A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC.

BACKGROUND: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%. METHODS: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. RESULTS: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. CONCLUSIONS: Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

Gene Interactions Provide Evidence for Signaling Pathways Involved in Cleft Lip/Palate in Humans.

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common craniofacial birth defect that has a complex etiology. Genome-wide association studies have recently identified new loci associated with NSCL/P, but these loci have not been analyzed in a Mexican Mestizo population. A complex etiology implies the presence of genetic interactions, but there is little available information regarding this in NSCL/P, and no signaling pathway has been clearly implicated in humans. Here, we analyzed the associations of 24 single nucleotide polymorphisms (SNPs) with NSCL/P in a Mexican Mestizo population (133 cases, 263 controls). The multifactorial dimensionality reduction method was used to examine gene-gene and gene-folic acid consumption interactions for the 24 SNPs analyzed in this study and for 2 additional SNPs that had previously been genotyped in the same study population. Six SNPs located in paired box 7, ventral anterior homeobox 1, sprouty RTK signaling antagonist 2, bone morphogenetic protein 4, and tropomyosin 1 genes were associated with higher risks of NSCL/P (P = 0.0001 to 0.04); 2 SNPs, 1 each in netrin 1 and V-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B, were associated with a lower risk of NSCL/P (P = 0.013 to 0.03); and 2 SNPs, 1 each in ATP binding cassette subfamily A member 4 (ABCA4) and noggin, showed associations with NSCL/P that approached the threshold of significance (P = 0.056 to 0.07). In addition, 6 gene-gene interactions (P = 0.0001 to 0.001) and an ABCA4-folic acid consumption interaction (P < 0.0001) were identified. On the basis of these results, combined with those of previous association studies in the literature and biological characterizations of murine models, we propose an interaction network in which interferon regulatory factor 6 plays a central role in the etiology of NSCL/P.

Transoral endoscopic-assisted management of subcondylar fractures in 17 patients: an alternative to open reduction with rigid internal fixation and closed reduction with maxillomandibular fixation.

The authors evaluate the results of transoral endoscopic-assisted open reduction and miniplate fixation of subcondylar fractures. Seventeen patients were treated from August 2005 to April 2007. Inclusion criteria were: adult patients, inability to achieve adequate occlusion with closed reduction, dislocation of the condylar fragment between 10 and 45 degrees , and 2-mm inter-fragment overlapping. Regular panoramic radiographs were taken postoperatively. Transbuccal incisions were used to place the screws for fixation in 15 patients. Pure intraoral access and angulated drills and screwdrivers were used in 2 patients. The condyle was placed into the condylar fossa in all cases. No damage to the facial nerve was observed. No visible scars were present. Mean surgical time was 80.36 minutes. Transitory hyposthesia was observed in 3 cases. Adequate reduction and consolidation of the fracture was achieved in 16 patients. No condylar reabsortion was present at the end of the follow-up period. The authors consider that transoral endoscopic-assisted open reduction constitutes a valid alternative to a transcutaneous approach for the reduction and fixation of subcondylar fractures in selected cases. It provides the benefits of open reduction and internal fixation without the potential complications. Advice is given on how to achieve adequate reduction and stability of the proximal fragment.

Reconstrucción de la articulación temporomandibular (ATM): prótesis aloplástica / Reconstruction of the temporomandibular joint (TMJ): alloplastic prostheses

La incapacidad de desarrollar sistemas inertes eficaces para la sustitución completa de la articulación temporo-mandibular durante décadas ha generado una variedad de soluciones biológicas para un problema biomecánico. Los injertos autólogos no ofrecen garantías en funcionalidad, simetría, o estabilidad oclusal; resultan técnicamente más complejos y tienen mayor potencial morbilidad. El paciente candidato a reconstrucción completa de la ATM debe contar con la posibilidad de una prótesis si otras opciones fracasan. La reconstrucción aloplástica garantiza estabilidad oclusal, técnica sencilla y reproducible, estancia hospitalaria predecible y baja tasa de complicaciones con los sistemas protésicos actuales. Siempre van a existir pacientes en los que ésta sea la única opción, por lo tanto es primordial la medición de la magnitud de las fuerzas implicadas en la mecánica de la ATM para poder diseñar prótesis en base a modelos fiables como en otras articulaciones en las que ya han resuelto el problema

Incapabability to develop effective inert systems to total temporomandibular joint substitution during decades has genered several biologic solutions for a biomecanic question. Autologous grafts don´t offer security in functioning, simmetry, or oclusal estability; its have more coplex technique and more potencial morbility. Alloplastic reconstruction guarantees oclusal stability, single and reproducible technique, predictable time in hospital, and low morbility with actual prosthetic systems. Patients whos prostheses is only one option are going to exist always, so that it is primordial measures of magnitude of implicated strenghts in TMJ mecanic to can design prosthesis based on reliable models like others articulations which have just resolved the question

Eficacia clínica de roxitromicina frente a amoxicilina/clavulánico en la profilaxis antimicrobiana tras cirugía de cordal incluido

Objetivo: Estudiar la eficacia y seguridad de roxitromicina 300 mg en una toma diaria y la asociación amoxicilina/clavulánico 500/125 mg cada 8 horas, en la profilaxis antimicrobiana de la cirugía de cordal incluido. Confirmar los datos de actividad anti-inflamatoria de roxitromicina publicados por otros autores. Diseño del estudio: Estudio ramdomizado, comparativo, prospectivo, no controlado, de fase IV. La eficacia clínica de ambos fármacos se valoró de acuerdo a la puntuación obtenida en la escala de "Criterios de Evaluación de Eficacia para Antibióticos" de la Sociedad Japonesa de Cirugía Oral; rango: 2 (más eficaz)-21 (menos eficaz) Resultados: Todos los pacientes reclutados (74) completaron el estudio. La puntuación total al final del estudio fue inferior en los pacientes que recibieron roxitromicina (2,9 ñ 1,5) frente a los tratados con amoxicilina/clavulánico (3,9 ñ 2,5) [p=0,l4]. También fueron mejores para roxitromicina el cociente entre la puntuación después y antes del tratamiento (0,41 ñ 0,21 frente a 0,53 ñ 0,39 [p=0,72]) y el porcentaje de pacientes que consideraron el tratamiento con el fármaco como excelente o eficaz (88,1 por ciento vs 70,9 por ciento; [p= 0,07]). El consumo de anti-inflamatorios fue similar en ambos grupos de tratamiento (7,4 ñ4,1 comprimidos semanales en el grupo roxitromicina vs. 8,0 ñ 4,1 comprimidos semanales en el grupo amoxicilina/clavulánico [p= 0,47]). En el grupo amoxicilina/clavulánico 29/32 pacientes comunicaron algún tipo de efecto adverso (90,6 por ciento) por tan sólo 12/42 pacientes en el grupo roxitromicina (29 por ciento) [p<0.0001]). Discusión: Roxitromicina a dosis de 300 mg/día y amoxicilina/clavulánico a dosis de 500/125 mg cada 8 horas son dos regímenes profilácticos igualmente efectivos en la prevención de las complicaciones infecciosas tras la cirugía de cordal incluido. Roxitromicina presenta un perfil de tolerabilidad y cumplimentación, significativamente superiores a las de amoxicilina/clavulánico, lo que la sitúa como un antibiótico de primera elección en la profilaxis antimicrobiana que acompaña estos procedimientos (AU)

Discoplasia con anclas Mitek(r) en el tratamiento del desplazamiento anterior del disco sin reducción de la ATM: estudio prospectivo clínico y con RMN / Discoplasty with Mitek(r) anchors for the treatment of the anterior dick displacement without redictio of the TMJ: A prospective clinical study with MRI

Entre enero de 1996 y diciembre de 1997 se trataron 12 pacientes con el diagnóstico clínico confirmado mediante resonancia magnética de desplazamiento anterior del disco modular sin reducción. Los pacientes en los que fracasó el tratamiento conservador fueron tratados mediante artrotomía y discoplastia clásica, fijando el disco al polo lateral y posterior del cóndilo mandibular mediante un ancla Mitek(r). Los pacientes se estudiaron de forma perspectiva a los 3, 6, 9, 12, 15, 18, 21 y 24 meses tras el tratamiento quirúrgico midiendo las siguientes variables: dolor articular (usando una escala analógica visual: 1-15), máxima apertura oral (MAO), protrusión mandibular (PM), lateralidad (LM) y presencia de ruidos articulares. Se realizaron estudios mediante resonancia magnética (cine-RMN sagital e imágenes coronales) antes y tras 6 meses de la cirugía. La edad media fue de 35,7 años (rango entre 19 y 66 años). Nueve eran mujeres y tres varones. El dolor articular subjetivo preoperatorio fue de 11,4ñ1,8, y de 3,2ñ2,1 a los 24 meses de la cirugía, La MAO preoperatoria fue de 29,1ñ2,5 mm y experimentó un aumento estadísticamente significativo (35,7ñ3,2 mm) a los 24 meses del tratamiento inicial. Se observó crepitación articular en 10 ariculaciones antes de la cirugía, persistiendo dicho signo en 8 de los casos y apareciendo en dos chasquidos reciprocos. El estudio por RMN obtenido a los 6 meses demostró una posición normal del disco en 10 articulaciones y un desplazamiento anterior del disco con reducción en los otros dos casos (AU)

Effusion in magnetic resonance imaging of the temporomandibular joint: a study of 123 joints.

PURPOSE: Effusion is the term used by radiologists for a hyperintensity signal seen inside a joint on magnetic resonance imaging (MRI). The aim of this study was to correlate the clinical and imaging features of this phenomenon, with the ultimate purpose of clarifying its meaning in dysfunctional processes of the temporomandibular joint (TMJ). PATIENTS AND METHODS: The clinical histories of 111 patients (123 joints) with effusion on MRI were reviewed. Thirty-one patients (46 joints) with articular pathology but without effusion, chosen at randomized, served as a control group. Five clinical variables (articular pain, radiating pain, limited mouth opening, clicking, and clinical stage) and five imaging findings (disc displacement, effusion location, disc morphology, osteophytes, avascular necrosis, and osteochondritis dissecans) were evaluated. RESULTS: Effusion in TMJ could be seen in relation to disc displacement and degenerative changes (osteophytes, avascular necrosis, osteochondritis dissecans). Clicking was more frequently found in TMJs without effusion. CONCLUSIONS: These results suggest that effusion may be a marker of articular degeneration in the TMJ.

Glenotemporal osteotomy as a definitive treatment for recurrent dislocation of the jaw.

Chronic Recurrent Dislocation of the jaw (CRD) is a relatively frequent occurrence, with a multifactorial aetiology. Both conservative and surgical treatments have been applied to this entity. This paper seeks to review the results of surgical treatment applied according to Norman's technique (1984), with certain modifications, applied to CRD. Ten patients were treated by glenotemporal osteotomy and interposition of bone grafts, (four cranial bone grafts and six iliac crest grafts). Previously, all of the patients had suffered numerous episodes, requiring hospital care on more than one occasion. Nine of the patients were female. All of the patients underwent clinical exploration and pre- and postoperative radiological study. Nuclear Magnetic Resonance (NMR) imaging was used in combination with tomography in the preoperative period to evaluate the state of the joint. In the postoperative period, tomography was used as the radiological investigation to carry out regular follow-ups. The patients were followed for between 5 and 51 months. The elements used in osteosynthesis were either wire, screws or nothing. None of the patients complained of any episode of RCD in the postoperative period. Oral opening, which could not be measured in the preoperative period, ranged between 28 and 38mm in the postoperative period. One of the patients operated on still suffered articular pain on attempting this function. In the postoperative period, radiology revealed different degrees of bone resorption in the cases of iliac crest bone grafts, yet this did not affect the clinical result of the operation.