis (31.9 vs. 54.7%, p = .002), with fewer patients presenting with BCLC-C stage disease (50.9 vs. 74.3%, p = .002). There was no significant difference in OS (median 14.9 vs. 15.1 months; HR 1.15, 95% CI 0.65-2.02 p = .63) and PFS (median 7.1 vs. 5.5 months; HR 1.11, 95% CI 0.54-1.92; p = .72) between older age and younger age. Older patients had similar ORR (27.6% vs. 20.0%; p = .27) and DCR (77.5% vs. 66.1%; p = .11) compared to younger patients. Atezolizumab-related (40.5% vs. 48.0%; p = .31) and bevacizumab-related (44.8% vs. 41.3%; p = .63) trAEs were comparable between groups. Rates of grade ≥3 trAEs and toxicity-related treatment discontinuation were similar between older and younger age patients. Patients 75 years and older had similar survival and safety outcomes compared to younger patients. CONCLUSIONS: Atezolizumab and bevacizumab therapy is associated with comparable efficacy and tolerability in older age patients with unresectable HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología
16.
J Cogn Psychother ; 2022 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-35577516

RESUMEN

We describe the perceptions of mental health clinicians practicing in the United States about the effects of the COVID-19 pandemic on the presentation and treatment course of active clients with anxiety. Clinician participants reported on client symptomology at the beginning of treatment, just before (prior to March 2020), and at a mid-pandemic timepoint (December 2020/January 2021). An initial sample of 70 clinicians responded to a survey assessing their clients' overall anxiety severity, anxiety sensitivity, pathological uncertainty, family accommodation, and avoidance levels. Of these, 54 clinician responses were included in study analyses, providing detailed clinical information on 81 clients. Findings suggest that the COVID-19 pandemic was associated with increases in anxiety severity in the majority of clients; overall, clinicians reported that 53% of clients had symptoms worsen due to COVID-19 and that only 16% experienced improvement of symptoms during treatment. Those who had lower levels of avoidance pre-pandemic and those who increased their frequency of treatment were more likely to experience increases in anxiety severity by the mid-pandemic timepoint. Further research is needed to understand the extended effects of the COVID-19 pandemic on anxiety symptomology and treatment.

17.
J Res Nurs ; 27(1-2): 82-98, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35392202

RESUMEN

Background: The clinical trials industry in China has enjoyed robust growth; the demand for qualified personnel to conduct clinical trials with higher quality has increased. The Clinical Research Nurse has emerged as a new workforce in China. Aims: This study aimed to examine the current work status of Clinical Research Nurses in China and to investigate their competencies in knowledge and behavior associated with this profession. Methods: An online survey was analyzed. The current work status of Clinical Research Nurses in China was characterized. In addition, their competencies were self-assessed across nine competency categories and the "contribution to science" domain, based on the International Association of Clinical Research Nurses Scope and Standards of Practice. Results: A total of 638 eligible questionnaires were included in the final analysis. Of whom, 98.28% (627/638) were females. The mean age was 35 years (range: 22-64 years). Over 80% of whom were working at the largest Chinese cities and the majority (78.2%) held a Bachelor's degree in nursing. The average time of clinical research experience was 5.67 years. Three quarters of the 638 had an annual income of <150,000 Yuan RMB. The average weekly working time was 45.46 h; clinical trial-related work accounted for 62.68% of their workload. There were some gaps between the Clinical Research Nurses' self-assessed competencies in knowledge and behavior, with the widest gaps along the ethical principles, leadership and professional development, protocol compliance, and document management categories. Conclusion: This is the first large-scale survey of Clinical Research Nurses in China. Our results profile this emerging workforce as a population of young, moderately trained/experienced, predominantly female nurses working in the largest Chinese cities. They performed well on most knowledge/behavior parameters; still, gaps exist. Therefore, there is a pressing need to enhance professional education and training for Clinical Research Nurses in China.

19.
Metabolites ; 12(3)2022 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-35323665

RESUMEN

Skeletal muscle is highly plastic and dynamically regulated by the body's physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina's Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.

20.
Hepatology ; 76(4): 1000-1012, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35313048

RESUMEN

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab (AtezoBev) is the standard of care for first-line treatment of unresectable HCC. No evidence exists as to its use in routine clinical practice in patients with impaired liver function. APPROACH AND RESULTS: In 216 patients with HCC who were consecutively treated with AtezoBev across 11 tertiary centers, we retrospectively evaluated treatment-related adverse events (trAEs) graded (G) according to Common Terminology Criteria for Adverse Events v5.0, including in the analysis all patients treated according to label (n = 202, 94%). We also assessed overall survival (OS), progression-free survival (PFS), overall response (ORR), and disease control rates (DCR) defined by Response Evaluation Criteria in Solid Tumors v1.1. Disease was mostly secondary to viral hepatitis, namely hepatitis C (n = 72; 36%) and hepatitis B infection (n = 35, 17%). Liver function was graded as Child-Pugh (CP)-A in 154 patients (76%) and CP-B in 48 (24%). Any grade trAEs were reported by 143 patients (71%), of which 53 (26%) were G3 and 3 (2%) G4. Compared with CP-A, patients with CP-B showed comparable rates of trAEs. Presence and grade of varices at pretreatment esophagogastroduodenoscopy did not correlate with bleeding events. After a median follow-up of 9.0 months (95% CI, 7.8-10.1), median OS was 14.9 months (95% CI, 13.6-16.3), whereas median PFS was 6.8 months (95% CI, 5.2-8.5). ORR and DCR were respectively 25% and 73%, with no difference across CP classes. CONCLUSIONS: This study confirms reproducible safety and efficacy of AtezoBev in routine practice. Patients with CP-B reported similar tolerability compared with CP-A, warranting prospective evaluation of AtezoBev in this treatment-deprived population.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Anticuerpos Monoclonales Humanizados , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/patología , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/patología , Estudios Retrospectivos
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