RESUMO
IMPORTANCE: Vitiligo is a chronic skin disorder causing depigmentation. There is a lack of evidence-based medical evidence regarding ruxolitinib efficacy and safety for vitiligo. OBJECTIVE: To assess the efficacy and safety of ruxolitinib cream in the treatment of vitiligo. METHODS: The databases of PubMed, Embase, and Cochrane Library were searched. The literature screening was independently conducted by two reviewers. DATA EXTRACTION AND SYNTHESIS: For continuous variables, weighted mean difference (WMD) along with a 95% confidence interval (CI) was performed. For dichotomous outcomes, we calculated the odds ratios (ORs) or risk ratios (RRs), and their corresponding 95% CIs. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). MAIN OUTCOMES AND MEASURES: Symptoms, quality of life, and safety were evaluated using various measures, including the Facial Vitiligo Area Scoring Index (F-VASI), Total Vitiligo Area Scoring Index (T-VASI), Facial Body Surface Area (F-BAS), Total Body Surface Area (T-BAS) and Treatment-emergent Adverse Events (TEAEs). RESULTS: Three trials, involving a total of 830 participants from nine countries were included (female 388, 46.7%, male 442, 53.3%). The meta-analysis demonstrated a significant increase in the likelihood of participants achieving F-VASI75 (OR, 4.34 [95% CI 2.67-7.06]; high), F-VASI50 (OR 4.71 [95% CI 3.24-6.84]; high), T-VASI75 (OR 2.78 [95% CI 1.10-7.00]; moderate), and T-VASI50 (OR 4.47 [95% CI 2.52-7.92]; high) when compared ruxolitinib to vehicle. Ruxolitinib was associated with more lowered percentage change of F-VASI scores (MD - 32.79 [95% CI - 36.37 to - 29.21]; moderate), and T-VASI scores (MD - 20.22 [95% CI - 23.11 to - 17.33]; moderate) from baseline compared to vehicle. There may not be a significant difference in the occurrence of TEAEs between ruxolitinib and vehicle (RR 1.46 [95% CI 0.85-2.49]; high). CONCLUSIONS: The findings suggest that ruxolitinib cream holds promise as a treatment option for vitiligo. Further long-term studies are needed to assess its sustained efficacy and safety profile. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023431112.
Assuntos
Nitrilas , Pirazóis , Pirimidinas , Vitiligo , Humanos , Vitiligo/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Nitrilas/uso terapêutico , Qualidade de Vida , Resultado do Tratamento , Creme para a Pele/uso terapêuticoRESUMO
Tofacitinib is an oral small-molecule Janus kinase (JAK) inhibitor that preferentially inhibits JAK1 and JAK3. Its efficacy in inducing and maintaining remission in ulcerative colitis (UC) as well as its safety profile has been demonstrated in multicenter, randomized, double-blind, placebo-controlled trials. Additionally, real-world studies evaluating the effectiveness and adverse effects of tofacitinib have been conducted, affirming its clinical efficacy in moderate-to-severe UC.
Assuntos
Colite Ulcerativa , Piperidinas , Inibidores de Proteínas Quinases , Pirimidinas , Indução de Remissão , Índice de Gravidade de Doença , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/diagnóstico , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Humanos , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Resultado do Tratamento , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Indução de Remissão/métodos , Inibidores de Janus Quinases/uso terapêutico , Inibidores de Janus Quinases/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Pirróis/uso terapêutico , Pirróis/efeitos adversos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 1/antagonistas & inibidoresRESUMO
Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.
Assuntos
Colite Ulcerativa , Inibidores de Janus Quinases , Janus Quinases , Piperidinas , Transdução de Sinais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/imunologia , Colite Ulcerativa/diagnóstico , Humanos , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Resultado do Tratamento , Pirimidinas/uso terapêutico , Indução de Remissão/métodos , Pirróis/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes , Piridinas , TriazóisRESUMO
BACKGROUND: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML har-boring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. METHODS: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46,Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. RESULTS: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCR-ABL1 levels were elevated above the MMR. CONCLUSIONS: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Translocação Genética , Humanos , Masculino , Adulto , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Evolução Clonal/genética , Proteínas de Fusão bcr-abl/genética , Mesilato de Imatinib/uso terapêutico , Pirimidinas/uso terapêutico , Cromossomos Humanos X/genética , Antineoplásicos/uso terapêuticoRESUMO
Trixacarus caviae is a sarcoptic mange mite infesting guinea pigs. Infestation in immunosuppressed animals produces severe dermatological problems, including alopecia, intense pruritus, hyperkeratosis and non-dermatological issues (e.g., seizures). Treatment options are limited and include topical application of macrocyclic lactones or amitraz or injectable administration of ivermectin or doramectin. Considering the severity of the disease and the challenging treatment, the present paper aimed to determine the efficacy of oral afoxolaner in a severe case of infestation with T. caviae in a pet guinea pig. One female guinea pig was referred to the New Companion Animal Clinic due to severe dermatological problems. A clinical evaluation was done, and skin scrapings were collected and examined under the microscope. Small mites were detected and morphologically identified as T. caviae. The animal was treated with a single oral dose of 2.50 mg/kg afoxolaner, and the lesions, presence/absence of mites and intensity of pruritus were evaluated periodically until 2 months post-treatment. A week after the medication, the lesions were milder, but pruritus was still present and was attributed to the healing process. Further examinations showed significant improvement with the complete remission of clinical signs and no mites at the microscopic examination after 4 weeks. Afoxolaner was safe and effective in this guinea pig for the treatment of T. caviae mange with no repetition needed.
Assuntos
Naftalenos , Animais , Cobaias , Feminino , Naftalenos/administração & dosagem , Naftalenos/uso terapêutico , Infestações por Ácaros/veterinária , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/parasitologia , Acaricidas/uso terapêutico , Acaricidas/administração & dosagem , Animais de Estimação , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Doenças dos Roedores/tratamento farmacológico , Doenças dos Roedores/parasitologia , IsoxazóisRESUMO
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
Assuntos
Dioxóis , Fibrose , Infarto do Miocárdio , Piridinas , Engenharia Tecidual , Animais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Camundongos , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Engenharia Tecidual/métodos , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Miocárdio/patologia , Miocárdio/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Transdução de Sinais , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Coração/fisiopatologia , Coração/efeitos dos fármacos , AmidasRESUMO
Objective: To explore the efficacy and safety of ibrutinib for the treatment of newly treated and relapsed refractory (R/R) lymphoplasmacytic lymphoma (LPL) /Waldenström macroglobulinemia (WM) . Methods: Retrospectively collected clinical data of 98 cases of newly treated and R/R LPL/WM patients who received ibrutinib treatment at the Hematology & Blood Diseases Hospital of the Chinese Academy of Medical Sciences from March 2016 to June 2023, and analyzed their efficacy and safety. Results: A total of 98 LPL/WM patients were included, which consisted of 45 newly treated patients and 53 R/R patients. Of these, 74 were males (75.5%) and the cohort had a median age of 64 (42-87) years. Eighty-eight patients were eligible for efficacy evaluation with a median treatment time of 20.8 (2.1-55.0) months, a major remission rate (MRR) of 78.4%, and an overall response rate (ORR) of 85.2%. The MRR and ORR of the newly treated patients were 78.4% and 86.5%, respectively, whereas the MRR and ORR of the R/R patients were 78.4% and 84.3%, respectively. There were no statistically significant differences in MRR and ORR between the initial treatment and R/R patients (all P values >0.05) . The median follow-up period was 29.1 (2.9-50.3) months and the median overall survival time for newly treated and R/R patients was not reached. The median progression-free survival time was 23.5 (95% CI 10.5-36.5) months and 45.0 (95% CI 34.0-56.0) months, respectively, with no statistically significant differences (all P values >0.05) . There were 25 deceased patients and no deaths were related to ibrutinib treatment. The main adverse reactions of ibrutinib were thrombocytopenia (5.1%) , pneumonia (8.1%) , and hyperuricemia (21.4%) . The incidence of atrial fibrillation was 2.0%. Conclusion: Ibrutinib exhibits good efficacy and safety for newly treated and R/R LPL/WM patients.
Assuntos
Adenina , Piperidinas , Pirimidinas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adenina/análogos & derivados , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: To report two cases of ibrutinib-related uveitis and review the literature to date. METHODS: We report two cases of ibrutinib-related uveitis using CARE guidelines and review the cases reported in the literature. RESULTS: Case 1) A 55-year-old female with recurrent primary central nervous system lymphoma presented with bilateral decreased visual acuity, photophobia, and floaters that started one month after initiating oral treatment with ibrutinib. Chronic non-granulomatous bilateral anterior-intermediate uveitis with macular edema was identified. Secondary causes were ruled out, and a presumptive diagnosis of ibrutinib-related uveitis was made. Case 2) A 57-year-old female with Waldenström macroglobulinemia who was treated with ibrutinib for two years presented with bilateral blurred vision, photophobia, red eyes, and floaters. A diagnosis of non-granulomatous, noninfectious panuveitis with bilateral cystoid macular edema was made. Secondary causes were ruled out, and ibrutinib toxicity was the most likely cause. CONCLUSION: Ibrutinib-related uveitis is a novel and under-diagnosed clinical entity. The most frequent clinical presentation in the literature is bilateral, non-granulomatous, anterior, and intermediate uveitis. Macular edema is a frequent complication. Uveitis usually requires topical treatment and the suspension of ibrutinib. Switching to second-generation Bruton tyrosine kinase inhibitors is proposed as a potential therapeutic alternative.
Assuntos
Adenina , Piperidinas , Humanos , Feminino , Adenina/análogos & derivados , Adenina/efeitos adversos , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Tomografia de Coerência Óptica , Acuidade Visual , Inibidores de Proteínas Quinases/efeitos adversos , Uveíte/induzido quimicamente , Uveíte/diagnóstico , Uveíte/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/diagnóstico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Edema Macular/induzido quimicamente , Edema Macular/diagnóstico , Edema Macular/tratamento farmacológico , Angiofluoresceinografia , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/diagnósticoRESUMO
BACKGROUND: Results of conventional induction chemotherapies in primary central nervous system lymphoma (PCNSL) need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results at relapse, supporting to further assess their individual use in combination with high-dose methotrexate-based chemotherapy. METHODS: Patients with newly diagnosed PCNSL were randomized to receive four 28-day cycles of ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3 + 3 design. Responders then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. RESULTS: Twenty-six patients (median age 52) were randomized. Four DLTs were observed: one grade 5 aspergillosis and pneumocystosis, one grade 4 catheter-related infection and two grade 3 increased alanine aminotransferase levels. RP2D of ibrutinib and lenalidomide were 560 mg daily (D3-14 and D17-28) and 15 mg daily (D1-21) respectively, in combination with R-MPV. In both arms, the most frequent grade ≥3 treatment-related adverse events were hepatic cytolysis, neutropenia and infections. One grade 4 Lyell's syndrome was reported at cycle 2 in the lenalidomide arm. After 4 induction cycles, the overall response rates were 76.9% and 83.3% in the lenalidomide and ibrutinib arm, respectively. CONCLUSION: Targeted induction therapies combining lenalidomide or ibrutinib with R-MPV are feasible for first-line PCNSL. The safety profile is consistent with the known safety profiles of R-MPV and both targeted therapies. The phase II part of the study is ongoing. TRIAL REGISTRATION: NCT04446962.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Lenalidomida , Piperidinas , Pirazóis , Pirimidinas , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Lenalidomida/efeitos adversos , Adenina/análogos & derivados , Adenina/administração & dosagem , Pessoa de Meia-Idade , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Masculino , Feminino , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Idoso , Adulto , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Vincristina/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Rituximab/efeitos adversos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Prednisona/efeitos adversos , Linfoma/tratamento farmacológicoRESUMO
Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible T-cell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-week-old female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzyme-linked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1ß, IL-6, transforming growth factor-ß1, interferon-γ, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinib-treated mice. The mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target.
Assuntos
Adenina , Tirosina Quinase da Agamaglobulinemia , Modelos Animais de Doenças , Oftalmopatia de Graves , Inflamação , Camundongos Endogâmicos BALB C , Piperidinas , Pirimidinas , Animais , Oftalmopatia de Graves/tratamento farmacológico , Oftalmopatia de Graves/metabolismo , Oftalmopatia de Graves/patologia , Adenina/análogos & derivados , Piperidinas/uso terapêutico , Camundongos , Feminino , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Receptores da Tireotropina/metabolismo , Receptores da Tireotropina/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Ruxolitinib cream 1.5% was first approved by the US Food and Drug Administration (FDA) in 2011. Opzelura™ cream was introduced by Incyte Dermatology in 2021 for the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis (AD) in non-immunocompromised patients aged ≥12 years, whose clinical manifestations are not controlled with prescribed topical therapies, such as topical corticosteroids, topical calcineurin inhibitors, or topical phosphodiesterase-4 ( PDE4) inhibitors, or when such therapies are not advisable. Ruxolitinib is a Janus kinase (JAK) inhibitor that addresses inflammation in AD. It selectively inhibits JAK1 and JAK2, blocking JAK and activating signal transducer and activator of transcription (STAT), thereby interrupting the cytokine pathways responsible for cutaneous inflammation. The targeted downstream cytokines include Interleukin- 4 (IL-4), IL-13, IL-31, and cytokine thymic stromal lymphopoietin (TSLP), which play pivotal roles in the itching and inflammation experienced by AD patients. Ruxolitinib cream is directly applied as a thin layer over AD lesions twice daily up to 20% body surface area (BSA) using no more than 60 g per week. It can be used for up to 8 weeks on delicate or thin skin surfaces.
Assuntos
Dermatite Atópica , Nitrilas , Pirazóis , Pirimidinas , Humanos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/administração & dosagem , Nitrilas/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Creme para a Pele , Administração Cutânea , Citocinas/metabolismoRESUMO
Here, the case of a female patient in her late 60s, who presented to hospital for a scheduled health check relating to a history of myelofibrosis for the previous 9 years, is described. She recently experienced weight loss and abdominal distention. Physical examination revealed no abnormality or tenderness. Laboratory examination showed decreased blood cells, platelets and haemoglobin, and normal renal function. Ultrasound and computed tomography scans revealed a massively enlarged spleen and displaced and compressed left kidney with abnormal features, but normal right kidney. The patient declined surgery and her myelofibrosis was treated with ruxolitinib, with a recommendation of annual follow-up observation. Despite many recorded cases of left renal displacement caused by splenomegaly, it is very rare for the left kidney to be pushed across the midline to the right side by an enlarged spleen. This article explores the causes and management of this uncommon condition and provides a review of previous literature reports with the aim of enhancing the understanding of unusual renal displacement due to massive splenomegaly, and its potential treatment options.
Assuntos
Rim , Esplenomegalia , Humanos , Esplenomegalia/diagnóstico por imagem , Esplenomegalia/etiologia , Esplenomegalia/diagnóstico , Esplenomegalia/patologia , Feminino , Rim/patologia , Rim/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Mielofibrose Primária/complicações , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/patologia , Pessoa de Meia-Idade , Ultrassonografia , Baço/diagnóstico por imagem , Baço/patologia , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêuticoRESUMO
BACKGROUND: Clinical amyopathic dermatomyositis is characterized by cutaneous symptoms but lacks muscle symptoms. Anti-melanoma differentiation-associated gene 5 antibodies are frequently found in Japanese patients with clinical amyopathic dermatomyositis. Patients with rapidly progressive interstitial lung disease with positive anti-melanoma differentiation-associated gene 5 antibodies have poor prognoses, and majority of them are treated with combination immunosuppressive therapy; however, the best treatment is yet to be determined. CASE PRESENTATION: A 52-year-old Asian male patient presented with a chief complaint of dyspnea on exertion. He had a typical skin rash and rapidly progressive interstitial pneumonia. Additionally, anti-melanoma differentiation-associated gene 5 antibodies were detected; therefore, he was diagnosed with dermatomyositis-associated interstitial pneumonia. Respiratory failure worsened despite administering steroid pulse therapy, tacrolimus, and cyclophosphamide. Consequently, plasma exchange was performed on day 13 of admission. After a slight improvement, the patient's respiratory failure worsened. Thus, cyclophosphamide was replaced by tofacitinib on day 28. Although respiratory failure improved and the progression of interstitial pneumonia seemed under control, ßD-glucan level increased and Aspergillus antigen was detected on day 49. Micafungin and voriconazole were administered, but the patient succumbed to worsening respiratory failure on day 61. The pathological autopsy revealed multiple nodular lesions with cavity formation in both lungs and the presence of Aspergillus with severe neutrophilic infiltration and necrosis, which supported the diagnosis of invasive pulmonary aspergillosis. CONCLUSION: The patient with anti-melanoma differentiation-associated gene 5 antibody-related rapidly progressive interstitial lung disease, whose disease was difficult to control after the administration of triple immunosuppressive therapy (steroids, tacrolimus, and cyclophosphamide), showed good response with tofacitinib. Unfortunately, the patient died of invasive pulmonary aspergillosis owing to severe immunosuppression; thus, the signs of complications should be promptly detected.
Assuntos
Dermatomiosite , Helicase IFIH1 Induzida por Interferon , Doenças Pulmonares Intersticiais , Piperidinas , Pirimidinas , Humanos , Dermatomiosite/tratamento farmacológico , Dermatomiosite/complicações , Dermatomiosite/imunologia , Masculino , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Helicase IFIH1 Induzida por Interferon/imunologia , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Autoanticorpos/sangue , Imunossupressores/uso terapêutico , Resultado do Tratamento , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Clazosentan prevents vasospasms after aneurysmal subarachnoid hemorrhage (SAH). However, clinical data on patients with SAH with ruptured vertebral artery dissecting aneurysms (VADAs) are limited. We report the case of a 49-year-old male patient with mild-grade (WFNS grade 1) thick and diffuse (modified Fisher grade 3) SAH who underwent endovascular trapping of a ruptured VADA, resulting in a poor functional outcome with a modified Rankin Scale score of 4 due to severe symptomatic vasospasm refractory to clazosentan, requiring repeated rescue endovascular therapies and chronic communicating hydrocephalus. A retrospective analysis of the clot density in the basal and Sylvian cisterns, assessed by the Hounsfield unit (HU) values of serial CT scans, in this patient showed persistent higher values, distinct from another VADA case that showed a decline in HU values with a good clinical course. These results imply the limited effectiveness of clazosentan in cases of thick and diffuse SAH after a ruptured VADA, even in good-clinical-grade patients treated with less invasive modalities. The HU values may become a simple quantitative marker for predicting symptomatic vasospasms and chronic hydrocephalus.
Assuntos
Dioxanos , Piridinas , Pirimidinas , Hemorragia Subaracnóidea , Sulfonamidas , Tetrazóis , Vasoespasmo Intracraniano , Humanos , Masculino , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Pessoa de Meia-Idade , Dioxanos/uso terapêutico , Sulfonamidas/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/complicações , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/diagnóstico por imagem , Pirimidinas/uso terapêutico , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/tratamento farmacológico , Aneurisma Roto/complicações , Estudos Retrospectivos , Procedimentos Endovasculares/métodosRESUMO
OBJECTIVE: The main adjuvant therapies for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer include ALK tyrosine kinase inhibitors (TKI) and chemotherapy. We aimed to compare differences in the incidence of thromboembolism (TE) among different treatment options. DESIGN: Using a systematic review and Bayesian network meta-analysis (NMA). DATA SOURCES: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and Web of Science databases before 10 June 2023. ELIGIBILITY CRITERIA: We included published randomised controlled trials (RCT) involving comparisons of treatments between chemotherapy and ALK-TKI drugs. DATA EXTRACTION AND SYNTHESIS: Assessed risk bias with Cochrane tool. Conducted NMA with GEMTC in R, we evaluate the model fit using the deviation information criteria. Estimated posterior distribution using Markov Chain Monte Carlo, 4 chains, 10 fine-tuned iterations, 10 000 iterations per chain, total 50 000 iterations. Monitored potential scale reduction factor for convergence. And checked convergence with Gelman-Rubin statistics and trace plot. Provided surface under the cumulative ranking, lower values indicate less TE event probability. RESULTS: Analysis of eight RCTs showed that, compared with that for crizotinib, there was a lower risk of total TE with chemotherapy (OR, 0.28; 95% credible intervals (CrI) 0.11 to 0.63), brigatinib (OR 0.31; 95% CrI 0.11 to 0.79) and ceritinib (OR 0.13; 95% CrI 0.03 to 0.45). In addition, analysis of venous TE (VTE) showed similar results, with a lower occurrence for chemotherapy (OR 0.27; 95% CrI 0.1 to 0.62), brigatinib (OR 0.18; 95% CrI 0.04 to 0.6) and ceritinib (OR 0.1; 95% CrI 0.02 to 0.43) compared with that for crizotinib. There were no significant differences in the occurrence of arterial TE among the different treatment options. CONCLUSION: Compared with chemotherapy, alectinib, lorlatinib, brigatinib and ceritinib, crizotinib significantly increased the risk of TE and VTE. PROSPERO REGISTRATION NUMBER: CRD42023373307.
Assuntos
Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas , Crizotinibe , Neoplasias Pulmonares , Metanálise em Rede , Inibidores de Proteínas Quinases , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Crizotinibe/uso terapêutico , Teorema de Bayes , Pirimidinas/uso terapêutico , Piperidinas/uso terapêutico , Antineoplásicos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Trombose , Éteres de Coroa/uso terapêutico , Compostos Organofosforados/uso terapêutico , Terapia de Alvo Molecular , Carbazóis , SulfonasRESUMO
Joint pain and osteoarthritis can occur as coronavirus disease 2019 (COVID-19) sequelae after infection. However, little is known about the damage to articular cartilage. Here we illustrate knee joint damage after wild-type, Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vivo. Rapid joint injury with cystic lesions at the osteochondral junction was observed in two patients with post-COVID osteoarthritis and recapitulated in a golden Syrian hamster model. SARS-CoV-2-activated endothelin-1 signalling increased vascular permeability and caused viral spike proteins leakage into the subchondral bone. Osteoclast activation, chondrocyte dropout and cyst formation were confirmed histologically. The US Food and Drug Administration-approved endothelin receptor antagonist, macitentan, mitigated cystic lesions and preserved chondrocyte number in the acute phase of viral infection in hamsters. Delayed macitentan treatment at post-acute infection phase alleviated chondrocyte senescence and restored subchondral bone loss. It is worth noting that it could also attenuate viral spike-induced joint pain. Our work suggests endothelin receptor blockade as a novel therapeutic strategy for post-COVID arthritis.
Assuntos
COVID-19 , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina , Mesocricetus , Osteoartrite , Pirimidinas , SARS-CoV-2 , Animais , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Humanos , COVID-19/virologia , COVID-19/complicações , COVID-19/metabolismo , COVID-19/patologia , Osteoartrite/tratamento farmacológico , Osteoartrite/virologia , Osteoartrite/patologia , Osteoartrite/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Antagonistas dos Receptores de Endotelina/farmacologia , Antagonistas dos Receptores de Endotelina/uso terapêutico , Sulfonamidas/farmacologia , Cricetinae , Masculino , Tratamento Farmacológico da COVID-19 , Condrócitos/virologia , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Cartilagem Articular/patologia , Cartilagem Articular/virologia , Cartilagem Articular/metabolismo , Cartilagem Articular/efeitos dos fármacos , Receptores de Endotelina/metabolismo , Endotelina-1/metabolismo , Feminino , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.
Assuntos
Neoplasias da Mama , Fulvestranto , Pirróis , Humanos , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Pirróis/efeitos adversos , Pirróis/farmacologia , Pirróis/uso terapêutico , Adulto , Pirimidinas/farmacologia , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptores de Estrogênio/metabolismo , Método Duplo-CegoRESUMO
BACKGROUND: To present findings from a retrospective study conducted by the Ultra-Rare Sarcoma Working Group on metastatic low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid (H)-LGFMS/SEF across 28 global centres. METHODS: Patients treated at participating institutions from January 2000 to September 2022 were retrospectively selected. Diagnosis was confirmed by expert pathologists. Primary endpoint was progression-free survival (PFS-1) from metastasis detection to first progression or death. PFS-2 was calculated from therapy initiation. RESULTS: A total of 101 patients were identified (32 LGFMS, 50 SEF, 19 H-LGFMS/SEF). Median (m) follow-up was 62.1 months. mPFS-1 was 28.7, 11.8, and 20.3 months for LGFMS, SEF, and H-LGFMS/SEF, respectively. mOS was 145.8, 41.9, and 113.5 months, respectively. Treatments included anthracycline-based chemotherapy, gemcitabine-based chemotherapy (G), pazopanib, trabectedin, others. mPFS-2 was: 20.1, 5.5, and 3.5 months in H-LGFMS/SEF, SEF, and LGFMS, respectively, with anthracyclines; 19.5, 7.7, and 6.9 months in LGFMS, SEF, and H-LGFMS/SEF, respectively, with pazopanib; 12.0, 9.7, and 3.1 months in H-LGFMS/SEF, LGFMS, and SEF, respectively. Occasional responses occurred with ifosfamide/oral cyclophosphamide, and prolonged stable disease with immune checkpoint inhibitors. CONCLUSIONS: In this series, the largest available, metastatic LGFMS, SEF, and H-LGFMS/SEF showed different courses. Systemic agents have modest efficacy, informing future trials of novel agents for these tumours.
Assuntos
Fibrossarcoma , Humanos , Estudos Retrospectivos , Feminino , Masculino , Fibrossarcoma/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Idoso , Adulto Jovem , Pirimidinas/uso terapêutico , Indazóis/uso terapêutico , Gencitabina , Trabectedina/uso terapêutico , Adolescente , Sulfonamidas/uso terapêutico , Gradação de Tumores , Antraciclinas/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/patologiaRESUMO
Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.
Assuntos
Monócitos , Fator de Crescimento Neural , Osteossarcoma , Microambiente Tumoral , Molécula 1 de Adesão de Célula Vascular , Osteossarcoma/metabolismo , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Humanos , Fator de Crescimento Neural/metabolismo , Animais , Microambiente Tumoral/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo , Camundongos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Macrófagos/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Camundongos NusRESUMO
BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.