RESUMEN
PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Lobular/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Receptor ErbB-2/inmunología , Vacunas de Subunidad/administración & dosificación , Adulto , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/inmunología , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Fragmentos de Péptidos , Pronóstico , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Método Simple Ciego , Tasa de Supervivencia , Vacunas de Subunidad/inmunologíaRESUMEN
BACKGROUND: The COVID-19 pandemic presents a unique challenge to surgical residency programs. Due to the restrictions recommended by the Centers for Disease Control and Prevention and other organizations, the educational landscape for surgical residents is rapidly changing. In addition, the time course of these changes is undefined. METHODS: We attempt to define the scope of the problem of maintaining surgical resident education while maintaining the safety of residents, educators, and patients. Within the basic framework of limiting in-person gatherings, postponing or canceling elective operations in hospitals, and limiting rotations between sites, we propose innovative solutions to maintain rigorous education. RESULTS: We propose several innovative solutions including the flipped classroom model, online practice questions, teleconferencing in place of in-person lectures, involving residents in telemedicine clinics, procedural simulation, and the facilitated use of surgical videos. Although there is no substitute for hands-on learning through operative experience and direct patient care, these may be ways to mitigate the loss of learning exposure during this time. CONCLUSIONS: These innovative solutions utilizing technology may help to bridge the educational gap for surgical residents during this unprecedented circumstance. The support of national organizations may be beneficial in maintaining rigorous surgical education.
Asunto(s)
Competencia Clínica , Infecciones por Coronavirus/epidemiología , Educación a Distancia/métodos , Educación de Postgrado en Medicina/organización & administración , Cirugía General/educación , Pandemias/estadística & datos numéricos , Neumonía Viral/epidemiología , Telecomunicaciones/organización & administración , COVID-19 , Centers for Disease Control and Prevention, U.S. , Infecciones por Coronavirus/prevención & control , Curriculum , Femenino , Humanos , Internado y Residencia/organización & administración , Masculino , Pandemias/prevención & control , Neumonía Viral/prevención & control , Medición de Riesgo , Estados Unidos , Realidad VirtualRESUMEN
The development of HER2-targeted therapy has decreased recurrence rates and improved survival, transforming the natural history of HER2-positive breast cancer. However only a minority of breast cancer patients benefit as these agents are not used in patients with tumors expressing low levels of HER2. Preclinical data suggests a synergistic action of HER2-targeted vaccination with trastuzumab. We report the initial safety interim analysis of a phase II trial that enrolled patients with HER2 low-expressing (IHC 1+/2+) breast cancer who were clinically disease-free after standard therapy. Patients were randomized to receive the HER2-peptide vaccine nelipepimut-Sâ¯+â¯GM-CSF with trastuzumab (vaccine arm) or trastuzumab + GM-CSF (control arm) and were followed for recurrence. A planned analysis that occurred after enrollment of 150 patients showed no significant differences in toxicity between the two arms, including cardiac toxicity. The clinical efficacy of this combination will be reported 6â¯months after the final patient was enrolled.
Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factores Inmunológicos/efectos adversos , Fragmentos de Péptidos/efectos adversos , Trastuzumab/efectos adversos , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Receptor ErbB-2 , Volumen Sistólico/efectos de los fármacos , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA-A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease-free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277.
Asunto(s)
Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Antígeno HLA-A2/genética , Inmunoterapia/métodos , Receptor ErbB-2/genética , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia , Receptor ErbB-2/inmunología , Proyectos de Investigación , Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Vacunación , Vacunas de SubunidadRESUMEN
In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39', an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE' received three E39 inoculations followed by three E39'; and arm E'E received three E39' inoculations, followed by three E39. Within each arm, the first five patients received 500⯵g of peptide and the remainder received 1000⯵g. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39' might produce the optimal immune response. TRIAL REGISTRATION: NCT02019524.
Asunto(s)
Neoplasias de la Mama/inmunología , Vacunas contra el Cáncer/inmunología , Receptores de Folato Anclados a GPI/inmunología , Neoplasias Ováricas/inmunología , Vacunas de Subunidad/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/efectos adversos , Femenino , Humanos , Hipersensibilidad Tardía/etiología , Hipersensibilidad Tardía/inmunología , Persona de Mediana Edad , Neoplasias Ováricas/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Vacunación/métodos , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversosRESUMEN
The management of rectal trauma has often been lumped in with colon trauma when, in fact, it is a unique entity. The anatomic nature of the rectum (with its intra- and extraperitoneal segments) lends itself to unique circumstances when it comes to management and treatment. From the four Ds (debridement, drainage, diversion, and distal irrigation), the management of rectal trauma has made some strides in light of the experiences coming out of the recent conflicts overseas as well as some rethinking of dogma. This article will serve to review the anatomy and types of injuries associated with rectal trauma. A treatment algorithm will also be presented based on our current literature review. We will also address controversial points and attempt to give our opinion in an effort to provide an update on an age-old problem.