RESUMO
BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).
Assuntos
Antineoplásicos Imunológicos , Melanoma , Terapia Neoadjuvante , Neoplasias Cutâneas , Humanos , Adjuvantes Imunológicos , Progressão da Doença , Melanoma/tratamento farmacológico , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Quimioterapia AdjuvanteRESUMO
BACKGROUND: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery. METHODS: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete. FINDINGS: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted. INTERPRETATION: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients. FUNDING: Deciphera Pharmaceuticals.
Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Humanos , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Idoso , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Resultado do Tratamento , Anilidas , QuinolinasRESUMO
INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CTLA-4 , Neoplasias da Vesícula Biliar , Ipilimumab , Nivolumabe , Receptor de Morte Celular Programada 1 , Humanos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Ipilimumab/administração & dosagem , Ipilimumab/uso terapêutico , Ipilimumab/efeitos adversos , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Antígeno CTLA-4/antagonistas & inibidores , Estudos Prospectivos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Adulto , Intervalo Livre de Progressão , Idoso de 80 Anos ou maisRESUMO
Ifosfamide is an alkylating chemotherapeutic agent used in the treatment of many malignancies. Ifosfamide-induced encephalopathy is one potential side effect that represents a major drawback to ifosfamide therapy and often necessitates discontinuation of chemotherapy. Previous reports demonstrate moderate effectiveness of prophylactic methylene blue at thwarting ifosfamide-induced encephalopathy. This is a report of a 64-year-old female with relapsed double-hit diffuse large B-cell lymphoma who developed severe altered mental status and neurological symptoms after receiving a second dose of ifosfamide as part of her salvage standard dose R-IE (rituximab, ifosfamide, etoposide), in preparation for chimeric antigen receptor T-cell therapy. Ifosfamide was stopped and extensive metabolic and infectious workups, in addition to brain images, were all unremarkable. Her symptoms were attributed to ifosfamide. Prior to initiating cycle 2 of R-IE, she was started on prophylactic oral thiamine 100 mg, once a day, one week prior to her admission, methylene blue 50 mg intravenous every 6 h (for a total of four doses) and intravenous hydration with normal saline starting on day one of admission. Ifosfamide was administered in the standard dose 2000 mg/m2, days 1-3 as continuous intravenous infusion over 24 h. She tolerated the first two days of ifosfamide well and only developed mild encephalopathy during her last dose of ifosfamide. Her symptoms resolved completely without any intervention the following day and she completed all scheduled doses. She eventually received chimeric antigen receptor T-cell therapy. Our report demonstrates the use of hydration, methylene blue, and thiamine as a successful secondary prevention regimen for ifosfamide-induced encephalopathy.
Assuntos
Encefalopatias/prevenção & controle , Ifosfamida/efeitos adversos , Azul de Metileno/administração & dosagem , Tiamina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Encefalopatias/induzido quimicamente , Etoposídeo/administração & dosagem , Feminino , Humanos , Ifosfamida/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Pessoa de Meia-Idade , Rituximab/administração & dosagemRESUMO
CD30 expression is the hallmark of the cutaneous CD30+ lymphoproliferative disorders, lymphomatoid papulosis and anaplastic large cell lymphoma. We report CD30 expression in cutaneous follicle center cell lymphoma and in cutaneous post-transplant peripheral T-cell lymphoma. Histopathologists should be aware of CD30 expression in cutaneous lymphomas outside the realm of so-called CD30+ lymphoproliferative disorders to avoid diagnostic errors and improper medical treatment.
Assuntos
Linfócitos B/metabolismo , Antígeno Ki-1/biossíntese , Linfoma de Células T Periférico/imunologia , Neoplasias Cutâneas/imunologia , Pele/patologia , Idoso , Linfócitos B/imunologia , Linfócitos B/patologia , Biópsia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Antígeno Ki-1/imunologia , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Pessoa de Meia-Idade , Prognóstico , Pele/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Lin28 is a family of RNA binding proteins and microRNA regulators. Two members of this family have been identified: Lin28A and Lin28B, which are encoded by genes localized in different chromosomes but share a high degree of sequence identity. The role of Lin28B in androgen-independent prostate cancer (AIPC) is not well understood. Lin28B is expressed in all grades of prostatic carcinomas and prostate cancer cell lines, but not in normal prostate tissue. In this study we found that Lin28B co-localized in the nucleus and cytoplasm of the DU145 AIPC. The expression of Lin28B protein positively correlated with the expression of the c-Myc protein in the prostate cancer cell lines and silencing of Lin28B also correlated with a lower expression of the c-Myc protein, but not with the downregulation of c-Myc messenger RNA (mRNA) in the DU145 AIPC cells. We hypothesized that Lin28B regul-ates the expression of c-Myc protein by altering intermediate c-Myc suppressors. Therefore, a microRNA profile of DU145 cells was performed after Lin28B siRNA silencing. Nineteen microRNAs were upregulated and eleven microRNAs were downregulated. The most upregulated microRNAs were miR-212 and miR-2278. Prior reports have found that miR-212 is suppressed in prostate cancer. We then ran TargetScan software to find potential target mRNAs of miR-212 and miR-2278, and it predicted Lin28B mRNA as a potential target of miR-212, but not miR-2278. TargetScan also predicted that c-Myc mRNA is not a potential target of miR-212 or miR-2278. These observations suggest that Lin28B:miR-212 may work as a regulatory loop in androgen-independent prostate cancer. Furthermore, we report a predictive 2-fold symmetric model generated by the superposition of the Lin28A structure onto the I-TASSER model of Lin28B. This structural model of Lin28B suggests that it shows unique microRNA binding characteristics. Thus, if Lin28B were to bind miRNAs in a manner similar to Lin28A, conformational changes would be necessary to prevent steric clashes in the C-terminal and linker regions between the CSD and ZNF domains.
Assuntos
MicroRNAs/genética , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas de Ligação a RNA/genética , Androgênios/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-myc/genética , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/biossínteseRESUMO
The epidermal growth factor receptor (EGFR) plays an important role in the development of many cancers, including non-small cell lung cancer. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a class of novel biologically-targeted agents widely used in the management of recurrent non-small cell lung cancer. Erlotinib, one of the EGFR TKIs, is currently FDA approved in second and third line therapy. However, recent studies showed that erlotinib is also effective as maintenance therapy after initial chemotherapy, improving disease free survival and possibly overall survival. Our current understanding of erlotinib's mechanism of action, with the discovery that EGFR mutation confers higher response rate, has propelled this agent into the first line setting. Advances in molecular testing and clinical research of this agent and other agents in this class will eventually change the way we utilize EGFR TKIs in the near future.