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1.
J Surg Educ ; 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38824089

RESUMO

OBJECTIVE: General surgery trainees interested in performing hepatopancreatobiliary (HPB) surgery can choose from multiple fellowship pathways, namely HPB, surgical oncology (SO), and abdominal transplant-HPB (TXP-HPB). Although focused on similar operations, each program offers distinct clinical and technical emphases. DESIGN: An annual inter-institutional exchange between TXP-HPB and SO fellowships, starting in 2014. SETTING AND PARTICIPANTS: TXP-HPB fellows from Washington University in St. Louis (WUSTL) and SO fellows from Memorial Sloan Kettering Cancer Center (MSKCC). RESULTS: About 14 fellows have participated in the exchange so far, 13 of whom responded to our survey. At MSKCC, TXP-HPB fellows performed a median of 24 cases, including 6 major pancreatic resections, 3 major hepatectomies, 4 hepatic artery infusion pump insertions, and 1 major biliary case. At WUSTL, SO fellows performed a median of 16 cases, including 5 liver transplants, 2 major pancreatic resections, 2 major hepatectomies, and 2 major biliary cases. About 92.3% of respondents stated they would repeat the rotation, with SO fellows emphasizing the exposure to vascular anastomoses and transplant-HPB fellows appreciating the oncologic focus. CONCLUSIONS: A monthlong inter-institutional exchange offers a unique opportunity to standardize and improve HPB education.

3.
Clin Transplant ; 37(11): e15103, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37605386

RESUMO

INTRODUCTION: Despite considerable interest in robotic surgery, successful incorporation of robotics into transplant programs has been challenging. Lack of a dedicated OR team with expertise in both robotics and transplant is felt to be a major barrier. This paper assesses the impact of a dedicated robotic transplant team (DART) on program growth and fellowship training at one of the largest robotic transplant programs in North America. METHODS: This is a single center, retrospective review of all robotic operations performed on the transplant surgery service from October 2017 to October 2022. DART was incorporated in February 2020 and included transplant first assists (RFAs), scrub technologists and circulating nurses who received robotic training. Robotic experience before and after DART was compared to assess its impact on program growth and training. RESULTS: Four hundred and two robotic cases were performed by five transplant surgeons: 63 pre-DART and 339 post-DART. 40% of cases were transplant-related and 59.5%, HPB. There was a significant increase in case volume (2.5-10.6 cases/month, p < .0001) and complexity (36.5% vs. 70.3% high complexity cases, p < .0001) post-DART. RFA case coverage increased from 17% to 95%, and participation of transplant fellows as primary surgeons increased from 17% to 95% post-DART period (both p < .05). Conversion rates (9.5% vs. 4.1%) and room turn-around-times (TAT) (58.4 vs. 40.3 min) were lower post-DART (p < .05). There were no emergent conversions, conversions in transplant patients, or robot-related complications in either group. CONCLUSION: OR teams with expertise in robotics and transplant surgery can accelerate growth of robotic transplant programs while maintaining patient safety.


Assuntos
Procedimentos Cirúrgicos Robóticos , Robótica , Cirurgiões , Humanos , Bolsas de Estudo , Salas Cirúrgicas
6.
Ann Surg Oncol ; 30(8): 4775-4780, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37210451

RESUMO

BACKGROUND: Hepatic artery infusion pump (HAIP) therapy has become increasingly commonplace in the treatment of intrahepatic tumors. When combined with standard chemotherapy, HAIP therapy demonstrates a higher response rate than chemotherapy alone. Biliary sclerosis is observed in up to 22 % of patients, for whom no treatment has been standardized. This report describes orthotopic liver transplantation (OLT) both as a treatment for HAIP-induced cholangiopathy and as a possible definitive oncologic treatment after HAIP-bridging therapy. METHODS: A retrospective study reviewed patients who had undergone HAIP placement followed by OLT at the authors' institution. Patient demographics, neoadjuvant treatment, and postoperative outcomes were reviewed. RESULTS: Seven OLTs were performed for patients with prior HAIP placement. The majority were women (n = 6), and the median age was 61 years (range, 44.5-65.5 years). Transplantation was performed for five patients due to biliary complications secondary to HAIP and two patients because of residual tumor after HAIP therapy. All the OLTs had difficult dissections due to adhesions. Because of HAIP-induced damage, atypical arterial anastomoses were required in six patients (2 patients used a recipient common hepatic artery below the gastroduodenal artery takeoff; 2 patients used recipient splenic arterial inflow; 1 patient used the junction of the celiac and splenic arteries; and 1 patient used the celiac cuff). The one patient with standard arterial reconstruction experienced an arterial thrombosis. The graft was salvaged with thrombolysis. Biliary reconstruction was duct-to-duct in five cases and Roux-en-Y in two cases. CONCLUSIONS: The OLT procedure is a feasible treatment option for end-stage liver disease after HAIP therapy. Technical considerations include a more challenging dissection and an atypical arterial anastomosis.


Assuntos
Artéria Hepática , Transplante de Fígado , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Artéria Hepática/cirurgia , Transplante de Fígado/métodos , Estudos Retrospectivos , Hepatectomia , Bombas de Infusão Implantáveis
7.
Cancer Immunol Immunother ; 72(8): 2813-2827, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37179276

RESUMO

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Antígenos de Neoplasias , Neoplasias Pancreáticas/terapia , Linfócitos T CD8-Positivos , Carcinoma Ductal Pancreático/terapia , Imunoterapia , Neoplasias Pancreáticas
8.
Am J Surg ; 225(2): 420-424, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36253318

RESUMO

BACKGROUND: An increasing number of transplant centers have adopted robot-assisted living donor nephrectomy. Thus, a transplant fellow assessment tool is needed for promoting operative independence in an objective and safe manner. METHODS: In this pilot study, data was prospectively collected on both fellow performance with focus on technique, efficiency, and communication ("overall RO-SCORE"), and operative steps ("operative steps RO-SCORE"). Robotic user performance metrics were analyzed from the da Vinci Xi system, including fellow percent active control time (ACT) and handoff counts. RESULTS: From July 2020 to February 2021, twenty-one robot-assisted donor nephrectomies were performed. In regression analysis, fellow performance (based on both RO-SCOREs and robot % ACT) was significantly associated with both time and case number, with time-to-independence modelled at 8.4-14.2 months, and case number-to-independence estimated at 15-22 cases. Robot user metrics provided valid objective measures alongside RO-SCOREs. CONCLUSIONS: This pilot study provides an effective assessment tool for promoting operative competency in robot-assisted donor nephrectomy among transplant fellows.


Assuntos
Laparoscopia , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Nefrectomia/métodos , Doadores Vivos , Procedimentos Cirúrgicos Robóticos/métodos , Bolsas de Estudo , Projetos Piloto , Laparoscopia/métodos
9.
J Surg Oncol ; 126(8): 1533-1542, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35962783

RESUMO

BACKGROUNDS AND OBJECTIVES: This investigation described clinicopathological features and outcomes of extraskeletal myxoid chondrosarcoma (EMC) patients. METHODS: EMC patients were identified from the United States Sarcoma Collaborative database between 2000 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and prognostic factors were analyzed. RESULTS: Sixty individuals with a mean age of 55 years were included, and 65.0% (n = 39) were male. 73.3% (n = 44) had a primary tumor. A total of 41.6% (n = 25) developed tumor relapse following resection. The locoregional recurrence rate was 30.0% (n = 18/60), and mean follow-up was 42.7 months. The 5-year OS was 71.0%, while the 5-year RFS was 41.4%. On multivariate analysis for all EMC, chemotherapy (hazard ratio [HR], 6.054; 95% confidence interval [CI], 1.33-27.7; p = 0.020) and radiation (HR, 5.07, 95% CI, 1.3-20.1; p = 0.021) were independently predictive of a worse RFS. Among patients with primary EMC only, the 5-year OS was 85.3%, with a 30.0% (n = 12) locoregional recurrence rate, though no significant prognostic factors were identified. CONCLUSIONS: Long-term survival with EMC is probable, however there exists a high incidence of locoregional recurrence. While chemotherapy and radiation were associated with a worse RFS, these findings were likely confounded by recurrent disease as significance was lost in the primary EMC-only subset.


Assuntos
Condrossarcoma , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Masculino , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Feminino , Condrossarcoma/cirurgia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/terapia , Sarcoma/cirurgia , Sarcoma/patologia
10.
Clin Cancer Res ; 27(24): 6761-6771, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34593529

RESUMO

PURPOSE: FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). RESULTS: Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27-Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. CONCLUSIONS: Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.


Assuntos
Terapia Neoadjuvante , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos , Fluoruracila/uso terapêutico , Humanos , Irinotecano , Leucovorina/uso terapêutico , Leucócitos Mononucleares , Oxaliplatina , Neoplasias Pancreáticas/tratamento farmacológico
11.
J Am Coll Surg ; 231(6): 628-637.e7, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33152488

RESUMO

BACKGROUND: Gun violence (GV) is a complex public health issue, and the management of GV as a disease engages the surgeon in technical and nontechnical skills. The Anatomy of Gun Violence (AGV) curriculum was developed to teach surgical trainees these seemingly disparate skills, training residents to manage the multiple aspects of firearm injury. STUDY DESIGN: The AGV curriculum was delivered over 6 weeks in the 2017-2018 and 2018-2019 academic years (AY), and used multiple educational methods including didactic lectures, mock oral examinations, a Bleeding Control training session, a GV survivor's personal story, a Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) training session, and the Surgery for Abdominal-thoracic ViolencE (SAVE) simulation lab. As surgical residents were involved over both AYs, components of the curriculum were available every other year to provide variety. As proof of concept, this novel curriculum was objectively evaluated by residents' improvement in knowledge and overall experience using pre- and post-surveys. RESULTS: Sixty surgical residents participated in the AGV curriculum in both AYs, with 41 and 36 residents completing the survey regarding their experiences with the curriculum. The curriculum was well received by residents overall in both AYs (median ± IQR 5 ± 0 and 5 ± 0.1, respectively), with the SAVE simulation lab being the most highly favored portion. Additionally, residents had an average 7.5% improvement in knowledge attributed to the curriculum, with a larger effect seen in the junior residents. CONCLUSIONS: This novel AGV curriculum created a well-received learning experience involving the technical and nontechnical skills necessary to care for GV victims. This comprehensive approach to GV may represent a unique opportunity to engage surgical trainees in both the treatment and prevention of firearm injury.


Assuntos
Internato e Residência/métodos , Ferimentos por Arma de Fogo/cirurgia , Currículo , Humanos , Ressuscitação/educação , Ressuscitação/métodos , Ensino
12.
J Surg Educ ; 76(3): 824-831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30595474

RESUMO

OBJECTIVE: The "Surgery for Abdomino-thoracic ViolencE (SAVE)" animate lab engages surgical residents in the management of complex penetrating injuries. We hypothesized that residents will improve their understanding of the management of trauma patients and will perform skills that they have not previously performed in training. DESIGN: Pre- and postlab assessments were reviewed from surgical residents participating in the SAVE lab over 2 years (2017-2018). Residents of varying levels were grouped and reviewed "real-life" trauma scenarios with supplemental imaging. Seniors were tasked with creating injuries while juniors performed as primary surgeons under supervision. Each successive scenario increased in difficulty, from hollow viscus injury and solid organ disruption, to great vessel and cardiac injuries with the goal to "SAVE" the patient. Assessments included a pre- and postlab multiple-choice questionnaire of trauma management knowledge and a survey of completed technical skills. SETTING: Academic General Surgery residency program. PARTICIPANTS: General, Vascular, Urology, and Plastic Surgery PGY1 to PGY5 residents. RESULTS: One hundred and nineteen residents participated in the SAVE lab in 2017 and 2018. PGY1 to PGY4 residents showed significant improvement in knowledge of trauma management on matched pre- and postlab assessments. The most significant improvement was seen in the PGY1 and PGY2 residents, with scores increasing by 21% (p < 0.001) and 13% (p < 0.001), respectively. PGY1-3 residents had a significant increase in new technical skills acquisition. PGY5 residents showed no significant changes in either realm. CONCLUSIONS: The SAVE lab was effective in increasing junior surgical residents' technical skills as well as fund of knowledge related to complex trauma care. While seniors had previously performed most of these skills as reflected in their assessments, the SAVE lab provided a way for them to assume the role of team leader, guiding management of complex, and high acuity situations. Future endeavors include teamwork and leadership skills' assessment through the SAVE lab.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina/métodos , Cirurgia Geral/educação , Traumatologia/educação , Ferimentos Penetrantes/cirurgia , Adulto , Currículo , Avaliação Educacional , Feminino , Humanos , Internato e Residência , Masculino , Equipe de Assistência ao Paciente/organização & administração , Treinamento por Simulação
13.
J Am Coll Surg ; 226(4): 425-431, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29309940

RESUMO

BACKGROUND: The Flexibility in Surgical Training (FIST) consortium project was designed to evaluate the feasibility and resident outcomes of optional subspecialty-focused training within general surgery residency training. STUDY DESIGN: After approval by the American Board of Surgery, R4 and R5 residents were permitted to customize up to 12 of the final 24 months of residency for early tracking into 1 of 9 subspecialty tracks. A prospective IRB-approved study was designed across 7 institutions to evaluate the impact of this option on operative experience, in-service exam (American Board of Surgery In-Training Examination [ABSITE]) and ACGME milestone performance, and resident and program director (PD) perceptions. The FIST residents were compared with chief residents before FIST initiation (controls) as well as residents during the study period who did not participate in FIST (no specialization track, NonS). RESULTS: From 2013 to 2017, 122 of 214 chief residents (57%) completed a FIST subspecialty track. There were no differences in median ABSITE scores between FIST, NonS residents, and controls. The ACGME milestones at the end of the R5 year favored the FIST residents in 13 of 16 milestones compared with NonS. Case logs demonstrated an increase in track-specific cases compared with NonS residents. Resident and PD surveys reported a generally favorable experience with FIST. CONCLUSIONS: In this prospective study, FIST is a feasible option in participating institutions. All FIST residents, regardless of track, met requirements for ABS Board eligibility, despite modifications to rotations and case experience. Future studies will assess the impact of FIST on ABS exam results and fellowship success.


Assuntos
Cirurgia Geral/educação , Internato e Residência/organização & administração , Atitude do Pessoal de Saúde , Competência Clínica , Currículo , Estudos de Viabilidade , Humanos , Estudos Prospectivos , Inquéritos e Questionários , Estados Unidos , Carga de Trabalho
14.
Gut ; 67(6): 1112-1123, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29196437

RESUMO

OBJECTIVE: Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. METHODS: Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. RESULTS: A systemic increase in CXCR2+ TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2+ TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2+ TAN or CCR2+ TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. CONCLUSION: Dual targeting of CCR2+ TAM and CXCR2+ TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Bases de Dados Factuais , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunomodulação , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Análise Serial de Tecidos , Microambiente Tumoral/efeitos dos fármacos
16.
J Surg Educ ; 74(6): e51-e54, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28756968

RESUMO

OBJECTIVE: Fundamentals of laparoscopic surgery (FLS) was developed by the Society of American Gastrointestinal and Endoscopic Surgeons to teach the physiology, fundamental knowledge, and technical skills required for basic laparoscopic surgery. We hypothesize that residents are doing more laparoscopic surgery earlier in residency, and therefore would benefit from an earlier assessment of basic laparoscopic skills. Here, we examine FLS test results and ACGME case logs to determine whether it is practical to administer FLS earlier in residency. DESIGN: FLS test results were reviewed for the 42 residents completing FLS between July 2011 and July 2016. ACGME case logs for current and former residents were reviewed for laparoscopic cases logged by each postgraduate year. Basic and complex laparoscopic cases were determined by ACGME General Surgery Defined Category and Minimums Report. Descriptive statistics were used for analysis. SETTING: Academic general surgery residency, Washington University in St. Louis School of Medicine. PARTICIPANTS: Current and former general surgery residents. RESULTS: A total of 42 residents took and passed FLS between July 2011 and July 2016. All residents successfully passed the FLS knowledge and skills examinations on the first attempt regardless of their postgraduate year (PGY 3n = 13, PGY 4n = 15, and PGY 5n = 14). Total laparoscopic case volume has increased over time. Residents who graduated in 2012 or 2013 completed 229 laparoscopic cases compared to 267 laparoscopic cases for those who graduated from 2014 to 2016 (p = 0.02). Additionally, current residents completed more laparoscopic cases in the first 2 years of residency than residents who graduated from 2012 to 2016 (median current = 38; former = 22; p < 0.001). Examining laparoscopic case numbers for current residents by PGY demonstrated that the number of total and complex laparoscopic cases increased in each of the first 3 years of residency with the largest increase occurring between the PGY 2 and PGY 3 years. In the PGY 4 and PGY 5 years, most laparoscopic cases were complex. CONCLUSION: Increased use of laparoscopic surgery has led to a corresponding increase in laparoscopic case volume among general surgery residents. We would advocate for FLS testing to serve as an early assessment of laparoscopic knowledge and skill and should be performed before a significant increase in complex laparoscopic surgery during training.


Assuntos
Competência Clínica , Educação de Pós-Graduação em Medicina/métodos , Cirurgia Geral/ética , Laparoscopia/educação , Laparoscopia/normas , Educação Baseada em Competências , Feminino , Humanos , Internato e Residência/métodos , Masculino , Estudos Retrospectivos , Sociedades Médicas/normas , Estados Unidos
17.
Immunity ; 47(2): 323-338.e6, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28813661

RESUMO

Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.


Assuntos
Carcinogênese , Carcinoma Ductal/imunologia , Macrófagos/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/imunologia , Animais , Carcinoma Ductal/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Movimento Celular , Matriz Extracelular/metabolismo , Desenvolvimento Fetal , Fibrose , Hematopoese , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/imunologia , Neoplasias Pancreáticas/patologia , Microambiente Tumoral
18.
Oncotarget ; 7(23): 33529-41, 2016 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-27244881

RESUMO

Cancer-selective drug delivery is an important concept in improving treatment while minimizing off-site toxicities, and sigma-2 receptors, which are overexpressed in solid tumors, represent attractive pharmacologic targets. Select sigma-2 ligands have been shown to be rapidly internalized selectively into cancer cells while retaining the capacity to deliver small molecules as drug cargoes. We utilized the sigma-2-based drug delivery concept to convert Erastin, a clinically underperforming drug, into a potent pancreatic cancer therapeutic. The Erastin derivative des-methyl Erastin (dm-Erastin) was chemically linked to sigma-2 ligand SV119 to create SW V-49. Conjugation increased the killing capacity of dm-Erastin by nearly 35-fold in vitro and reduced the size of established tumors and doubled the median survival in syngeneic and patient-derived xenograft models when compared to non-targeted dm-Erastin. Mechanistic analyses demonstrated that cell death was associated with robust reactive oxygen species production and could be efficiently antagonized with antioxidants. Mass spectrometry was employed to demonstrate selective uptake into pancreatic cancer cells. Thus, targeted delivery of dm-Erastin via conjugation to the sigma-2 ligand SV119 produced efficient tumor control and prolonged animal survival with minimal off-target toxicities, and SW V-49 represents a promising new therapeutic with the potential to advance the fight against pancreatic cancer.


Assuntos
Antineoplásicos/farmacocinética , Compostos Azabicíclicos/farmacologia , Carbamatos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Piperazinas/farmacologia , Animais , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Receptores sigma , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Hepatobiliary Pancreat Dis Int ; 13(2): 198-202, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24686548

RESUMO

BACKGROUND: Multi-visceral resection for extra-pancreatic carcinoma is an uncommon procedure that may offer palliation and potential cure but must be balanced against the risk for morbidity and mortality. METHODS: A retrospective analysis was made of patients who had undergone multi-visceral resection of non-pancreatic carcinoma. Factors influencing this procedure included histology, pathologic confirmation of pancreaticoduodenal invasion, tumor clearance, peri-operative morbidity and outcome. RESULTS: Sixteen patients had en bloc resection including a Whipple procedure (6 patients) and a distal resection (10). Primary pathology mostly originated from the stomach and adenocarcinoma was predominately histological. An R0 resection was made in 13 patients, and actual cancer invasion or abutment into the pancreas or duodenum was confirmed pathologically in 11 patients. Twelve patients suffered from at least one complication. Ten patients required therapeutic intervention for complications. There were 2 in-hospital deaths. The median survival of deceased patients was 7.5 months. Six patients are alive at a median of 21 months, and 4 patients have no evidence of disease to the present. CONCLUSIONS: Multi-visceral resections for extra-pancreatic carcinoma are associated with substantial morbidity that requires therapeutic intervention. Clinical determination of pancreaticoduodenal abutment and achievement of tumor clearance is excellent. Survival with and without recurrent disease is often limited, supporting that it is necessary to cautiously perform the aggressive procedures in consideration of neoadjuvant therapy.


Assuntos
Carcinoma/cirurgia , Neoplasias do Sistema Digestório/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Neoplasias do Sistema Digestório/mortalidade , Neoplasias do Sistema Digestório/patologia , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Intervalo Livre de Doença , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
20.
J Am Coll Surg ; 218(4): 636-41, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24529811

RESUMO

BACKGROUND: For more than a decade, operative decisions (resection plus anastomosis vs diversion) for colon injuries, at our institution, have followed a defined management algorithm based on established risk factors (pre- or intraoperative transfusion requirements of more than 6 units packed RBCs and/or presence of significant comorbid diseases). However, this management algorithm was originally developed for patients managed with a single laparotomy. The purpose of this study was to evaluate the applicability of this algorithm to destructive colon injuries after abbreviated laparotomy (AL) and to determine whether additional risk factors should be considered. STUDY DESIGN: Consecutive patients over a 17-year period with colon injuries after AL were identified. Nondestructive injuries were managed with primary repair. Destructive wounds were resected at the initial laparotomy followed by either a staged diversion (SD) or a delayed anastomosis (DA) at the subsequent exploration. Outcomes were evaluated to identify additional risk factors in the setting of AL. RESULTS: We identified 149 patients: 33 (22%) patients underwent primary repair at initial exploration, 42 (28%) underwent DA, and 72 (49%) had SD. Two (1%) patients died before re-exploration. Of those undergoing DA, 23 (55%) patients were managed according to the algorithm and 19 (45%) were not. Adherence to the algorithm resulted in lower rates of suture line failure (4% vs 32%, p = 0.03) and colon-related morbidity (22% vs 58%, p = 0.03) for patients undergoing DA. No additional specific risk factors for suture line failure after DA were identified. CONCLUSIONS: Adherence to an established algorithm, originally defined for destructive colon injuries after single laparotomy, is likewise efficacious for the management of these injuries in the setting of AL.


Assuntos
Traumatismos Abdominais/cirurgia , Algoritmos , Colo/lesões , Técnicas de Apoio para a Decisão , Laparotomia/métodos , Traumatismos Abdominais/mortalidade , Adulto , Anastomose Cirúrgica , Colectomia , Colo/cirurgia , Feminino , Humanos , Escala de Gravidade do Ferimento , Masculino , Reoperação , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Ferimentos não Penetrantes/cirurgia , Ferimentos Penetrantes/cirurgia
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