RÉSUMÉ
Background: Angioimmunoblastic T-cell lymphoma (AITL) is known for its unfavorable survival prognosis. Chidamide has shown efficacy in relapsed/refractory AITL, but its efficacy in newly diagnosed AITL is uncertain. Objective: This retrospective research aimed to evaluate the effectiveness and safety of chidamide when used with doxorubicin, cyclophosphamide, prednisone, and vincristine (CHOP) in comparison to CHOP by itself for individuals newly diagnosed with AITL, and to examine the impact of transplantation. Method: This was an analysis that compared outcomes among patients who received chidamide + CHOP on a clinical trial vs. historical controls who received CHOP alone, enrolling a total of sixty-six treatment-naive AITL patients between April 2014 and November 2022. Among them, thirty-three received chidamide in addition to CHOP (chidamide group), while thirty-three received CHOP alone (control group). The clinical characteristics were balanced between the two groups. All patients were scheduled to undergo up to six courses of treatment before transplantation. Results: The chidamide group had a significantly longer median overall survival (OS) compared to the control group, with a median OS that was not reached, as opposed to 20 months in the control group (p = 0.002). In the control group, the median progression-free survival (PFS) was 11 months, while in the chidamide group, it was 22 months (p = 0.080). In the high-risk group (IPI ≥ 3), the chidamide group demonstrated notably superior complete response (CR) and overall response rate (ORR) compared to the control cohort (p = 0.002, p = 0.034). The PFS and OS in the chidamide group were not reached, and there were significant differences compared to the control group (p = 0.007, p = 0.003). The median OS of the transplanted group was longer than the non-transplanted group (p = 0.004). On multivariate analysis, chidamide group reduced the hazards of death in the total cohort. Conclusion: As the study was non-random and retrospective, Chidamide combined with chemotherapy should be tested in randomized trials given its potential to improve prognosis in treatment-naive AITL patients. Furthermore, autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated enhanced overall survival in individuals with AITL. Clinical trial registration: https://clinicaltrials.gov/, NCT03268889.
Sujet(s)
Aminopyridines , Protocoles de polychimiothérapie antinéoplasique , Benzamides , Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Aminopyridines/usage thérapeutique , Aminopyridines/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Benzamides/usage thérapeutique , Benzamides/administration et posologie , Benzamides/effets indésirables , Cyclophosphamide/usage thérapeutique , Cyclophosphamide/administration et posologie , Doxorubicine/usage thérapeutique , Doxorubicine/administration et posologie , Doxorubicine/effets indésirables , Lymphome T/mortalité , Lymphome T/thérapie , Lymphome T/traitement médicamenteux , Lymphome T/diagnostic , Prednisone/usage thérapeutique , Prednisone/administration et posologie , Études rétrospectives , Résultat thérapeutique , Vincristine/usage thérapeutique , Vincristine/administration et posologieRÉSUMÉ
BACKGROUND: In the last decade, a fundamental shift in the treatment of cystic fibrosis (CF) took place due to the introduction of CF transmembrane conductance regulator (CFTR) modulators. Adequate medication adherence is a prerequisite for their effectiveness, but little is known about adherence to CFTR modulators. We aimed to assess the extent of medication adherence to CFTR modulators in patients with CF and assess which characteristics are associated with adherence. METHODS: A systematic review following PRISMA guidelines was performed. Studies needed to report adherence to CFTR modulators. Main outcomes were: 1) level of medication adherence and 2) associations of demographic and/or clinical characteristics with adherence. RESULTS: In total, 4082 articles were screened and 21 full-text papers were assessed for eligibility. Ultimately, seven studies were included. Most studies were retrospective and focused on adherence to ivacaftor or lumacaftor-ivacaftor with only one focusing on elexacaftor-tezacaftor-ivacaftor. The majority used pharmacy refill data with adherence determined with the proportion of days covered (PDC) or the medication possession ratio (MPR). One study additionally used electronic monitoring and patient self-reported adherence. Adherence was 0.62-0.99 based on pharmacy data (PDC or MPR), 61% via electronic monitoring and 100% via self-report. Age <18â years appeared to be associated with good adherence, as was a higher lung function. CONCLUSIONS: Despite the wide variety of adherence methods used, adherence to CFTR modulators is suboptimal, based on objective measures such as pharmacy refill data or electronic monitoring. CFTR modulator adherence measurement and definitions requires more standardisation with a preference for objective and granular methods.
Sujet(s)
Protéine CFTR , Mucoviscidose , Adhésion au traitement médicamenteux , Mucoviscidose/traitement médicamenteux , Mucoviscidose/physiopathologie , Humains , Protéine CFTR/génétique , Résultat thérapeutique , Agonistes de canaux chlorure/usage thérapeutique , Quinolinone/usage thérapeutique , Femelle , Mâle , Adolescent , Jeune adulte , Association médicamenteuse , Adulte , Enfant , Aminophénols/usage thérapeutique , Aminopyridines/usage thérapeutique , Poumon/effets des médicaments et des substances chimiques , Poumon/physiopathologie , Enfant d'âge préscolaire , BenzodioxolesRÉSUMÉ
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
Sujet(s)
Aminopyridines , Protocoles de polychimiothérapie antinéoplasique , Tumeurs du sein , Pipérazines , Purines , Pyridines , Récepteur ErbB-2 , Récepteurs des oestrogènes , Humains , Pipérazines/administration et posologie , Pipérazines/effets indésirables , Pipérazines/usage thérapeutique , Femelle , Pyridines/administration et posologie , Pyridines/usage thérapeutique , Pyridines/effets indésirables , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/mortalité , Tumeurs du sein/anatomopathologie , Aminopyridines/administration et posologie , Aminopyridines/usage thérapeutique , Aminopyridines/effets indésirables , Purines/administration et posologie , Purines/effets indésirables , Adulte d'âge moyen , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Études rétrospectives , Thaïlande/épidémiologie , Sujet âgé , Récepteur ErbB-2/métabolisme , Adulte , Récepteurs des oestrogènes/métabolisme , Inhibiteurs de l'aromatase/administration et posologie , Inhibiteurs de l'aromatase/usage thérapeutique , Récepteurs à la progestérone/métabolisme , Survie sans progressionRÉSUMÉ
BACKGROUND: Abemaciclib was newly approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer (EBC). Clinical guidelines recommended abemaciclib as the first-line treatment for HR+/ HER2- EBC (early use) or HR+/ HER2- metastatic breast cancer (MBC) (delayed use). OBJECTIVE: To compare the cost-effectiveness of early vs delayed use of abemaciclib for treatment of HR+/HER2- high-risk EBC. Early use was defined as combined abemaciclib and endocrine therapy as first-line therapy for EBC, followed by treatment with fulvestrant for MBC. Delayed use was defined as endocrine therapy for EBC, followed by combined abemaciclib and fulvestrant therapy for MBC. METHODS: A 5-state model was developed to estimate lifetime costs, life-years (LYs), and quality-adjusted life-years (QALYs) of hypothetical patients with HR+/ HER2- EBC from a third-party US payer's perspective. Key clinical and safety data were derived from the monarchE and MONARCH 2 clinical trials. Costs, utilities, and disutility values of adverse events were obtained from the literature. We calculated the incremental cost-effectiveness ratio (ICER) of early vs delayed abemaciclib use and compared it with a willingness-to-pay (WTP) threshold of $100,000 per LY or QALY. Deterministic and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the base-case model. RESULTS: Base-case analysis showed early use yielded 21.08 LYs and 17.93 QALYs for $586,213 and delayed use yielded 11.14 LYs and 9.38 QALYs for $157,576. The ICER of early vs delayed use was $43,136/LY and $50,104/QALY, which was cost-effective at the WTP threshold of $100,000. The PSA result indicated that a 94.6% likelihood of early use (vs delayed use) was cost-effective at the WTP threshold of $100,000 per QALY. CONCLUSIONS: This study suggests that giving abemaciclib in the early stage rather than waiting until patients develop metastatic disease (current standard of care in MBC) is a cost-effective strategy.
Sujet(s)
Aminopyridines , Protocoles de polychimiothérapie antinéoplasique , Benzimidazoles , Tumeurs du sein , Analyse coût-bénéfice , Années de vie ajustées sur la qualité , Récepteur ErbB-2 , Humains , Benzimidazoles/économie , Benzimidazoles/usage thérapeutique , Benzimidazoles/administration et posologie , Aminopyridines/économie , Aminopyridines/usage thérapeutique , Aminopyridines/administration et posologie , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Récepteur ErbB-2/métabolisme , Protocoles de polychimiothérapie antinéoplasique/économie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Récepteurs des oestrogènes/métabolisme , Récepteurs à la progestérone/métabolismeRÉSUMÉ
BACKGROUND: In relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. METHODS: A cohort of 27 ineligible patients with R/R DLBCL participated in an open - label, single - arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one-week discontinuation period, in conjunction with intravenous R-GDP every 21 days. RESULTS: Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C-R-GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%-83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%-49.9%) and a partial response rate of 33.3% (95% CI: 29.3%-37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow-up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression-free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. CONCLUSIONS: Chidamide combined with R-GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.
Sujet(s)
Aminopyridines , Protocoles de polychimiothérapie antinéoplasique , Benzamides , Lymphome B diffus à grandes cellules , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Femelle , Humains , Mâle , Adulte d'âge moyen , Aminopyridines/effets indésirables , Aminopyridines/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Benzamides/effets indésirables , Benzamides/usage thérapeutique , Lymphome B diffus à grandes cellules/traitement médicamenteux , Lymphome B diffus à grandes cellules/mortalité , Récidive tumorale locale , Études prospectives , Transplantation autologueRÉSUMÉ
BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangements are rare in non-myofibroblastic sarcoma and there is limited data on the efficacy of ALK tyrosine kinase inhibitors (TKIs) and mechanisms of resistance in these patients. CASE: A 58 year-old man with metastatic non-myofibroblastic sarcoma was found to have an EML4-ALK fusion on molecular sequencing. After progression on first line systemic therapy with doxorubicin, the patient received alectinib, a second generation ALK inhibitor, and had a marked clinical and radiological response. He progressed after 5 months of treatment. Repeat lung biopsy identified the emergence of an ALK I1171N resistance mutation. He was then treated with lorlatinib, again with rapid clinical improvement and significant partial radiological response. He progressed after 4 months, at which time a repeat lung biopsy identified a new ALK kinase domain mutation G1202R. The patient was subsequently treated with chemotherapy, though unfortunately died shortly after due to rapidly progressive disease. CONCLUSION: This case report adds to a body of evidence demonstrating the potential transformative response to targeted therapy in non-lung solid organ tumours harbouring ALK fusions. This is the first description tracking the development of resistance mutations in a patient with non-myofibroblastic sarcoma and questions the utility of the presence of G1202R mutation as a marker of lorlatinib sensitivity in non-lung ALK rearranged tumours, contrary to experience in lung cancer.
Sujet(s)
Kinase du lymphome anaplasique , Résistance aux médicaments antinéoplasiques , Lactames macrocycliques , Lactames , Mutation , Protéines de fusion oncogènes , Inhibiteurs de protéines kinases , Sarcomes , Humains , Mâle , Protéines de fusion oncogènes/génétique , Adulte d'âge moyen , Résistance aux médicaments antinéoplasiques/génétique , Inhibiteurs de protéines kinases/usage thérapeutique , Kinase du lymphome anaplasique/génétique , Kinase du lymphome anaplasique/antagonistes et inhibiteurs , Sarcomes/génétique , Sarcomes/traitement médicamenteux , Sarcomes/anatomopathologie , Lactames macrocycliques/usage thérapeutique , Pyrazoles/usage thérapeutique , Issue fatale , Aminopyridines/usage thérapeutique , Carbazoles/usage thérapeutique , Carbazoles/administration et posologie , Pipéridines/usage thérapeutiqueRÉSUMÉ
Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods: The study population consisted of patients aged ≥40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010-2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for "ever use" of roflumilast, compared to "never use", were 1.12 (95% CI, 1.08-1.17) in Germany, 1.00 (95% CI, 0.92-1.08) in Norway, 0.98 (95% CI, 0.92-1.04) in Sweden, and 1.16 (95% CI, 1.12-1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among "current users" in Germany (HR: 0.93, 95% CI: 0.88-0.98), Norway (HR: 0.77, 95% CI: 0.67-0.87), and Sweden (HR: 0.80, 95% CI: 0.73-0.88). Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.
Sujet(s)
Aminopyridines , Benzamides , Cyclopropanes , Bases de données factuelles , Inhibiteurs de la phosphodiestérase-4 , Broncho-pneumopathie chronique obstructive , Humains , Cyclopropanes/effets indésirables , Cyclopropanes/usage thérapeutique , Broncho-pneumopathie chronique obstructive/traitement médicamenteux , Broncho-pneumopathie chronique obstructive/mortalité , Broncho-pneumopathie chronique obstructive/diagnostic , Mâle , Femelle , Inhibiteurs de la phosphodiestérase-4/effets indésirables , Inhibiteurs de la phosphodiestérase-4/usage thérapeutique , Benzamides/effets indésirables , Benzamides/usage thérapeutique , Adulte d'âge moyen , Sujet âgé , Aminopyridines/usage thérapeutique , Aminopyridines/effets indésirables , Facteurs temps , Résultat thérapeutique , Facteurs de risque , États-Unis/épidémiologie , Bronchite chronique/traitement médicamenteux , Bronchite chronique/mortalité , Bronchite chronique/épidémiologie , Appréciation des risques , Allemagne , Adulte , Suède/épidémiologie , Sujet âgé de 80 ans ou plusRÉSUMÉ
INTRODUCTION: Psoriasis is an immune-mediated inflammatory skin disease. First-line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti-inflammatory mechanisms and promising efficacy profiles. MATERIALS AND METHODS: This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment. RESULTS: Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild-to-moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects. DISCUSSION: Tapinarof and roflumilast offer once-daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost-effectiveness between the two drugs. CONCLUSION: Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice.
Sujet(s)
Aminopyridines , Benzamides , Cyclopropanes , Psoriasis , Humains , Aminopyridines/administration et posologie , Aminopyridines/effets indésirables , Aminopyridines/usage thérapeutique , Psoriasis/traitement médicamenteux , Cyclopropanes/effets indésirables , Cyclopropanes/administration et posologie , Cyclopropanes/usage thérapeutique , Benzamides/effets indésirables , Benzamides/administration et posologie , Benzamides/usage thérapeutique , Résultat thérapeutique , Administration par voie topique , Inhibiteurs de la phosphodiestérase-4/administration et posologie , Inhibiteurs de la phosphodiestérase-4/effets indésirables , Inhibiteurs de la phosphodiestérase-4/usage thérapeutique , Produits dermatologiques/administration et posologie , Produits dermatologiques/effets indésirables , Produits dermatologiques/usage thérapeutique , Administration par voie cutanée , Résorcinol , StilbènesRÉSUMÉ
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Sujet(s)
Aminopyridines , Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Pipérazines , Inhibiteurs de protéines kinases , Purines , Pyridines , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Adulte d'âge moyen , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Pyridines/usage thérapeutique , Études rétrospectives , Sujet âgé , Pipérazines/usage thérapeutique , Aminopyridines/usage thérapeutique , Purines/usage thérapeutique , Taïwan , Inhibiteurs de protéines kinases/usage thérapeutique , Récidive tumorale locale/traitement médicamenteux , Adulte , Récepteurs des oestrogènes/métabolisme , Récepteurs à la progestérone/métabolisme , Résultat thérapeutique , Métastase tumorale , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , AsiatiquesRÉSUMÉ
BACKGROUND: The MONALEESA7 and 2 phase 3 randomized trials demonstrated a statistically significant progressionfree survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre and postmenopausal patients with hormone receptorpositive (HR+)/human epidermal growth factor receptor 2negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre and postmenopausal patients with HR+/HER2 ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA7 and 2 studies. METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigatorassessed PFS. RESULTS: As of April 25, 2022, the median followup was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. CONCLUSIONS: These data demonstrate a favorable benefitrisk profile for ribociclib + ET in Chinese patients.
Sujet(s)
Aminopyridines , Protocoles de polychimiothérapie antinéoplasique , Tumeurs du sein , Létrozole , Post-ménopause , Purines , Récepteur ErbB-2 , Récepteurs des oestrogènes , Humains , Aminopyridines/administration et posologie , Aminopyridines/usage thérapeutique , Aminopyridines/effets indésirables , Femelle , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/mortalité , Tumeurs du sein/anatomopathologie , Tumeurs du sein/métabolisme , Purines/administration et posologie , Purines/effets indésirables , Adulte d'âge moyen , Récepteur ErbB-2/métabolisme , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Récepteurs des oestrogènes/métabolisme , Létrozole/administration et posologie , Létrozole/usage thérapeutique , Adulte , Chine , Sujet âgé , Récepteurs à la progestérone/métabolisme , Préménopause , Survie sans progression , Goséréline/administration et posologie , Goséréline/usage thérapeutique , Inhibiteurs de l'aromatase/administration et posologie , Inhibiteurs de l'aromatase/usage thérapeutique , Peuples d'Asie de l'EstRÉSUMÉ
BACKGROUND: In luminal breast cancer, adjuvant CDK4/6 inhibitors (eg, abemaciclib) improve invasive disease-free survival. In patients with T1-2, grade 1-2 tumours, and one or two sentinel lymph node metastases, completion axillary lymph node dissection (cALND) is the only prognostic tool available that can reveal four or more nodal metastases (pN2-3), which is the only indication for adjuvant abemaciclib in this setting. However, this technique can lead to substantial arm morbidity in patients. We aimed to pragmatically describe the potential benefit and harm of this strategy on the individual patient level in patients from the ongoing SENOMAC trial. METHODS: In the randomised, phase 3, SENOMAC trial, patients aged 18 years or older, of any performance status, with clinically node-negative T1-T3 breast cancer and one or two sentinel node macrometastases from 67 sites in five European countries (Denmark, Germany, Greece, Italy, and Sweden) were randomly assigned (1:1), via permutated block randomisation (random block size of 2 and 4) stratified by country, to either cALND or its omission (ie, they had a sentinel lymph node biopsy only). The primary outcome is overall survival, which is yet to be reported. In this post-hoc analysis, patients from the SENOMAC per-protocol population, with luminal oestrogen-receptor positive, HER2-negative, T1-2, histological grade 1-2 breast cancer, with tumour size of 5 cm or smaller were selected to match the characteristics of cohort 1 of the monarchE trial who would only have an indication for adjuvant abemaciclib if found to have 4 or more nodal metastases. The primary study objective was to determine the number of patients who developed patient-reported severe or very severe impairment of physical arm function after cALND (as measured by the Lymphedema Functioning, Disability, and Health [Lymph-ICF] Questionnaire) 1 year after surgery to avoid one invasive disease-free survival event at 5 years with 2 years of adjuvant abemaciclib, using invasive disease-free survival event data from cohort 1 of the monarchE trial. The SENOMAC trial is registered with ClincialTrials.gov, NCT02240472, and is closed to accrual and ongoing. FINDINGS: Between Jan 31, 2015, and Dec 31, 2021, 2766 patients were enrolled in SENOMAC and randomly assigned to cALND (n=1384) or sentinel node biopsy only (n=1382), of whom 2540 were included in the per-protocol population. 1705 (67%) of 2540 patients met this post-hoc study's eligibility criteria, of whom 802 (47%) had a cALND and 903 (53%) had a sentinel lymph node biopsy only. Median age at randomisation was 62 years (IQR 52-71), 1699 (>99%) of 1705 patients were female, and six (<1%) were male. Among 1342 patients who responded to questionnaires, after a median follow-up of 45·2 months (IQR 25·6-59·8; data cutoff Nov 17, 2023), patient-reported severe or very severe impairment of physical arm function was reported in 84 (13%) of 634 patients who had cALND versus 30 (4%) of 708 who had sentinel lymph node biopsy only (χ2 test p<0·0001). To avoid one invasive disease-free survival event at 5 years with adjuvant abemaciclib, cALND would need to be performed in 104 patients, and would result in nine patients having severe or very severe impairment of physical arm function 1 year after surgery. INTERPRETATION: As a method to potentially identify an indication for abemaciclib, and subsequently avoid invasive disease-free survival events at 5 years with 2 years of adjuvant abemaciclib, cALND carries a substantial risk of severe or very severe arm morbidity and so cALND should be discouraged for this purpose. FUNDING: Swedish Research Council, the Swedish Cancer Society, the Nordic Cancer Union, and the Swedish Breast Cancer Association.
Sujet(s)
Tumeurs du sein , Lymphadénectomie , Métastase lymphatique , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/chirurgie , Femelle , Adulte d'âge moyen , Sujet âgé , Traitement médicamenteux adjuvant , Aisselle , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Adulte , Aminopyridines/usage thérapeutique , Stadification tumorale , Inhibiteurs de protéines kinases/usage thérapeutique , Survie sans rechute , BenzimidazolesRÉSUMÉ
CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Inhibiteurs de protéines kinases , Femelle , Humains , Aminopyridines/usage thérapeutique , Aminopyridines/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Benzimidazoles/usage thérapeutique , Benzimidazoles/effets indésirables , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Traitement médicamenteux adjuvant , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirables , Purines/usage thérapeutique , Purines/effets indésirables , Essais contrôlés randomisés comme sujetRÉSUMÉ
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.
Sujet(s)
Aminopyridines , Benzamides , Étoposide , Glucocorticoïdes , Lymphohistiocytose hémophagocytaire , Humains , Étoposide/administration et posologie , Étoposide/effets indésirables , Étoposide/usage thérapeutique , Mâle , Femelle , Lymphohistiocytose hémophagocytaire/traitement médicamenteux , Lymphohistiocytose hémophagocytaire/mortalité , Adulte , Adulte d'âge moyen , Benzamides/administration et posologie , Benzamides/effets indésirables , Benzamides/usage thérapeutique , Glucocorticoïdes/administration et posologie , Glucocorticoïdes/usage thérapeutique , Glucocorticoïdes/effets indésirables , Aminopyridines/administration et posologie , Aminopyridines/effets indésirables , Aminopyridines/usage thérapeutique , Résultat thérapeutique , Sujet âgé , Association de médicaments , Inhibiteurs de désacétylase d'histone/usage thérapeutique , Inhibiteurs de désacétylase d'histone/effets indésirables , Inhibiteurs de désacétylase d'histone/administration et posologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirablesRÉSUMÉ
BACKGROUND: Painful diabetic neuropathy (PDN) is closely linked to inflammation, which has been demonstrated to be associated with pyroptosis. Emerging evidence has implicated TANK-binding kinase 1 (TBK1) in various inflammatory diseases. However, it remains unknown whether activated TBK1 causes hyperalgesia via pyroptosis. METHODS: PDN mice model of type 1 or type 2 diabetic was induced by C57BL/6J or BKS-DB mice with Lepr gene mutation. For type 2 diabetes PDN model, TBK1-siRNA, Caspase-1 inhibitor Ac-YVAD-cmk or TBK1 inhibitor amlexanox (AMX) were delivered by intrathecal injection or intragastric administration. The pain threshold and plantar skin blood perfusion were evaluated through animal experiments. The assessments of spinal cord, dorsal root ganglion, sciatic nerve, plantar skin and serum included western blotting, immunofluorescence, ELISA, and transmission electron microscopy. RESULTS: In the PDN mouse model, we found that TBK1 was significantly activated in the spinal dorsal horn (SDH) and mainly located in microglia, and intrathecal injection of chemically modified TBK1-siRNA could improve hyperalgesia. Herein, we described the mechanism that TBK1 could activate the noncanonical nuclear factor κB (NF-κB) pathway, mediate the activation of NLRP3 inflammasome, trigger microglia pyroptosis, and ultimately induce PDN, which could be reversed following TBK1-siRNA injection. We also found that systemic administration of AMX, a TBK1 inhibitor, could effectively improve peripheral nerve injury. These results revealed the key role of TBK1 in PDN and that TBK1 inhibitor AMX could be a potential strategy for treating PDN. CONCLUSIONS: Our findings revealed a novel causal role of TBK1 in pathogenesis of PDN, which raises the possibility of applying amlexanox to selectively target TBK1 as a potential therapeutic strategy for PDN.
Sujet(s)
Neuropathies diabétiques , Microglie , Protein-Serine-Threonine Kinases , Pyroptose , Animaux , Mâle , Souris , Aminopyridines/pharmacologie , Aminopyridines/usage thérapeutique , Neuropathies diabétiques/anatomopathologie , Modèles animaux de maladie humaine , Hyperalgésie/anatomopathologie , Souris de lignée C57BL , Microglie/métabolisme , Microglie/anatomopathologie , Microglie/effets des médicaments et des substances chimiques , Facteur de transcription NF-kappa B/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/métabolisme , Protéine-3 de la famille des NLR contenant un domaine pyrine/génétique , Protéine-3 de la famille des NLR contenant un domaine pyrine/antagonistes et inhibiteurs , Protein-Serine-Threonine Kinases/métabolisme , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protein-Serine-Threonine Kinases/génétique , Pyroptose/effets des médicaments et des substances chimiques , Petit ARN interférent/métabolisme , Petit ARN interférent/génétiqueRÉSUMÉ
Patients with anaplastic lymphoma kinase (ALK) fusion lung adenocarcinoma may develop drug resistance after treatment with ALK-tyrosine kinase inhibitor (ALK-TKI), and the mechanisms of this resistance are not yet fully defined. The Affiliated Hospital of Zunyi Medical University admitted a patient who was resistant to ALK fusion after ALK-TKI treatment, leading to disease progression and subsequent biopsy indicating a transformation to small cell lung cancer in September 2021. The patient, a 54-year-old female, initially presented with symptoms of cough, sputum production, and chest pain for 4 months. Chest CT showed a neoplastic lesion in the posterior segment of the right upper lobe to right lower lobe with obstructive pneumonia, metastasis in the right lower lobe, increased and enlarged mediastinal and right hilar lymph nodes, and thickening of the right hilar soft tissue. Bronchoscopy and pathological biopsy confirmed the diagnosis of lung adenocarcinoma. The results of next-generation sequencing indicated that echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion is associated with tumor protein 53 (TP53) and retinoblastoma 1 (RB1) gene mutations. The patient received second-generation ALK-TKI aletinib, achieving a progression-free survival of 11 months before disease progression suggested aletinib resistance. Subsequently, the third-generation ALK-TKI lorlatinib administered for one month without efficacy, resulting in rapid systemic disease progression. The neuron specific enolase (NSE) was significantly increased, and the patient developed new pleural, pericardial, intracranial, liver, and multiple bone metastases occurred in a short period. A second biopsy indicated small cell lung cancer. Modification of treatment regimen to chemotherapy combined with immunotherapy proved effective. The mechanisms of drug resistance of ALK-TKI treatment for advanced non-small cell lung cancer with ALK fusion are complex, and small cell transformation of pathological type is one such mechanism, although rare. Concurrent TP53 and RB1 gene mutations may be characteristic of this transformation. Elevated NSE can serve as a predictive serum marker for adenocarcinoma transforming to small cell carcinoma. Timely re-biopsy and selection of subsequent treatments based on different resistance mechanisms are crucial for comprehensive disease management.
Sujet(s)
Adénocarcinome pulmonaire , Kinase du lymphome anaplasique , Tumeurs du poumon , Humains , Femelle , Adénocarcinome pulmonaire/génétique , Adénocarcinome pulmonaire/anatomopathologie , Adénocarcinome pulmonaire/traitement médicamenteux , Adulte d'âge moyen , Tumeurs du poumon/génétique , Tumeurs du poumon/anatomopathologie , Tumeurs du poumon/traitement médicamenteux , Kinase du lymphome anaplasique/génétique , Protéines de fusion oncogènes/génétique , Résistance aux médicaments antinéoplasiques/génétique , Inhibiteurs de protéines kinases/usage thérapeutique , Carcinome pulmonaire à petites cellules/génétique , Carcinome pulmonaire à petites cellules/traitement médicamenteux , Carcinome pulmonaire à petites cellules/anatomopathologie , Protéine p53 suppresseur de tumeur/génétique , Aminopyridines/usage thérapeutiqueRÉSUMÉ
Until the discovery of the gene for cystic fibrosis (CF) in 1989, diagnostic developments were limited, and treatment focused on symptom alleviation. However, following the genetic breakthrough, some 2,000 mutations of the gene have been identified. More recently CF transmembrane conductance regulator modulator triple therapy (CFTRm) has been introduced in the form of triple therapy with ivacaftor, lumacaftor and tezacaftor (ETI), in the United States from 2019, Europe from 2020 and then Australia from 2021. The new treatment option has revolutionised both the quality of life and life expectancy of many persons diagnosed with CF. This editorial reviews major developments in the clinical care that can now be provided to patients, and reflects on the legal and ethical ramifications of the improved situation for many patients in the contexts of medical negligence, damages assessment, family law and criminal law. It also considers the difficult issues of access and equity caused by the limited availability of the triple therapy in low- and middle-income countries.
Sujet(s)
Aminophénols , Protéine CFTR , Mucoviscidose , Quinolinone , Humains , Quinolinone/usage thérapeutique , Aminophénols/usage thérapeutique , Protéine CFTR/génétique , Aminopyridines/usage thérapeutique , Benzodioxoles/usage thérapeutique , Indoles/usage thérapeutique , Australie , Faute professionnelle/législation et jurisprudence , États-UnisRÉSUMÉ
Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are known to play supportive roles in tumor development and progression, but their interactions in colorectal cancer (CRC) remain unclear. Here, we investigated the effects of colon-cancer-derived CAFs on TAM differentiation, migration, and tumor immunity, both in vitro and in vivo. When co-cultured with monocytes, CAFs attracted monocytes and induced their differentiation into M2 macrophages. Immunohistology of surgically resected human CRC specimens and orthotopically transplanted mouse tumors revealed a correlation between numbers of CAFs and numbers of M2 macrophages. In a mouse model of CRC orthotopic transplantation, treatment with an inhibitor of the colony-stimulating factor-1 receptor (PLX3397) depleted M2 macrophages and increased CD8-positive T cells infiltrating the tumor nest. While this treatment had a minor effect on tumor growth, combining PLX3397 with anti-PD-1 antibody significantly reduced tumor growth. RNA-seq following combination therapy showed activation of tumor immunity. In summary, CAFs are involved in the induction and mobilization of M2 macrophage differentiation in the CRC tumor immune microenvironment, and the combination of cancer immunotherapy and PLX3397 may represent a novel therapeutic option for CRC.
Sujet(s)
Fibroblastes associés au cancer , Différenciation cellulaire , Tumeurs colorectales , Inhibiteurs de points de contrôle immunitaires , Macrophages , Microenvironnement tumoral , Animaux , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/immunologie , Tumeurs colorectales/anatomopathologie , Tumeurs colorectales/métabolisme , Fibroblastes associés au cancer/métabolisme , Fibroblastes associés au cancer/effets des médicaments et des substances chimiques , Fibroblastes associés au cancer/immunologie , Souris , Inhibiteurs de points de contrôle immunitaires/pharmacologie , Inhibiteurs de points de contrôle immunitaires/usage thérapeutique , Différenciation cellulaire/effets des médicaments et des substances chimiques , Humains , Macrophages/immunologie , Macrophages/métabolisme , Macrophages/effets des médicaments et des substances chimiques , Microenvironnement tumoral/effets des médicaments et des substances chimiques , Microenvironnement tumoral/immunologie , Aminopyridines/pharmacologie , Aminopyridines/usage thérapeutique , Pyrrolidines/pharmacologie , Pyrrolidines/usage thérapeutique , Lignée cellulaire tumorale , Macrophages associés aux tumeurs/immunologie , Macrophages associés aux tumeurs/effets des médicaments et des substances chimiques , Macrophages associés aux tumeurs/métabolisme , Modèles animaux de maladie humaine , Pyrroles/pharmacologie , Pyrroles/usage thérapeutique , Femelle , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Lymphocytes T CD8+/effets des médicaments et des substances chimiquesRÉSUMÉ
The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients.