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1.
Ann Surg Oncol ; 31(1): 622-629, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37880514

RESUMEN

BACKGROUND: Peritoneal metastasis (PM) is the most common site of dissemination of gastric cancer (GC) and is associated with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for GC with PM remains controversial due to modest survival and significant morbidity. METHODS: We conducted a retrospective analysis of patients with GC and PM treated with CRS and HIPEC with cisplatin and paclitaxel for 90 min from June 2019 to December 2022. RESULTS: Twenty-two patients were included and received a median of 7 (interquartile range [IQR] 4-8) cycles of neoadjuvant systemic therapy. Seventeen patients (77%) underwent a single neoadjuvant laparoscopic HIPEC, and six (27%) patients received chemoradiation. The median Peritoneal Carcinomatosis Index at the time of CRS was 1 (IQR 0-4), and 21 patients (95%) underwent complete cytoreduction (CC-0). An R0 resection was achieved in 20 (91%) patients, and the median length of stay was 5.5 (IQR 4-7.5) days. There were six (27%) 90-day major complications (Clavien-Dindo grade ≥ 3), one (4%) Common Terminology Classification for Adverse Events (CTCAE) grade 4 cytopenia, and one (4%) acute kidney injury. The rate of anastomotic leak (all grades) was 14%, the 30-day readmission rate was 18%, and the 90-day mortality rate was 0%. At a median follow-up of 24 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 1-, 2-, and 3-year PFS rates were 65%, 56%, and 40%, respectively, and the 1-, 2-, and 3-year OS rates were 96%, 78%, and 55%, respectively. CONCLUSIONS: CRS and HIPEC with paclitaxel and cisplatin is well tolerated and is associated with favorable oncologic and perioperative outcomes.


Asunto(s)
Hipertermia Inducida , Neoplasias Peritoneales , Neoplasias Gástricas , Humanos , Cisplatino , Neoplasias Gástricas/patología , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Neoplasias Peritoneales/secundario , Paclitaxel , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tasa de Supervivencia
2.
J Hepatol ; 78(1): 142-152, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36162702

RESUMEN

BACKGROUND & AIMS: There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, Yes-associated protein (YAP), is oncogenic in CCA, but has historically been difficult to target therapeutically. Recently, we described a novel role for the LCK proto-oncogene, Src family tyrosine kinase (LCK) in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK is a viable therapeutic target in CCA via regulation of YAP activity. METHODS: A novel tyrosine kinase inhibitor with relative selectivity for LCK, NTRC 0652-0, was pharmacodynamically profiled in vitro and in CCA cells. A panel of eight CCA patient-derived organoids were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft models bearing fibroblast growth factor receptor 2 (FGFR2)-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. RESULTS: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in CCA cells. LCK inhibition with NTRC 0652-0 led to decreased tyrosine phosphorylation, nuclear localization, and co-transcriptional activity of YAP, and resulted in apoptotic cell death in CCA cell lines. A subset of tested patient-derived organoids demonstrated sensitivity to NTRC 0652-0. CCAs with FGFR2 fusions were identified as a potentially susceptible and clinically relevant genetic subset. In patient-derived xenograft models of FGFR2 fusion-positive CCA, daily oral treatment with NTRC 0652-0 resulted in stable plasma and tumor drug levels, acceptable toxicity, decreased YAP tyrosine phosphorylation, and significantly decreased tumor growth. CONCLUSIONS: A novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell lines, and patient-derived organoid and xenograft models. IMPACT AND IMPLICATIONS: Although aberrant YAP activation is frequently seen in CCA, YAP targeted therapies are not yet clinically available. Herein we show that a novel LCK-selective tyrosine kinase inhibitor (NTRC 0652-0) effectively inhibits YAP tyrosine phosphorylation and cotranscriptional activity and is well tolerated and cytotoxic in multiple preclinical models. The data suggest this approach may be effective in CCA with YAP dependence or FGFR2 fusions, and these findings warrant further investigation in phase I clinical trials.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Neoplasias de los Conductos Biliares/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Fosfoproteínas/genética , Factores de Transcripción/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas Señalizadoras YAP , Colangiocarcinoma/genética , Conductos Biliares Intrahepáticos/patología , Tirosina/genética , Tirosina/metabolismo , Tirosina/uso terapéutico , Línea Celular Tumoral
3.
Respirology ; 28(1): 66-73, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36104312

RESUMEN

BACKGROUND AND OBJECTIVE: Currently, computed tomography-guided transthoracic biopsy (CTTB) is the most accurate diagnostic approach for pulmonary nodules suspected of malignancy. Traditional bronchoscopy has shown suboptimal diagnostic sensitivity, but the emergence of robotic-assisted bronchoscopy (RAB) has the potential to improve diagnostic accuracy, maximize diagnostic yield and complete mediastinal and hilar staging in a single procedure. We aim to assess the efficacy and diagnostic performance of RAB compared to CTTB for diagnosing pulmonary nodules suspected of lung cancer. METHODS: A multicenter retrospective review of consecutive patients who underwent RAB and CTTB for evaluating pulmonary nodules from January 2019 to March 2021 at Mayo Clinic Florida and Mayo Clinic Rochester, United States. Clinical and demographic information, nodule characteristics, outcomes and complications were compared between RAB and CTTB. RESULTS: A total of 225 patients were included: 113 in the RAB group and 112 in the CTTB group. Overall diagnostic yield was 87.6% for RAB and 88.4% for CTTB. For malignant disease, RAB had a sensitivity of 82.1% and a specificity of 100%, CTTB had a sensitivity of 88.5% and a specificity of 100%. Complication rate was significantly higher for CTTB compared to RAB (17% vs. 4.4%; p = 0.002). CONCLUSION: RAB, when available, can be as accurate as CTTB for sampling pulmonary nodules with similar or reduced complications and should be considered as a means for nodule biopsy, particularly when mediastinal staging is also clinically warranted.


Asunto(s)
Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Procedimientos Quirúrgicos Robotizados , Nódulo Pulmonar Solitario , Humanos , Broncoscopía/métodos , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/patología , Biopsia Guiada por Imagen/métodos , Tomografía Computarizada por Rayos X/métodos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Nódulo Pulmonar Solitario/diagnóstico por imagen , Nódulo Pulmonar Solitario/patología , Pulmón/diagnóstico por imagen , Pulmón/patología
4.
HPB (Oxford) ; 24(10): 1748-1756, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35718679

RESUMEN

BACKGROUND: Intrahepatic Cholangiocarcinoma (iCCA) is an aggressive cancer with diverse mutational profiles. An important molecular subtype is fibroblast growth factor receptor 2 (FGFR2) fusion. The effect of FGFR2 fusions on prognosis is unknown. Our aim was to assess the outcomes in resected CCA patients in relation to FGFR2 status. METHODS: Surgically treated CCA patients from a single institution were retrospectively reviewed between 2008 and 2014. FGFR rearrangements were detected by fluorescence in situ hybridization (FISH). Data included patient demographics, tumor pathology, disease-free survival (DFS) and overall survival (OS). RESULTS: Ninety-five patients underwent surgical resection for iCCA. Twelve (13%) of these were found to have FGFR2 fusion, none of which were treated with FGFR targeted therapy. Patients with FGFR2 fusions were found to have a longer 5-year (83 vs. 32%, p = 0.01) and 10-year (46 vs. 22%, p = 0.04) OS. Five and 10-year DFS was also increased (68 vs. 33% p = 0.04) and (68 vs. 25 %, p = 0.02,). FGFR2 fusion status was the strongest independent factor associated with improved OS (HR 0.23, 0.09-0.62, p=0.003) and DFS (HR 0.18, 0.05-0.67, p=0.01). CONCLUSION: Patients with CCA FGFR2 fusion have improved OS and DFS following surgical resection.


Asunto(s)
Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/metabolismo , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/cirugía , Neoplasias de los Conductos Biliares/metabolismo , Hibridación Fluorescente in Situ , Estudios Retrospectivos , Colangiocarcinoma/genética , Colangiocarcinoma/cirugía , Colangiocarcinoma/metabolismo , Fusión Génica , Conductos Biliares Intrahepáticos/patología
5.
HPB (Oxford) ; 22(7): 1074-1081, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31839391

RESUMEN

BACKGROUND: Preoperative opioid use in patients undergoing low complexity operations has been associated with increased complications, but its relationship to procedures of greater complexity is unclear. We aimed to assess this impact on outcomes following pancreaticoduodenectomy (PD). METHODS: A single institution, retrospective cohort of adults undergoing elective PD for cancer (1/2009-9/2015). Preoperative opioid users were defined as patients documented as taking opioids up to 90 days preoperatively. Discharge prescriptions were converted into Oral Morphine Equivalents (OME) and ten-point pain scores were abstracted. Univariate and multivariable analyses compared outcomes of naïve and preoperative opioid users overall and for laparoscopic vs open surgery. RESULTS: Of 661 PD patients, 131 (19.8%) were preoperative opioid users. These patients had greater mean pain scores over the first three days after surgery (3.4 ± 1.6, vs 2.8 ± 1.4, p < 0.001), max pain (7.9 ± 1.9 vs 7.2 ± 2.0, p < 0.001), and discharge pain (2.3 ± 1.9 vs 1.8 ± 1.6, p = 0.01) than naïve patients. Preoperative opioid users received more opioids at discharge (mean 496 ± 764 OME) than naïve (320 ± 489 OME, p = 0.03). Thirty-day refill rates were 12.6% (19.1% preoperative vs 10.9% naïve, p = 0.02). After controlling for tumor type, pancreas texture, and duct size, naïve patients had similar odds of clinically significant post-operative pancreatic fistulas (grade B or C) (OR 1.13, p = 0.68) and delayed gastric emptying (OR 1.05, p = 0.87). After controlling for age and complications, preoperative opioid use was associated with increased odds of LOS ≥9 days (OR 1.59, p = 0.04). CONCLUSION: Following PD, preoperative opioid users had worse pain scores, received more opioids at discharge, refilled prescriptions more frequently, and were more likely to have prolonged LOS. As most opioid utilization research has been focused on low complexity surgery, additional work aimed at optimizing opioid use in complex oncologic operations is warranted.


Asunto(s)
Analgésicos Opioides , Pancreaticoduodenectomía , Adulto , Analgésicos Opioides/efectos adversos , Humanos , Tiempo de Internación , Dolor Postoperatorio/diagnóstico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/etiología , Pancreaticoduodenectomía/efectos adversos , Estudios Retrospectivos
6.
J Surg Res ; 232: 643-646, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30463786

RESUMEN

BACKGROUND: Treatment of cardiovascular implantable device pocket infections (CIDPIs) requires a multimodal approach that includes antimicrobials, device explantation, and local wound care. Our institution implemented a practice management guideline (PMG) to standardize the care of CIDPIs and engage our acute care surgeons in 2013. Our PMG includes wound culture, complete capsulectomy, pulse lavage, and the placement of a negative pressure wound therapy appliance at the time of device extraction. Forty-eight hours later, wounds are irrigated and closed in a delayed primary fashion over drains. Our objective was to compare the outcomes of patients who underwent device extraction before and after the implementation of the PMG for the treatment of CIDPIs. METHODS: An IRB-approved retrospective review of 155 patients at our institution from 2012 to 2015 who underwent device explantation. Evaluated outcomes measured included days from device explant to wound closure, and postoperative complications. Outcomes data were analyzed before (pre-PMG) and after (post-PMG) enactment of the PMG. RESULTS: Fifty-eight patients (42 males; mean age 68 years) were managed prior to PMG implementation; 97 (72 males; mean age 67) were managed after. Mean days from device explantation to wound closure were compared (pre-PMG 6 ± 3.5 and post-PMG 2.8 ± 1.8), and time to closure was reduced by 3-d post-PMG implementation (P < 0.05). No increase in surgical site infection, hematoma, or unplanned return to operating room was demonstrated between groups (P < 0.05). CONCLUSIONS: The implementation of a PMG for the management of CIDPIs is effective in reducing the number of days to pocket wound closure; acute care surgeons are well equipped to participate in this practice and improve patient outcomes.


Asunto(s)
Desfibriladores Implantables/efectos adversos , Remoción de Dispositivos , Marcapaso Artificial/efectos adversos , Guías de Práctica Clínica como Asunto , Infecciones Relacionadas con Prótesis/terapia , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia de Presión Negativa para Heridas , Estudios Retrospectivos
7.
Hepatology ; 74(3): 1692-1694, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33928664

Asunto(s)
Hepatocitos , Hígado
8.
J Gastrointest Surg ; 2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39209560

RESUMEN

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMNs) can progress to pseudomyxoma peritonei (PMP). The incidence and risk factors for recurrence are unclear, and there is a lack of consensus on the need and duration of surveillance imaging. METHODS: Patients at the Mayo Clinic in Rochester, Minnesota, with a histologic diagnosis of LAMNs confined to the appendix and limited involvement of the right lower quadrant from 1992 to 2023 were included. Associations between recurrence and risk factors were assessed using Kaplan-Meier curves and Cox proportional hazards regression. RESULTS: A total of 125 patients with LAMNs underwent abdominal imaging surveillance for a median of 51.2 months (IQR, 26-92). Of note, 5 patients (4%) recurred, all of which were PMP. Overall, the 5- and 10-year cumulative recurrence incidence rates were 3% and 6%, respectively. The median time to recurrence was 24 months (IQR, 23-87). Only LAMNs limited to the right lower quadrant and LAMN tumor size of <2 cm were associated with recurrence (P < .05). The 5- and 10-year cumulative recurrence risks were 12% and 30%, respectively, for the 21 patients with either risk factor. Only 1% of patients without these 2 risk factors developed a recurrence at 10 years. CONCLUSION: The overall recurrence risk of LAMN after resection is low. Appendectomy is sufficient for LAMN. Select patients with acellular mucin confined to the right lower quadrant and a tumor size of <2 cm are at higher risk of recurrence. Thus, long-term surveillance is recommended for high-risk individuals. Conversely, LAMNs without risk factors can be safely observed expectantly.

9.
PNAS Nexus ; 3(3): pgae096, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38528952

RESUMEN

Dysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

10.
J Vasc Surg Cases Innov Tech ; 8(4): 678-687, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36325311

RESUMEN

In the current endovascular era, open repair of complex aortic aneurysms is becoming a rare, but indispensable, part of vascular surgeons' skill set in specific scenarios. For young, low-risk patients and patients with connective tissue disorders, early target vessel bifurcation, a horseshoe kidney, or pedunculated intraluminal aortic thrombus, fenestrated-branched stent graft technology will not be applicable without significant risks. Thus, an open surgical approach has been recommended for these patients. Most vascular surgeons will be familiar with a transperitoneal approach or a retroperitoneal approach with a lateral incision. For patients with a horseshoe kidney, an inflammatory aneurysm, or a history of multiple intraperitoneal procedures, a retroperitoneal approach should be preferred. In the present report, we have described in detail the optimization of a retroperitoneal approach through a midline incision that provides excellent exposure to the paravisceral aorta, improves exposure to the right renal artery and right iliac artery bifurcation (which is limited using the left flank retroperitoneal approach), and avoids division of the lateral abdominal wall muscles, which has often been associated with iatrogenic muscle denervation and postoperative bulging for four patients who had required complex aortic reconstruction.

11.
JCI Insight ; 7(15)2022 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-35763355

RESUMEN

Disrupted liver regeneration following hepatectomy represents an "undruggable" clinical challenge associated with poor patient outcomes. Yes-associated protein (YAP), a transcriptional coactivator that is repressed by the Hippo pathway, is instrumental in liver regeneration. We have previously described an alternative, Hippo-independent mechanism of YAP activation mediated by downregulation of protein tyrosine phosphatase nonreceptor type 11 (PTPN11, also known as SHP2) inhibition. Herein, we examined the effects of YAP activation with a selective SHP1/SHP2 inhibitor, NSC-87877, on liver regeneration in murine partial hepatectomy models. In our studies, NSC-87877 led to accelerated hepatocyte proliferation, improved liver regeneration, and decreased markers of injury following partial hepatectomy. The effects of NSC-87877 were lost in mice with hepatocyte-specific Yap/Taz deletion, and this demonstrated dependence on these molecules for the enhanced regenerative response. Furthermore, administration of NSC-87877 to murine models of nonalcoholic steatohepatitis was associated with improved survival and decreased markers of injury after hepatectomy. Evaluation of transcriptomic changes in the context of NSC-87877 administration revealed reduction in fibrotic signaling and augmentation of cell cycle signaling. Cytoprotective changes included downregulation of Nr4a1, an apoptosis inducer. Collectively, the data suggest that SHP2 inhibition induces a pro-proliferative and cytoprotective enhancement of liver regeneration dependent on YAP.


Asunto(s)
Hepatectomía , Regeneración Hepática , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Hígado/metabolismo , Regeneración Hepática/fisiología , Ratones , Proteínas Señalizadoras YAP
12.
J Clin Invest ; 130(10): 5380-5396, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32663198

RESUMEN

Immune checkpoint blockade (ICB) has revolutionized cancer therapeutics. Desmoplastic malignancies, such as cholangiocarcinoma (CCA), have an abundant tumor immune microenvironment (TIME). However, to date, ICB monotherapy in such malignancies has been ineffective. Herein, we identify tumor-associated macrophages (TAMs) as the primary source of programmed death-ligand 1 (PD-L1) in human and murine CCA. In a murine model of CCA, recruited PD-L1+ TAMs facilitated CCA progression. However, TAM blockade failed to decrease tumor progression due to a compensatory emergence of granulocytic myeloid-derived suppressor cells (G-MDSCs) that mediated immune escape by impairing T cell response. Single-cell RNA sequencing (scRNA-Seq) of murine tumor G-MDSCs highlighted a unique ApoE G-MDSC subset enriched with TAM blockade; further analysis of a human scRNA-Seq data set demonstrated the presence of a similar G-MDSC subset in human CCA. Finally, dual inhibition of TAMs and G-MDSCs potentiated ICB. In summary, our findings highlight the therapeutic potential of coupling ICB with immunotherapies targeting immunosuppressive myeloid cells in CCA.


Asunto(s)
Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/terapia , Células Supresoras de Origen Mieloide/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Macrófagos Asociados a Tumores/inmunología , Animales , Antígeno B7-H1/deficiencia , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/patología , Quimiocina CXCL2/metabolismo , Colangiocarcinoma/inmunología , Colangiocarcinoma/patología , Perfilación de la Expresión Génica , Humanos , Inmunoterapia , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Supresoras de Origen Mieloide/clasificación , Receptor de Muerte Celular Programada 1/inmunología , Análisis de la Célula Individual , Microambiente Tumoral/inmunología
13.
Mol Cancer Res ; 18(10): 1574-1588, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32646966

RESUMEN

The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAPY357 even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in cholangiocarcinomas. A screen for YAP-interacting tyrosine phosphatases identified SHP2, and characterization of cholangiocarcinomas cell lines demonstrated an inverse relationship between SHP2 levels and pYAPY357. Human sequencing data demonstrated lower SHP2 levels in cholangiocarcinomas tumors as compared with normal liver. Cell lines with low SHP2 expression and higher levels of pYAPY357 were resistant to gemcitabine and cisplatin. In cholangiocarcinomas cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAPY357 phosphorylation and expression of YAP target genes, including the antiapoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2, which could be overcome by utilizing an MCL1 inhibitor. IMPLICATIONS: These findings demonstrate a role for SHP2 in regulating YAP activity and chemosensitivity, and suggest that decreased phosphatase activity may be a mechanism of chemoresistance in cholangiocarcinoma via a MCL1-mediated mechanism.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Colangiocarcinoma/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Factores de Transcripción/metabolismo , Animales , Colangiocarcinoma/patología , Humanos , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Transfección , Proteínas Señalizadoras YAP
14.
J Surg Educ ; 75(3): 787-791, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28970180

RESUMEN

BACKGROUND: Endoscopic totally extraperitoneal inguinal hernia repair (TEP-IHR) requires practice and training to perform well. We developed a simple, low-cost, inanimate model to teach surgical residents inguinal anatomy and the technique of mesh insertion for a safe, endoscopic TEP-IHR. The objective of this study was to compare our model vs cadaveric dissection for teaching anatomy and mesh insertion. METHODS: A total of 14 general surgery residents participated in an institutional review board approved, prospective, and randomized study. Participants received a timed, web-based, interactive pretest assessing relevant anatomy and operative-based techniques. They then performed endoscopic TEP-IHRs on either a cadaver or our low-cost model. Participants then received a timed, web-based interactive posttest consisting of the same questions. Participants were surveyed anonymously regarding the degree to which either the model or the cadaver was educationally effective. RESULTS: Both groups of trainees (cadaver = 7, low-cost model = 7) scored higher on the posttest (p<0.05) with similar improvement (cadaver group: pretest = 78% correct, posttest = 87%; low-cost model group: 77% vs 86%). Survey results revealed the trainees preferred for both initial learning and understanding of mesh placement using low-cost models (5 out of 5, 4.8/5, respectively) over cadavers (4.0/5, 3.8/5, respectively; p<0.05). Trainees preferred the cadaver (4.7) over the low-cost model (3.9, p<0.05) in overall experience. No differences were found in the trainees' preference between the cadaver (4.5) and low-cost model (4.7) in the overall educational value. CONCLUSION: While the overall educational experience of 14 learners favored a cadaver experience to learn TEP-IHR, initial anatomical learning and placing the mesh was better with an inanimate model. Given the educational value of the 2 methods was equivalent, the $1500 cost for cadavers make the inexpensive and repeatable inanimate model an attractive early resource for learning TEP-IHR.


Asunto(s)
Competencia Clínica , Educación de Postgrado en Medicina/métodos , Endoscopía/educación , Hernia Inguinal/cirugía , Herniorrafia/educación , Centros Médicos Académicos , Cadáver , Disección/métodos , Femenino , Cirugía General/educación , Humanos , Masculino , Minnesota , Modelos Anatómicos , Estudios Prospectivos
15.
Acad Med ; 93(6): 920-928, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29419552

RESUMEN

PURPOSE: To determine whether "chronometric pressure" (i.e., a verbal prompt to increase speed) could predictably alter medical learners' speed-accuracy trade-off during a simulated surgical task, thus modifying the challenge. METHOD: The authors performed a single-task, interrupted time-series study, enrolling surgery residents and medical students from two institutions in September and October 2015. Participants completed 10 repetitions of a simulated blood vessel ligation (placement of two ligatures 1 cm apart). Between repetitions 5 and 6, participants were verbally encouraged to complete the next repetition 20% faster than the previous one. Outcomes included time and accuracy (ligature tightness, placement distance). Data were analyzed using random-coefficients spline models. RESULTS: The authors analyzed data from 78 participants (25 medical students, 16 first-year residents, 37 senior [second-year or higher] residents). Overall, time decreased from the 1st (mean [standard deviation] 39.8 seconds [18.4]) to the 10th (29.6 [12.5]) repetition. The spline model showed a decrease in time between repetitions 5 and 6 of 8.6 seconds (95% confidence interval: -11.1, -6.1). The faster time corresponded with declines in ligature tightness (unadjusted difference -19%; decrease in odds 0.86 [0.76, 0.98]) and placement accuracy (unadjusted difference -5%; decrease in odds 0.86 [0.75, 0.99]). Significant differences in the speed-accuracy trade-off were seen by training level, with senior residents demonstrating the greatest decline in accuracy as speed increased. CONCLUSIONS: Chronometric pressure influenced the speed-accuracy trade-off and modified the challenge level in a simulated surgical task. It may help unmask correctable deficiencies or false plateaus in learners' skill development.


Asunto(s)
Fenómenos Cronobiológicos , Internado y Residencia/métodos , Aprendizaje/fisiología , Entrenamiento Simulado/métodos , Estudiantes de Medicina/psicología , Adulto , Competencia Clínica , Femenino , Humanos , Análisis de Series de Tiempo Interrumpido , Ligadura/educación , Masculino , Tiempo de Reacción , Análisis y Desempeño de Tareas , Factores de Tiempo
16.
J Surg Educ ; 75(3): 836-843, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29037821

RESUMEN

OBJECTIVE: To evaluate the validity of a novel inverted peg transfer (iPT) task for assessing laparoscopic skills of novices and experts and compare iPT to the regular PT (rPT) task to ensure surgical trainee acquisition of an adequate advanced laparoscopic skills level for safe laparoscopic practice in the operating room. DESIGN: Prospective crossover study. SETTING: Multidisciplinary simulation center and motion analysis laboratory, Mayo Clinic. PARTICIPANTS: Novices were medical students and surgical interns without laparoscopic experience. Experts were surgeons with at least 3 years of experience in laparoscopic surgery. METHODS: This was the first exposure to iPT for both groups. Completion time and performance metrics were recorded. A scoring rubric was used to calculate a normalized performance score between 0 and 100. Wilcoxon rank sum and Mann-Whitney tests were performed with α = 0.05. Receiver-operating characteristic curves were graphed for the 2 task scores to assess the tasks' sensitivity and specificity in differentiating laparoscopic experience level. MAIN OUTCOME MEASURES: Performance measures of completion time, transferred triangles, dropped triangles (errors), and the overall performance score on both tasks between- and within-subjects (i.e., novices and experts). RESULTS: Thirty-six novices and eight experts participated. Both experts and novices had longer completion time and lower scores during iPT than rPT (p < 0.05). Within iPT, novice completion times were 144 seconds longer (p = 0.04), and performance score was 35 points lower than experts (p < 0.01). No differences between novices and experts were observed for completion time or performance scores (p > 0.05) for rPT. The iPT scores had a higher sensitivity and specificity than the rPT (area under the receiver-operating characteristic curve: iPT = 0.91; rPT = 0.69). CONCLUSIONS: iPT is a valid assessment of advanced laparoscopic skills for surgical trainees with higher specificity and sensitivity than rPT. As advanced minimally invasive surgery becomes more common, it is important that tasks such as iPT be included in surgical simulation curricula and training assessment.


Asunto(s)
Competencia Clínica , Cirugía General/educación , Laparoscopía/educación , Destreza Motora , Entrenamiento Simulado/métodos , Adulto , Estudios Cruzados , Femenino , Humanos , Laparoscopios , Laparoscopía/métodos , Masculino , Tempo Operativo , Estudios Prospectivos , Curva ROC , Estadísticas no Paramétricas , Análisis y Desempeño de Tareas
17.
J Surg Educ ; 74(1): 79-83, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-27993626

RESUMEN

OBJECTIVE: Many institutions use social media to share research with the general public. However, the influence of social media on the dissemination of a surgical research article itself is unknown. Our objective was to determine whether a blog post highlighting the findings of a surgical research article would lead to increased dissemination of the article itself. DESIGN: We prospectively followed the online page views of an article that was published online in Surgery in May 2015 and published in print in August 2015. The authors subsequently released a blog post in October 2015 to promote the research. The number of article page views from the journal's website was obtained before and after the blog post, along with the page views from the blog post itself. Social media influence data were collected, including social activity in the form of mentions on social media sites, scholarly activity in online libraries, and scholarly commentary. RESULTS: The article's online activity peaked in the first month after online publication (475 page views). Online activity plateaued by 4 months after publication, with 118 monthly page views, and a blog post was subsequently published. The blog post was viewed by 1566 readers, and readers spent a mean of 2.5 minutes on the page. When compared to the projected trend, the page views increased by 33% in the month after the blog post. The blog post resulted in a 9% increase in the social media influence score and a 5% absolute increase in total article page views. CONCLUSIONS: Social media is an important tool for sharing surgical research. Our data suggest that social media can increase distribution of an article's message and also potentially increase dissemination of the article itself. We believe that authors should consider using social media to increase the dissemination of traditionally published articles.


Asunto(s)
Investigación Biomédica , Cirugía General , Difusión de la Información , Publicaciones Periódicas como Asunto , Medios de Comunicación Sociales/estadística & datos numéricos , Blogging , Predicción , Humanos , Medios de Comunicación Sociales/tendencias , Estados Unidos
18.
Am J Surg ; 213(3): 526-529, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27839687

RESUMEN

BACKGROUND: We pondered if preoperative scripting might better prepare residents for the operating room (OR). METHODS: Interns rotating on a general surgeon's service were instructed to script randomized cases prior to entering the OR. Scripts contained up to 20 points highlighting patient information perceived important for surgical management. The attending was blinded to the scripting process and completed a feedback sheet (Likert scale) following each procedure. Feedback questions were categorized into "preparedness" (aware of patient specific details, etc.) and "performance" (provided better assistance, etc.). RESULTS: Eight surgical interns completed 55 scripted and 61 non-scripted cases. Total scores were higher in scripted cases (p = 0.02). Performance scores were higher for scripted cases (3.31 versus 3.13, p = 0.007), while preparedness did not differ (3.65 and 3.62, p = 0.51). CONCLUSIONS: This pilot study suggests scripting cases may be a useful preoperative planning tool to increase interns' operative and patient care performance but may not affect perceived preparedness.


Asunto(s)
Cirugía General/educación , Internado y Residencia , Planificación de Atención al Paciente , Cuidados Preoperatorios/métodos , Competencia Clínica , Retroalimentación , Humanos , Minnesota , Proyectos Piloto , Estudios Prospectivos
19.
J Surg Educ ; 74(6): 952-957, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28666958

RESUMEN

OBJECTIVE: To create a novel "at-home" preresidency preparatory adjunct for medical students entering surgical residency. DESIGN: Preparatory resources were mailed to match medical students before residency matriculation in 2015. This included "how-to" videos, low-cost models, and surgical instruments for 5 "stations" (arterial blood gas analysis, anatomy and imaging knowledge, knot tying ability, and suturing dexterity) of our program's biannual general surgery intern objective assessment activity (Surgical Olympics: total 13 stations, 10 points each). Scores from 2015 were compared with 2014 historical controls in a retrospective manner using the Student's t-test. SETTING: Academic, tertiary care referral center with a large general surgery training program. PARTICIPANTS: Postgraduate year 1 general surgery trainees (interns) from the years 2014 and 2015. RESULTS: Twenty-six interns participated in the 2015 assessment and were compared to thirty-two 2014 interns. Overall mean scores were low, but higher (19.7 vs. 15.4, p = 0.04) in the 2015 class. The largest increase was noted in the anatomy knowledge station (mean = 5.0 vs. 1.9, p < 0.01). Scores in stations assessing technical competence were similar to controls. The number of perfect scores among the 5 stations was higher (10 vs. 5) in the 2015 group. Mean scores from the other 8 stations, for which no resources were mailed, showed no difference (29.3 vs. 28.3, p = 0.75). CONCLUSIONS: Enacting a simple, home-based curriculum for medical students before surgical residency, improved performance on early knowledge assessments.


Asunto(s)
Selección de Profesión , Competencia Clínica , Educación a Distancia/métodos , Cirugía General/educación , Internado y Residencia/métodos , Estudiantes de Medicina , Centros Médicos Académicos , Adulto , Curriculum , Evaluación Educacional , Femenino , Humanos , Masculino , Proyectos Piloto , Estudios Retrospectivos , Grabación en Video
20.
J Surg Educ ; 73(6): e71-e76, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27476792

RESUMEN

OBJECTIVE: Surgical training programs often lack objective assessment strategies. Complicated scheduling characteristics frequently make it difficult for surgical residents to undergo formal assessment; actually having the time and opportunity to remediate poor performance is an even greater problem. We developed a novel methodology of assessment for residents and created an efficient remediation system using a combination of simulation, online learning, and self-assessment options. DESIGN: Postgraduate year (PGY) 2 to 5 general surgery (GS) residents were tested in a 5 station, objective structured clinical examination style event called the Surgical X-Games. Stations were 15 minutes in length and tested both surgical knowledge and technical skills. Stations were scored on a scale of 1 to 5 (1 = Fail, 2 = Mediocre, 3 = Pass, 4 = Good, and 5 = Stellar). Station scores ≤ 2 were considered subpar and required remediation to a score ≥ 4. Five remediation sessions allowed residents the opportunity to practice the stations with staff surgeons. Videos of each skill or test of knowledge with clear instructions on how to perform at a stellar level were offered. Trainees also had the opportunity to checkout take-home task trainers to practice specific skills. Residents requiring remediation were then tested again in-person or sent in self-made videos of their performance. SETTING: Academic medical center. PARTICIPANTS: PGY2, 3, 4, and 5 GS residents at Mayo Clinic in Rochester, MN. RESULTS: A total of, 35 residents participated in the Surgical X-Games in the spring of 2015. Among all, 31 (89%) had scores that were deemed subpar on at least 1 station. Overall, 18 (58%) residents attempted remediation. All 18 (100%) achieved a score ≥ 4 on the respective stations during a makeup attempt. Overall X-Games scores and those of PGY2s, 3s, and 4s were higher after remediation (p < 0.05). No PGY5s attempted remediation. CONCLUSIONS: Despite difficulties with training logistics and busy resident schedules, it is feasible to objectively assess most GS trainees and offer opportunities to remediate if performance is poor. Our multifaceted remediation methodology allowed 18 residents to achieve good or stellar performance on each station after deliberate practice. Enticing chief residents to participate in remediation efforts in the spring of their final year of training remains a work in progress.


Asunto(s)
Competencia Clínica , Evaluación Educacional/métodos , Cirugía General/educación , Internado y Residencia/métodos , Educación Compensatoria/métodos , Centros Médicos Académicos , Adulto , Educación de Postgrado en Medicina/métodos , Femenino , Humanos , Masculino , Minnesota , Tempo Operativo , Análisis y Desempeño de Tareas , Habilidades para Tomar Exámenes
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