RESUMEN
BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.
Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Proteína-Lisina 6-Oxidasa , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/patología , Animales , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/patología , Proteína-Lisina 6-Oxidasa/antagonistas & inhibidores , Ratones , Humanos , Microambiente Tumoral/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Masculino , Aminoácido Oxidorreductasas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Línea Celular TumoralRESUMEN
OBJECTIVE: Medical students often feel inadequately prepared for the responsibilities of surgical internship because of insufficient exposure to resident responsibilities prior to starting residency. This lack of preparation may contribute to burnout and attrition early in residency. Sub-internships should provide these experiences. Significant variation, however, exists in the structure of these rotations. We conducted a targeted needs assessment to inform the development of a didactic curriculum to address gaps in the surgical sub-internship experience and better prepare students for general surgery residency. DESIGN: A 25-item needs assessment survey was developed and distributed to senior medical students in their surgical sub-internship, current junior residents, and prior students (alumni) from the past 4 years who matched into general surgery residencies at other institutions. SETTING: Geisel School of Medicine at Dartmouth/Dartmouth-Hitchcock Medical Center, a tertiary-care academic medical center. PARTICIPANTS: Nine senior medical students; 12 current residents and 14 alumni, including 9 PGY-1, 13 PGY-2, and 4 PGY-3 residents. RESULTS: The topics rated most important by medical students were floor management topics, specifically lines, tubes, and drains, hypotension, post-operative fever, chest pain, oliguria, and post-operative pain. In contrast, there was a wider variety of topics rated highly by residents. Residents emphasized non-technical communication and documentation skills. Residents at every training level rated presenting patients on rounds as the most important skill for incoming interns to acquire, whereas only one-third of medical students considered this to be an essential topic. CONCLUSIONS: Medical students rank management of common clinical problems as the most critical aspect in their preparation for residency. Residents recognized these topics as important, but also placed high emphasis on non-technical communication and documentation skills. The findings from this need's assessment can be used to guide content structure for a sub-intern curriculum.