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1.
World J Gastroenterol ; 30(9): 1154-1163, 2024 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-38577186

RESUMEN

BACKGROUND: Inflammatory bowel disease (IBD) was previously regarded as a Western disease; however, its incidence is increasing in the East. The epidemiology of IBD in Asia differs significantly from the patterns in the West. AIM: To comprehensively investigate the epidemiology of IBD in South Korea, including its incidence, prevalence, medication trends, and outcomes. METHODS: We analyzed claims data from the Health Insurance Review and Assessment Service and Rare and Intractable Diseases (RIDs), operated by the National Health Insurance Service of South Korea. Patients with IBD were identified based on the International Classification of Diseases, Tenth Revision, and RID diagnostic codes for Crohn's disease (CD) and ulcerative colitis (UC) from 2010 to 2018. RESULTS: In total, 14498 and 31409 patients were newly diagnosed with CD and UC, respectively, between 2010 and 2018. The annual average incidence of CD was 3.11 cases per 105 person-years, and that of UC was 6.74 cases per 105 person-years. Since 2014, the incidence rate of CD has been stable, while that of UC has steadily increased, shifting the peak age group from 50-year-olds in 2010 to 20-year-olds in 2018. The CD and UC prevalence increased consistently over the study period; the use of 5-aminosalicylates and corticosteroids gradually decreased, while that of immunomodulators and biologics steadily increased in both CD and UC. The clinical outcomes of IBD, such as hospitalization and surgery, decreased during the study period. CONCLUSION: The CD incidence has been stable since 2014, but that of UC has increased with a shift to a younger age at peak incidence between 2010 and 2018. IBD clinical outcomes improved over time, with increased use of immunomodulators and biologics.


Asunto(s)
Productos Biológicos , Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Enfermedades Inflamatorias del Intestino/diagnóstico , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/epidemiología , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Incidencia , Factores Inmunológicos/uso terapéutico , República de Corea/epidemiología , Productos Biológicos/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico
2.
J Exp Clin Cancer Res ; 43(1): 109, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600583

RESUMEN

BACKGROUND: The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response. METHODS: The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis. RESULTS: In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68-1.00) for patient response prediction. CONCLUSIONS: The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.


Asunto(s)
Carcinoma in Situ , Ácido Hialurónico/análogos & derivados , Paclitaxel/análogos & derivados , Neoplasias de la Vejiga Urinaria , Humanos , Vejiga Urinaria/patología , Ácido Hialurónico/uso terapéutico , Vacuna BCG/uso terapéutico , Microambiente Tumoral , Paclitaxel/uso terapéutico , Neoplasias de la Vejiga Urinaria/patología , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/patología , Adyuvantes Inmunológicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico
4.
N Engl J Med ; 390(15): 1359-1371, 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38631003

RESUMEN

BACKGROUND: Adjuvant pembrolizumab therapy after surgery for renal-cell carcinoma was approved on the basis of a significant improvement in disease-free survival in the KEYNOTE-564 trial. Whether the results regarding overall survival from the third prespecified interim analysis of the trial would also favor pembrolizumab was uncertain. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 1:1 ratio) participants with clear-cell renal-cell carcinoma who had an increased risk of recurrence after surgery to receive pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks for up to 17 cycles (approximately 1 year) or until recurrence, the occurrence of unacceptable toxic effects, or withdrawal of consent. A significant improvement in disease-free survival according to investigator assessment (the primary end point) was shown previously. Overall survival was the key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 participants were assigned to receive pembrolizumab and 498 to receive placebo. As of September 15, 2023, the median follow-up was 57.2 months. The disease-free survival benefit was consistent with that in previous analyses (hazard ratio for recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87). A significant improvement in overall survival was observed with pembrolizumab as compared with placebo (hazard ratio for death, 0.62; 95% CI, 0.44 to 0.87; P = 0.005). The estimated overall survival at 48 months was 91.2% in the pembrolizumab group, as compared with 86.0% in the placebo group; the benefit was consistent across key subgroups. Pembrolizumab was associated with a higher incidence of serious adverse events of any cause (20.7%, vs. 11.5% with placebo) and of grade 3 or 4 adverse events related to pembrolizumab or placebo (18.6% vs. 1.2%). No deaths were attributed to pembrolizumab therapy. CONCLUSIONS: Adjuvant pembrolizumab was associated with a significant and clinically meaningful improvement in overall survival, as compared with placebo, among participants with clear-cell renal-cell carcinoma at increased risk for recurrence after surgery. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).


Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/cirugía , Método Doble Ciego , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Supervivencia sin Enfermedad , Terapia Combinada , Análisis de Supervivencia
6.
JAMA ; 331(11): 938-950, 2024 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-38502075

RESUMEN

Importance: In January 2023, the US Centers for Disease Control and Prevention and the US Food and Drug Administration noted a safety concern for ischemic stroke among adults aged 65 years or older who received the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine. Objective: To evaluate stroke risk after administration of (1) either brand of the COVID-19 bivalent vaccine, (2) either brand of the COVID-19 bivalent plus a high-dose or adjuvanted influenza vaccine on the same day (concomitant administration), and (3) a high-dose or adjuvanted influenza vaccine. Design, Setting, and Participants: Self-controlled case series including 11 001 Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine (among 5 397 278 vaccinated individuals). The study period was August 31, 2022, through February 4, 2023. Exposures: Receipt of (1) either brand of the COVID-19 bivalent vaccine (primary) or (2) a high-dose or adjuvanted influenza vaccine (secondary). Main Outcomes and Measures: Stroke risk (nonhemorrhagic stroke, transient ischemic attack, combined outcome of nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke) during the 1- to 21-day or 22- to 42-day risk window after vaccination vs the 43- to 90-day control window. Results: There were 5 397 278 Medicare beneficiaries who received either brand of the COVID-19 bivalent vaccine (median age, 74 years [IQR, 70-80 years]; 56% were women). Among the 11 001 beneficiaries who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there were no statistically significant associations between either brand of the COVID-19 bivalent vaccine and the outcomes of nonhemorrhagic stroke, transient ischemic attack, nonhemorrhagic stroke or transient ischemic attack, or hemorrhagic stroke during the 1- to 21-day or 22- to 42-day risk window vs the 43- to 90-day control window (incidence rate ratio [IRR] range, 0.72-1.12). Among the 4596 beneficiaries who experienced stroke after concomitant administration of either brand of the COVID-19 bivalent vaccine plus a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window for the Pfizer-BioNTech BNT162b2; WT/OMI BA.4/BA.5 COVID-19 bivalent vaccine (IRR, 1.20 [95% CI, 1.01-1.42]; risk difference/100 000 doses, 3.13 [95% CI, 0.05-6.22]) and a statistically significant association between vaccination and transient ischemic attack during the 1- to 21-day risk window for the Moderna mRNA-1273.222 COVID-19 bivalent vaccine (IRR, 1.35 [95% CI, 1.06-1.74]; risk difference/100 000 doses, 3.33 [95% CI, 0.46-6.20]). Among the 21 345 beneficiaries who experienced stroke after administration of a high-dose or adjuvanted influenza vaccine, there was a statistically significant association between vaccination and nonhemorrhagic stroke during the 22- to 42-day risk window (IRR, 1.09 [95% CI, 1.02-1.17]; risk difference/100 000 doses, 1.65 [95% CI, 0.43-2.87]). Conclusions and Relevance: Among Medicare beneficiaries aged 65 years or older who experienced stroke after receiving either brand of the COVID-19 bivalent vaccine, there was no evidence of a significantly elevated risk for stroke during the days immediately after vaccination.


Asunto(s)
COVID-19 , Vacunas contra la Influenza , Gripe Humana , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Anciano , Femenino , Humanos , Masculino , Vacuna nCoV-2019 mRNA-1273/efectos adversos , Vacuna nCoV-2019 mRNA-1273/uso terapéutico , Adyuvantes Inmunológicos/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Vacuna BNT162/efectos adversos , Vacuna BNT162/uso terapéutico , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/uso terapéutico , Accidente Cerebrovascular Hemorrágico/inducido químicamente , Accidente Cerebrovascular Hemorrágico/epidemiología , Accidente Cerebrovascular Hemorrágico/etiología , Vacunas contra la Influenza/efectos adversos , Vacunas contra la Influenza/uso terapéutico , Ataque Isquémico Transitorio/inducido químicamente , Ataque Isquémico Transitorio/epidemiología , Ataque Isquémico Transitorio/etiología , Medicare , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Estados Unidos/epidemiología , Vacunación/efectos adversos , Vacunación/métodos , Vacunas Combinadas/efectos adversos , Vacunas Combinadas/uso terapéutico , Centers for Disease Control and Prevention, U.S./estadística & datos numéricos , United States Food and Drug Administration/estadística & datos numéricos , Accidente Cerebrovascular Isquémico/inducido químicamente , Accidente Cerebrovascular Isquémico/epidemiología , Accidente Cerebrovascular Isquémico/etiología , Gripe Humana/prevención & control , Anciano de 80 o más Años
7.
Nat Commun ; 15(1): 2153, 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38461323

RESUMEN

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama , Femenino , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Docetaxel/uso terapéutico , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/patología , Receptor ErbB-2/uso terapéutico , Trastuzumab/uso terapéutico
8.
Front Immunol ; 15: 1348305, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38464539

RESUMEN

Type I hypersensitivity, or so-called type I allergy, is caused by Th2-mediated immune responses directed against otherwise harmless environmental antigens. Currently, allergen-specific immunotherapy (AIT) is the only disease-modifying treatment with the potential to re-establish clinical tolerance towards the corresponding allergen(s). However, conventional AIT has certain drawbacks, including long treatment durations, the risk of inducing allergic side effects, and the fact that allergens by themselves have a rather low immunogenicity. To improve AIT, adjuvants can be a powerful tool not only to increase the immunogenicity of co-applied allergens but also to induce the desired immune activation, such as promoting allergen-specific Th1- or regulatory responses. This review summarizes the knowledge on adjuvants currently approved for use in human AIT: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine, and MPLA, as well as novel adjuvants that have been studied in recent years: oil-in-water emulsions, virus-like particles, viral components, carbohydrate-based adjuvants (QS-21, glucans, and mannan) and TLR-ligands (flagellin and CpG-ODN). The investigated adjuvants show distinct properties, such as prolonging allergen release at the injection site, inducing allergen-specific IgG production while also reducing IgE levels, as well as promoting differentiation and activation of different immune cells. In the future, better understanding of the immunological mechanisms underlying the effects of these adjuvants in clinical settings may help us to improve AIT.


Asunto(s)
Desensibilización Inmunológica , Hipersensibilidad , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Alérgenos , Hidróxido de Aluminio , Adyuvantes Farmacéuticos
9.
Front Immunol ; 15: 1369110, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38455058

RESUMEN

Hepatocellular carcinoma (HCC) is a prevalent malignancy, often associated with compromised immune function in affected patients. This can be attributed to the secretion of specific factors by liver cancer cells, which hinder the immune response and lead to a state of immune suppression. Polysaccharides derived from traditional Chinese medicine (TCM) are valuable constituents known for their immunomodulatory properties. This review aims to look into the immunomodulatory effects of TCM polysaccharides on HCC. The immunomodulatory effects of TCM polysaccharides are primarily manifested through the activation of effector T lymphocytes, dendritic cells, NK cells, and macrophages against hepatocellular carcinoma (HCC) both in vivo and in vitro settings. Furthermore, TCM polysaccharides have demonstrated remarkable adjuvant antitumor immunomodulatory effects on HCC in clinical settings. Therefore, the utilization of TCM polysaccharides holds promising potential for the development of novel therapeutic agents or adjuvants with advantageous immunomodulatory properties for HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Medicina Tradicional China , Adyuvantes Inmunológicos/uso terapéutico , Polisacáridos/farmacología , Polisacáridos/uso terapéutico
10.
Eur J Cancer ; 202: 114023, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38518533

RESUMEN

BACKGROUND: Clinical trials have demonstrated promising outcomes for adjuvant immunotherapy in patients with resected melanoma. Real-life data provide valuable insights to support patient guidance and treatment decisions. METHODS: Observational population-based study examining a national cohort of patients with resected stage III-IV melanoma referred for adjuvant therapy. Data were extracted from the Danish Metastatic Melanoma Database (DAMMED). RESULTS: Between November 2018 and January 2022, 785 patients received adjuvant anti-PD-1. The majority had stage III resected melanoma (87%), normal LDH levels (80%), and performance score 0 (87%). Patients were followed for a median of 25.6 months (95%CI 24-28). The median recurrence-free survival (RFS) and melanoma-specific survival (MSS) were not reached. The RFS was 78% (95%CI 75-81), 66% (63-70), and 59% (55-63); MSS was 97% (95-98), 93% (91-95), and 87% (84-90) at 1-, 2-, and 3-year; respectively. Less than half (42%) of the patients finalized planned therapy, 32% discontinued due to toxicity, and 19% due to melanoma recurrence. Patients discontinuing adjuvant treatment prematurely, without recurrence, had similar outcomes as patients finalizing therapy. In a multivariable analysis, ipilimumab plus nivolumab did not improve outcomes compared to ipilimumab monotherapy as a first-line metastatic treatment after adjuvant anti-PD-1. CONCLUSION: Survival outcomes in real-world patients with melanoma treated with adjuvant anti-PD-1 align with results from the randomized controlled trials. Patients discontinuing therapy prematurely, for other reasons than recurrence, had similar outcomes as patients finalizing planned treatment. First-line metastatic treatment with ipilimumab and nivolumab post-adjuvant anti-PD-1 did not show improved outcomes compared to ipilimumab/anti-PD-1 monotherapy.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/inducido químicamente , Adyuvantes Inmunológicos/uso terapéutico , Inmunoterapia/métodos
11.
PLoS One ; 19(3): e0300339, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38489298

RESUMEN

BACKGROUND: The Oncotype DX® Breast Recurrence Score assay can guide recommendations made to patients with oestrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer regarding post-surgery adjuvant therapy. Standard practice is to order the test in the post-operative setting on a specimen from the excised invasive carcinoma. However, it has been shown to be technically possible to perform the test on the diagnostic core biopsy. By testing the diagnostic core biopsy in the pre-operative setting, the wait for excised invasive carcinoma Recurrence Score results could be reduced allowing patients to be more accurately counselled regarding their treatment pathway sooner with any adjuvant treatment recommendations expedited. This would allow for more efficient streaming of follow up appointments. The aim of this study is to compare the impact on the patient treatment pathway of performing the Oncotype DX® test on the diagnostic core biopsy pre-operatively (intervention) as opposed to the excised invasive carcinoma (control). METHODS AND ANALYSIS: This parallel group randomised controlled trial aims to recruit 330 newly diagnosed patients with grade 2 or grade 3, ER+, HER2-, invasive intermediate risk early-stage breast cancer. Participants will be randomised 2:1 to the preoperative testing of the diagnostic core biopsy compared to the post-operative testing of the excision specimen. The primary endpoint is number of clinical touchpoints between treating team and patient from initial approach until offer and prescription of the first adjuvant treatment. Secondary endpoints include time from diagnosis to offer and prescription of the first adjuvant treatment, patient-reported anxiety scores and health cost impact analysis collected at baseline, following the post-operative clinic and following the offer of adjuvant treatment, and number of alterations in treatment sequence from original planned surgical treatment to neoadjuvant therapy. TRIAL REGISTRATION: The study was registered on ISRCTN (ISRCTN14337451) on the 16th August 2022.


Asunto(s)
Neoplasias de la Mama , Carcinoma , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Receptores de Estrógenos/metabolismo , Quimioterapia Adyuvante/métodos , Terapia Neoadyuvante , Adyuvantes Inmunológicos/uso terapéutico , Perfilación de la Expresión Génica/métodos , Carcinoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Ensayos Clínicos Controlados Aleatorios como Asunto
12.
Bull Cancer ; 111(4): 356-362, 2024 Apr.
Artículo en Francés | MEDLINE | ID: mdl-38453587

RESUMEN

INTRODUCTION: Evaluating the benefits and risks of prolonged hormonal treatment with aromatase inhibitors (AIs) for treating hormone-dependent breast cancer. METHODS: A systematic review and meta-analysis was conducted. Studies reporting on randomized clinical trials concerning prolongating hormonal therapy with AIs as compared to a placebo or no prolongation, after an initial five years of hormonal therapy, were eligible. RESULTS: Seven clinical trials were included. Prolonged AI therapy was associated with a statistically significant improvement in disease-free survival (RR=0.70, 95% CI 0.60 to 0.80). A statistically significant increase was observed for osteoporosis (RR=1.17, 95% CI 1.03 to 1.33), hot flushes/flashes (RR=1.27, 95% CI 1.08 to 1.49), myalgia (RR=1.23, 95% CI 1.09 to 1.39), fractures (RR=1.26, 95% CI 1.09 to 1.45) and arthralgia (RR=1.17, 95% CI 1.10 to 1.25). However, no statistically significant association was observed between prolonged AI therapy and overall survival, cardiovascular events, and bone pain. DISCUSSION: Prolonged AI therapy has significant benefits in terms of disease-free survival in women with hormone-dependent breast cancer. However, adverse effects and a lack of evidence for a benefit on overall survival must be considered in the decision-making process regarding adjuvant hormone therapy extension.


Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de la Aromatasa/efectos adversos , Terapia Combinada , Quimioterapia Adyuvante/efectos adversos , Adyuvantes Inmunológicos/uso terapéutico , Hormonas/uso terapéutico , Antineoplásicos Hormonales/efectos adversos , Tamoxifeno/efectos adversos
13.
World J Urol ; 42(1): 185, 2024 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-38512511

RESUMEN

PURPOSE: The International Bladder Cancer Group designated the subgroup that is resistant to Bacillus Calmette-Guérin (BCG) but does not meet the criteria for BCG-unresponsive NMIBC as "BCG-exposed high-risk NMIBC" to guide optimal trial design. We aimed to investigate the treatment patterns and prognoses of patients with BCG-exposed NMIBC. METHODS: We conducted a retrospective chart review of 3283 patients who received intravesical BCG therapy for NMIBC at 14 participating institutions between January 2000 and December 2019. Patients meeting the criteria for BCG-exposed and BCG-unresponsive NMIBC, as defined by the Food and Drug Administration and International Bladder Cancer Group, were selected. To compare treatment patterns and outcomes, high-risk recurrence occurring more than 24 months after the last dose of BCG was defined as "BCG-treated NMIBC." In addition, we compared prognoses between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. RESULTS: Of 3283 patients, 108 (3.3%), 150 (4.6%), and 391 (11.9%) were classified as having BCG-exposed, unresponsive, and treated NMIBC, respectively. BCG-exposed NMIBC demonstrated intermediate survival curves for intravesical recurrence-free and progression-free survival, falling between those of BCG-unresponsive and treated NMIBC. Among patients with BCG-exposed NMIBC, 48 (44.4%) received BCG rechallenge, which was the most commonly performed treatment, and 19 (17.6%) underwent early cystectomy. No significant differences were observed between BCG rechallenge and early cystectomy in patients with BCG-exposed NMIBC. CONCLUSIONS: The newly proposed definition of BCG-exposed NMIBC may serve as a valuable disease subgroup for distinguishing significant gray areas, except in cases of BCG-unresponsive NMIBC.


Asunto(s)
Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Estudios Retrospectivos , Adyuvantes Inmunológicos/uso terapéutico , Pronóstico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Análisis de Datos , Administración Intravesical , Invasividad Neoplásica , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/tratamiento farmacológico
14.
Bull Exp Biol Med ; 176(4): 466-471, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38488964

RESUMEN

We studied the possibility of using 4-hexylresorcinol to increase the efficiency of anti-mycobacterial chemotherapy. In an in vitro experiment, 4-hexylresorcinol increased the efficiency of rifampicin, kanamycin, and isoniazid against Mycobacterium smegmatis by 3-5 times. Experiments in sanitation of BALB/c mice infected with M. smegmatis showed the best efficacy of the isoniazid and 4-hexylresorcinol combination in comparison with isoniazid monotherapy. The growth-inhibiting activity of the combination of antibiotic rifabutin with 4-hexylresorcinol was shown on 6 strains of M. tuberculosis. A 2-fold decrease in the minimum inhibitory concentration of this antibiotic in the presence of half-minimum inhibitory concentration of 4-hexylresorcinol was demonstrated for monoresistant strain M. tuberculosis 5360/42Hr. On the mouse model of experimental tuberculosis caused by M. tuberculosis H37Rv, a 5-fold decrease in lung contamination and more rapid complete cure were achieved in animals treated with the combination of rifabutin and 4-hexylresorcinol in comparison with rifabutin monotherapy.


Asunto(s)
Hexilresorcinol , Mycobacterium tuberculosis , Tuberculosis , Animales , Ratones , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Isoniazida/farmacología , Isoniazida/uso terapéutico , Hexilresorcinol/farmacología , Rifabutina/farmacología , Rifabutina/uso terapéutico , Tuberculosis/tratamiento farmacológico , Pruebas de Sensibilidad Microbiana , Adyuvantes Inmunológicos/uso terapéutico
15.
J Immunother Cancer ; 12(3)2024 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-38485189

RESUMEN

BACKGROUND: Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) versus placebo in the phase 3 KEYNOTE-716 study of resected stage IIB or IIC melanoma. At the prespecified third interim analysis (data cut-off, January 4, 2022), the HR for RFS in the overall population was 0.64 (95% CI, 0.50 to 0.84) and the HR for DMFS was 0.64 (95% CI, 0.47 to 0.88). We present a post hoc analysis of efficacy by subtypes defined by histopathologic characteristics. METHODS: Patients aged ≥12 years with newly diagnosed, resected stage IIB or IIC melanoma were randomly assigned (1:1) to pembrolizumab 200 mg every 3 weeks (2 mg/kg up to 200 mg for pediatric patients) or placebo. The primary end point was RFS per investigator review; DMFS per investigator review was secondary. Subgroups of interest were melanoma subtype (nodular vs non-nodular), tumor thickness (≤4 mm vs >4 mm), presence of ulceration (yes vs no), mitotic rate (<5 per mm2 (median) vs ≥5 per mm2), and presence of tumor-infiltrating lymphocytes (TILs; absent vs present). RESULTS: Between September 23, 2018, and November 4, 2020, 976 patients were assigned to pembrolizumab (n=487) or placebo (n=489). Median follow-up was 27.4 months (range, 14.0-39.4). The HR (95% CI) for RFS was 0.54 (0.37 to 0.79) for nodular and 0.77 (0.53 to 1.11) for non-nodular melanoma; 0.57 (0.37 to 0.89) for thickness ≤4 mm and 0.69 (0.50 to 0.96) for >4 mm; 0.66 (0.50 to 0.89) for ulceration and 0.57 (0.32 to 1.03) for no ulceration; 0.57 (0.35 to 0.92) for mitotic rate <5 per mm2 and 0.57 (0.40 to 0.80) for ≥5 per mm2; and 0.89 (0.52 to 1.54) for TILs absent and 0.51 (0.34 to 0.76) for TILs present. DMFS results were similar. In a Cox multivariate analysis, treatment arm, tumor thickness, and mitotic rate were significant independent factors for RFS, and treatment arm and mitotic rate were significant independent factors for DMFS. CONCLUSIONS: In this post hoc analysis, the benefit of pembrolizumab was largely consistent with the overall study population regardless of histopathologic characteristics. These results support the use of adjuvant pembrolizumab in patients with resected stage IIB or IIC melanoma. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT03553836.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Niño , Melanoma/patología , Neoplasias Cutáneas/patología , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Combinada , Adyuvantes Inmunológicos/uso terapéutico
16.
Arch Ital Urol Androl ; 96(1): 12244, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38502039

RESUMEN

PURPOSE: To understand the treatment plans suggested for BCG-unresponsive non-muscle invasive disease (NMIBC) patients in the Arab countries and therapeutic decisions applied for BCG-naive patients during BCG shortage time. METHODS: A 10-minute online survey was distributed through the Arab Association of Urology (AAU) office to urologists in the Arab countries who treat patients with NMIBC. RESULTS: One hundred six urologists responded to the survey. The majority of urologists had treated, in the past 6 months, > 10 patients with NMIBC who were considered BCG-unresponsive (55% of respondents). Radical cystectomy (RC) was the most popular treatment option (recommended by 50%) for these patients. This was followed by intravesical chemotherapy (30%), repeat BCG therapy (12%), resection with ongoing surveillance (8%). Clinical trials and intravenous checkpoint inhibitors were never selected. The most preferred intravesical chemotherapy was by ranking: 60% gemcitabine, 19% mitomycin C, 8% docetaxel, 8% gemcitabine/docetaxel, 4% sequential gemcitabine/mitomycin C, and 1% valrubicin. The use of intravesical chemotherapy appears limited by Arab urologists due to concerns regarding clinical efficacy (fear of progression) and the lack of clear recommendations by urology societies. Given the BCG shortage, which may vary per Arab country, Arab urologists have adjusted by prioritizing BCG for T1 and carcinoma in situ (CIS) patients over Ta, adapting intravesical chemotherapy, and reducing the dose/strength of BCG administered. Most physicians report an eagerness to utilize novel therapies to address the BCG deficit, especially to try intravesical chemotherapy. CONCLUSIONS: Even though Arab urologists are in the majority of cases selecting RC for BCG-unresponsive cases, one-third of them are most recently initiating intravesical chemotherapy as an alternative option. To further assist Arab urologists in the appropriate selection of BCG unresponsive high risk NMIBC patient treatments, enhanced education and pathway protocols are needed.


Asunto(s)
Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Mitomicina/uso terapéutico , Gemcitabina , Vacuna BCG/uso terapéutico , Urólogos , Docetaxel/uso terapéutico , Árabes , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Invasividad Neoplásica , Adyuvantes Inmunológicos/uso terapéutico , Recurrencia Local de Neoplasia
17.
JAMA Dermatol ; 160(4): 385-386, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38477923

RESUMEN

This Viewpoint reviews the evidence for immune checkpoint inhibitor use in the adjuvant setting, discusses the individual and societal risks, benefits, and costs associated with immune checkpoint inhibitors, and highlights the need for more targeted patient selection approaches.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adyuvantes Inmunológicos/uso terapéutico , Inmunoterapia , Medición de Riesgo
18.
J Alzheimers Dis ; 98(2): 361-372, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38393913

RESUMEN

 There is growing awareness that infections may contribute to the development of senile dementia including Alzheimer's disease (AD), and that immunopotentiation is therefore a legitimate target in the management of diseases of the elderly including AD. In Part I of this work, we provided a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents, culminating in the development of the tuberculosis vaccine strain Bacille Calmette-Guérin (BCG) as a treatment for some types of cancer as well as a prophylactic against infections of the elderly such as pneumonia. In Part II, we critically review studies that BCG and other vaccines may offer a measure of protection against dementia development. Five studies to date have determined that intravesicular BCG administration, the standard of care for bladder cancer, is followed by a mean ∼45% reduction in subsequent AD development in these patients. Although this could potentially be ascribed to confounding factors, the finding that other routine vaccines such as against shingles (herpes zoster virus) and influenza (influenza A virus), among others, also offer a degree of protection against AD (mean 29% over multiple studies) underlines the plausibility that the protective effects are real. We highlight clinical trials that are planned or underway and discuss whether BCG could be replaced by key components of the mycobacterial cell wall such as muramyl dipeptide. We conclude that BCG and similar agents merit far wider consideration as prophylactic agents against dementia.


Asunto(s)
Enfermedad de Alzheimer , Vacunas contra la Tuberculosis , Humanos , Anciano , Vacuna BCG/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/tratamiento farmacológico
19.
Urol Oncol ; 42(3): 69.e17-69.e25, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38302296

RESUMEN

BACKGROUND: In patients affected by high-risk nonmuscle invasive bladder cancer (HR-NMIBC) progression to muscle invasive status is considered as the main indicator of local treatment failure. We aimed to investigate the effect of progression and time to progression on overall survival (OS) and to investigate their validity as surrogate endpoints. METHODS: A total of 1,510 patients from 18 different institutions treated for T1 high grade NMIBC, followed by a secondary transurethral resection and BCG intravesical instillation. We relied on random survival forest (RSF) to rank covariates based on OS prediction. Cox's regression models were used to quantify the effect of covariates on mortality. RESULTS: During a median follow-up of 49.0 months, 485 (32.1%) patients progressed to MIBC, while 163 (10.8%) patients died. The median time to progression was 82 (95%CI: 78.0-93.0) months. In RSF time-to-progression and age were the most predictive covariates of OS. The survival tree defined 5 groups of risk. In multivariable Cox's regression models accounting for progression status as time-dependent covariate, shorter time to progression (as continuous covariate) was associated with longer OS (HR: 9.0, 95%CI: 3.0-6.7; P < 0.001). Virtually same results after time to progression stratification (time to progression ≥10.5 months as reference). CONCLUSION: Time to progression is the main predictor of OS in patients with high risk NMIBC treated with BCG and might be considered a coprimary endpoint. In addition, models including time to progression could be considered for patients' stratification in clinical practice and at the time of clinical trials design.


Asunto(s)
Neoplasias Vesicales sin Invasión Muscular , Neoplasias de la Vejiga Urinaria , Humanos , Vacuna BCG/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias de la Vejiga Urinaria/cirugía , Insuficiencia del Tratamiento , Invasividad Neoplásica , Administración Intravesical , Adyuvantes Inmunológicos/uso terapéutico , Estudios Retrospectivos
20.
Biochim Biophys Acta Rev Cancer ; 1879(2): 189084, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38354828

RESUMEN

Immunotherapy has revolutionized cancer treatment. However, it's well-recognized that a considerable proportion of patients fail to benefit from immunotherapy, and to improve immunotherapy response is clinically urgent. Insufficient immune infiltration and immunosuppressive tumor microenvironments (TME) are main contributors to immunotherapy resistance. Thus sustaining functional self-renewal capacity for immune cells and subverting immune-suppressive signals are potential strategies for boosting the efficacy of immunotherapy. Interleukin-21 (IL-21), a crucial cytokine, which could enhance cytotoxic function of immune cells and reduces immunosuppressive cells enrichment in TME, shows promising orientations as an immunoadjuvant in tumor immunotherapy. This review focuses on IL-21 in cancer treatment, including function and mechanisms of IL-21, preclinical and clinical studies, and future directions for IL-21-assisted therapies.


Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Inmunoterapia , Interleucinas/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias/patología
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