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1.
Cancer Cell ; 37(6): 834-849.e13, 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32442403

RESUMO

Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.

2.
Proc Natl Acad Sci U S A ; 117(12): 6622-6629, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32156729

RESUMO

A more comprehensive understanding of the molecular mechanisms underlying pancreatic diseases, including pancreatitis and cancer, is essential to improve clinical management. MEN1 has established roles in epigenetic regulation and tumor suppression in the endocrine pancreas; however, intriguing recent data suggest MEN1 may also function in the exocrine pancreas. Using physiologically relevant genetic mouse models, we provide direct evidence that Men1 is essential for exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Men1 loss causes increased injury and impaired regeneration following acute caerulein-induced pancreatitis, leading to more severe damage, loss of the normal acinar compartment, and increased cytokeratin 19-positive metaplasias and immune cell infiltration. We further demonstrate the Men1 protein is stabilized in response to insult, and loss of Men1 is associated with the overexpression of proinflammatory Jund target genes, suggesting that loss of Men1-mediated repression of Jund activity is, at least in part, responsible for the impaired response. Finally, we demonstrate that Men1 loss significantly accelerates mutant Kras-dependent oncogenesis. Combined, this work establishes Men1 as an important mediator of pancreas homeostasis in vivo.


Assuntos
Carcinogênese/patologia , Homeostase , Inflamação/patologia , Pâncreas Exócrino/patologia , Neoplasias Pancreáticas/patologia , Pancreatite/patologia , Proteínas Proto-Oncogênicas/fisiologia , Animais , Biomarcadores/análise , Carcinogênese/imunologia , Carcinogênese/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diferenciação Celular , Feminino , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Pâncreas Exócrino/imunologia , Pâncreas Exócrino/metabolismo , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/imunologia , Pancreatite/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética
3.
J Gastrointest Surg ; 24(2): 368-379, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30820801

RESUMO

BACKGROUND: Resection of the superior mesenteric and/or portal vein (SMV-PV) is increasingly performed with pancreatectomy for adenocarcinoma. We sought to analyze the impact of cancer at the transected edge(s) of the vein wall. METHODS: Patients who underwent pancreatectomy with vein resection between 2003 and 2015 at a single center were evaluated. R1 resection was defined per guidelines from the American Joint Commission on Cancer and the College of American Pathologists. Specimens were also evaluated for the presence (V+) or absence (V-) of cancer cells at the transected edge(s) and depth of vein invasion. RESULTS: Among 127 evaluated patients, 114 (90%) received preoperative therapy. R-status was categorized as margin-negative (R0)/V- (n = 72, 57%), R0/V+ (n = 19, 15%), margin-positive (R1)/V- (n = 24, 19%), and R1/V+ (n = 12, 9%). Patients with V- specimens had similar median durations of recurrence-free survival (RFS) (12 vs 9 months) and overall survival (OS) (30 vs 28 months) as did patients with V+ specimens (P > 0.05). In contrast, cancer invasion into the lumen was associated with RFS and OS (P < 0.05). Among patients who underwent R0 resection, V-status had no association with OS, RFS, or local control (P > 0.05). CONCLUSION: Cancer invasion into the superior mesenteric and/or portal vein was adversely associated with survival, but cancer at the vein edge(s) was not. Transection of the SMV-PV through macroscopically normal vein may be performed to minimize resected vein length without fear of negatively affecting oncologic outcomes.

4.
Surgery ; 167(2): 442-447, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31727324

RESUMO

BACKGROUND: First postoperative day drain fluid amylase (DFA1) <5000 U/L is commonly used for early drain removal. We manage patients with risk-stratified pancreatectomy care pathways determined preoperatively by risk for postoperative pancreatic fistula. We hypothesized that preoperative risk stratification would yield unique DFA1/DFA3 cutoffs for safe early drain removal. METHODS: Patients with DFA1/DFA3 values after pancreaticoduodenectomy or distal pancreatectomy were identified. Patients were risk stratified as "low-risk pancreaticoduodenectomy," "high-risk pancreaticoduodenectomy," or "distal pancreatectomy." Receiver operator characteristic analyses yielded clinically relevant sensitivity thresholds for International Study Group on Pancreatic Surgery grade B/C postoperative pancreatic fistulas. RESULTS: From October 2016 to April 2018, 174 patients were preoperatively stratified as low-risk pancreaticoduodenectomy (n = 78, 45%), high-risk pancreaticoduodenectomy (n = 51, 29%), and distal pancreatectomy (n = 45, 26%). B/C postoperative pancreatic fistulas developed in 3% (n = 2) of low-risk pancreaticoduodenectomies, 37% (n = 19) of high-risk pancreaticoduodenectomies, and 24% (n = 11) of distal pancreatectomies (low- vs high-risk pancreaticoduodenectomy P < .001, low-risk pancreaticoduodenectomy versus distal pancreatectomy P = .004, high-risk pancreaticoduodenectomy versus distal pancreatectomy P = .25). B/C postoperative pancreatic fistulas occurred in 16% (n = 21) pancreaticoduodenectomy patients (high- + low-risk pancreaticoduodenectomy), and B/C postoperative pancreatic fistulas were excluded in pancreaticoduodenectomy with 100% sensitivity if DFA1 ≤ 136 or DFA3 ≤ 93. DFA1 < 5000 excluded B/C postoperative pancreatic fistulas with only 57% sensitivity after pancreaticoduodenectomy. Exclusion of B/C postoperative pancreatic fistulas occurred with 100% sensitivity if DFA1 ≤ 661 or DFA3 ≤ 141 in low-risk pancreaticoduodenectomy patients, DFA1 ≤ 136 or DFA3 ≤ 93 in high-risk pancreaticoduodenectomy patients, and DFA1 < 49 or DFA3 < 26 in distal pancreatectomy patients. CONCLUSION: Preoperative risk stratification results in unique DFA1/DFA3 thresholds to exclude B/C postoperative pancreatic fistulas, thus allowing for safe drain removal and potential for accelerated discharge. Rather than applying generic DFA cutoffs based on national databases, we propose institution-specific DFA1 and DFA3 values tailored to 3 replicable postoperative pancreatic fistula-risk pathways.


Assuntos
Amilases/análise , Fístula Pancreática/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Fístula Pancreática/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Medição de Risco , Texas/epidemiologia , Adulto Jovem
5.
Endosc Ultrasound ; 9(1): 53-58, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31552914

RESUMO

Background and Objectives: The current knowledge about the psychological impact of pancreatic cancer (PC) screening is limited. We aimed to assess the changes in quality of life (QOL) and level of distress after undergoing EUS in individuals with pancreatic cystic lesions (PCLs) and in patients at high risk for PC based on genetic and familial factors. Methods: Eighty patients with PCL and/or increased genetic or familial risk for PC who had undergone EUS were contacted. Fifty percent of those patients successfully completed the brief profile of mood states (POMS) and the linear analog scale assessment (LASA) QOL questionnaires to evaluate their pre/post-EUS overall QOL. The effect size (ES) method was used to assess clinically meaningful changes in the scores. Results: There was a significant difference in patients' overall QOL scores before and after the EUS procedure (LASA, mean difference 0.73, standard deviation (SD) 1.76, ES 0.58, P < 0.01; brief POMS, mean difference -5.46, SD -6.72, ES 0.81, P < 0.01). Conclusions: QOL of patients with PCL or increased risk factors for PC is significantly improved after a EUS/EUS-guided fine-needle aspiration (FNA) negative for malignancy.

6.
Sci Rep ; 9(1): 13966, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562341

RESUMO

The efficacy of chemotherapy is reduced by dysfunctional tumor vasculature, which may limit chemotherapy delivery to tumors. Preclinical studies have shown that moderate aerobic exercise improves tumor vascular function and increases chemotherapy efficacy in mouse models, but the effect of exercise on human tumor vasculature has not yet been determined. Here, we demonstrate that exercise remodels the tumor vasculature, accelerates the regression, and delays the regrowth of pancreatic ductal adenocarcinoma in a patient-derived xenograft mouse model treated with gemcitabine. By evaluating pancreatic adenocarcinoma specimens from patients treated with preoperative chemotherapy or chemoradiation therapy, we also demonstrate for the first time that tumor vascular remodeling occurs in association with exercise in humans. Future studies will evaluate whether exercise-induced vascular remodeling improves gemcitabine or other chemotherapy efficacy in patients, as this study evaluated only changes in tumor vascular structure.

7.
Cancer Res ; 79(21): 5612-5625, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492820

RESUMO

Mutated KRAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic KRAS are still under investigation or awaiting clinical approval. Using a specific KRAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic KRAS. We identified and validated decitabine, an FDA-approved drug, as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed KRAS dependency. Mechanistically, decitabine efficacy was linked to KRAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in KRAS-dependent tumors cells. These findings also showed that gene signatures related to KRAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of patients with KRAS-mutated pancreatic cancer. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant KRAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease. SIGNIFICANCE: Decitabine is a promising drug for cancer cells dependent on RAS signaling.

8.
Cell ; 178(4): 795-806.e12, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398337

RESUMO

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.


Assuntos
Carcinoma Ductal Pancreático/microbiologia , Carcinoma Ductal Pancreático/mortalidade , Microbioma Gastrointestinal , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Animais , Bactérias/classificação , Linhagem Celular Tumoral , Estudos de Coortes , Transplante de Microbiota Fecal , Fezes/microbiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Análise de Sequência de RNA , Taxa de Sobrevida
9.
J Surg Res ; 243: 90-99, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31170555

RESUMO

BACKGROUND: Portal vein (PV) circulating tumor cells (CTCs) and elevated peripheral blood (PB) levels of biomarkers have been associated with poor outcomes in pancreatic ductal adenocarcinoma (PDAC). Although transforming growth factor-beta (TGFß) is associated with CTCs in breast cancer, there are limited data evaluating a comprehensive biomarker panel and CTCs in PDAC patients. The authors hypothesized that tumor progression biomarkers would be associated with PV CTCs. METHODS: PDAC patients at one institution were enrolled January to August 2018 and underwent preincision PB draws (T0) and on postoperative day 1 (T3), plus intraoperative PV draws before tumor manipulation (T1) and after resection (T2). CTCs were detected using CellSearch. Plasma biomarker levels (pg/mL) were measured with a multiplex bead assay. Patients were divided into two groups: high (≥3 CTCs/7.5 mL blood) versus low (<3). Clinicopathologic variables and biomarkers were compared in the two groups. RESULTS: Fourteen had complete blood draws with PDAC resection, with five demonstrating high CTCs. Fewer patients in the high-CTC group received preoperative radiation (78 versus 20%), whereas more of the high-CTC had pT3 tumors (80 versus 11%) (all P < 0.037). High-CTC patients demonstrated higher TGFß-2 levels (T0 [906 versus 586], T1 [1337 versus 627], T2 [1149 versus 445]), as well as higher TGFß-3 (T0 [320 versus 173], T2 [605 versus 120]) (all P < 0.021). CONCLUSIONS: PDAC patients with high CTCs demonstrated a distinct biomarker profile with elevated PB and PV levels of immunosuppressive cytokines (TGFß-2 and TGFß-3). These exploratory results prompt further study into interrupting TGFß signaling.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/patologia , Células Neoplásicas Circulantes , Pancreatectomia , Fator de Crescimento Transformador beta/sangue , Adenocarcinoma/sangue , Adenocarcinoma/diagnóstico , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/sangue , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/cirurgia , Estudos de Viabilidade , Feminino , Humanos , Cuidados Intraoperatórios , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Veia Porta , Estudos Prospectivos , Transdução de Sinais
10.
Clin Cancer Res ; 25(19): 5984-5996, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227505

RESUMO

PURPOSE: Mutant KRAS is a major driver of pancreatic oncogenesis and therapy resistance, yet KRAS inhibitors are lacking in the clinic. KRAS requires farnesylation for membrane localization and cancer-causing activity prompting the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. However, KRAS becomes geranylgeranylated and active when cancer cells are treated with FTIs. To overcome this geranylgeranylation-dependent resistance to FTIs, we designed FGTI-2734, a RAS C-terminal mimetic dual FT and geranylgeranyltransferase-1 inhibitor (GGTI). EXPERIMENTAL DESIGN: Immunofluorescence, cellular fractionation, and gel shift assays were used to assess RAS membrane association, Western blotting to evaluate FGTI-2734 effects on signaling, and mouse models to demonstrate its antitumor activity. RESULTS: FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induced apoptosis and inhibited the growth in mice of mutant KRAS-dependent but not mutant KRAS-independent human tumors. Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors. FGTI-2734 was also highly effective at inhibiting, in three-dimensional cocultures with resistance promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from eight patients with pancreatic cancer. Finally, FGTI-2734 suppressed oncogenic pathways mediated by AKT, mTOR, and cMYC while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo. CONCLUSIONS: The development of this novel dual FGTI overcomes a major hurdle in KRAS resistance, thwarting growth of patient-derived mutant KRAS-driven xenografts from patients with pancreatic cancer, and as such it warrants further preclinical and clinical studies.

11.
Pancreas ; 48(6): 837-843, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31210666

RESUMO

OBJECTIVES: Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC. METHODS: We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes. RESULTS: Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041). CONCLUSIONS: When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno CA-19-9/sangue , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Pancreatectomia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Falha de Tratamento
12.
Ann Surg Oncol ; 26(11): 3428-3435, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31243665

RESUMO

BACKGROUND: Despite advances in enhanced surgical recovery programs, strategies limiting postoperative inpatient opioid exposure have not been optimized for pancreatic surgery. The primary aims of this study were to analyze the magnitude and variations in post-pancreatectomy opioid administration and to characterize predictors of low and high inpatient use. METHODS: Clinical characteristics and inpatient oral morphine equivalents (OMEs) were downloaded from electronic records for consecutive pancreatectomy patients at a high-volume institution between March 2016 and August 2017. Regression analyses identified predictors of total OMEs as well as highest and lowest quartiles. RESULTS: Pancreatectomy was performed for 158 patients (73% pancreaticoduodenectomy). Transversus abdominus plane (TAP) block was performed for 80% (n = 127) of these patients, almost always paired with intravenous patient-controlled analgesia (IV-PCA), whereas 15% received epidural alone. All the patients received scheduled non-opioid analgesics (median, 2). The median total OME administered was 423 mg (range 0-4362 mg). Higher total OME was associated with preoperative opioid prescriptions (p < 0.001), longer hospital length of stay (LOS; p < 0.001), and no epidural (p = 0.006). The lowest and best quartile cutoff was 180 mg of OME or less, whereas the highest and worst quartile cutoff began at 892.5 mg. After adjustment for inpatient team, only epidural use [odds ratio (OR) 0.3; p = 0.04] predicted lowest-quartile OME. Preoperative opioid prescriptions (OR 8.1; p < 0.001), longer operative time (OR 3.4; p = 0.05), and longer LOS (OR 1.1; p = 0.007) predicted highest-quartile OME. CONCLUSIONS: Preoperative opioid prescriptions and longer LOS were associated with increased inpatient OME, whereas epidural use reduced inpatient OME. Understanding the predictors of inpatient opioid use and the variables predicting the lowest and highest quartiles can inform decision-making regarding preoperative counseling, regional anesthetic block choice, and novel inpatient opioid weaning strategies to reduce initial postoperative opioid exposure.


Assuntos
Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/normas , Pacientes Internados/estatística & dados numéricos , Dor Pós-Operatória/tratamento farmacológico , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos
13.
HPB (Oxford) ; 21(9): 1203-1210, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30799277

RESUMO

BACKGROUND: Neoadjuvant therapy (NT) remains controversial in early-stage pancreatic ductal adenocarcinoma (PDAC), defined as clinical (c)Stage I-II. Our aim was to analyze rates of pathologic upstaging/downstaging for resectable PDAC treated with surgery-first (SF) vs. NT. METHODS: Utilizing the National Cancer Data Base (NCDB), patients with cStage I-II PDAC who underwent pancreatoduodenectomy in 2006-2013 were pathologically staged using the AJCC 8th edition and compared by treatment sequencing. RESULTS: Among 13,871 patients, 15.3% received NT. Despite higher pre-treatment T-stage (cT2: 71.9% vs. 56.3%, p < 0.001), NT patients had lower rates of pathologic nodal metastases (46.2% vs. 69.2% in SF, p < 0.001), suggesting higher rates of pathologic downstaging. In cStage II, 33.0% were upstaged to stage III after SF, vs. only 14.0% after NT. In cStage I, 65.5% were upstaged following SF, vs. 46.7% after NT (all p < 0.001). Patients with NT (HR-0.77, p < 0.001) or downstaging (HR-0.80, p < 0.001) had improved overall survival (OS). CONCLUSION: NT is associated with reduction in unexpected upstaging, reduction in nodal positivity, and improved OS, compared to SF approach in putatively early-stage PDAC. Because clinical staging underestimates the underlying disease burden in resectable PDAC, patients with cStage I-II should be considered for NT.


Assuntos
Adenocarcinoma/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Neoplasias Pancreáticas/cirurgia , Adenocarcinoma/patologia , Idoso , Carcinoma Ductal Pancreático/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Estudos Retrospectivos
14.
Pancreas ; 48(2): 216-222, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30629022

RESUMO

OBJECTIVES: Although the use of neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma is increasing, the optimal preoperative treatment regimen remains poorly defined. METHODS: All patients with resectable pancreatic ductal adenocarcinoma who received preoperative chemotherapy alone (12%) or chemoradiation therapy (CRT) alone (88%) before pancreatectomy between 1999 and 2014 were included. Propensity score matching with inverse probability weighting was conducted based on age, baseline carbohydrate antigen 19-9, and procedure type. RESULTS: Patients who received preoperative CRT were more likely to undergo a margin negative (91% vs 79%, P < 0.01) and node negative (53% vs 23%, P < 0.01) resection and experience less locoregional recurrence (LR; 16% vs 33%, P < 0.01) but similar median overall survival (OS; 33.6 vs 26.4 months, P = 0.09). On multivariate analysis, carbohydrate antigen 19-9 (hazard ratio, 1.2; 95% confidence interval [CI], 1.1-1.3) and positive lymph nodes (hazard ratio, 1.5; 95% CI, 1.0-2.2) were associated with OS, whereas tumor size (odds ratio [OR], 1.5; 95% CI, 1.3-1.8), positive lymph nodes (OR, 3.1; 95% CI, 1.8-5.6), and preoperative chemotherapy (OR, 1.8; 95% CI, 1.1-2.9) were associated with LR. CONCLUSIONS: Preoperative CRT is associated with less margin and lymph node positivity, reduced LR, and similar OS compared with preoperative chemotherapy.


Assuntos
Carcinoma Ductal Pancreático/terapia , Avaliação de Resultados em Cuidados de Saúde/métodos , Neoplasias Pancreáticas/terapia , Pontuação de Propensão , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Tratamento Farmacológico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Período Pré-Operatório , Estudos Retrospectivos
16.
HPB (Oxford) ; 21(7): 841-848, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30501986

RESUMO

BACKGROUND: Perioperative blood transfusion (PBT) during resection of pancreatic adenocarcinoma (PDAC) has been linked to worse short-term and oncologic outcomes. However, little is known about contemporary rates of transfusion utilization among patients requiring pancreaticoduodenectomy with vein resection (PDVR). The primary aims of this study were to evaluate rates of PBT and to identify modifiable factors associated with PBT during PDVR. METHODS: Patients with PDAC treated with preoperative therapy and PDVR (2008-15) were analyzed from a prospective, single-institution database. RESULTS: Among 120 total patients, approximately half (52.5%) of all patients received PBT; rates decreased significantly in the most recent years [70.7%, 2008-10 vs. 36.8%, 2014-15 (p = 0.013)]. Lower preoperative hemoglobin, greater intraoperative percent drop in hemoglobin, increased EBL, and advanced age were all associated with PBT (p < 0.01). The only factors independently associated with PBT by multivariable analysis were age [OR-1.08 per year (95% CI 1.02-1.14)] and EBL [OR-1.30 per 100 mL, (95% CI 1.13-1.50)]. CONCLUSION: PBT for PDVR for PDAC have decreased, with only 1/3 of contemporary patients requiring PBT. As preoperative therapy and PDVR become more ubiquitous, addressing anemia during preoperative therapy and limiting EBL may reduce blood utilization. Re-evaluation of clinical thresholds for transfusions may further reduce transfusion rates.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Carcinoma Ductal Pancreático/cirurgia , Veias Mesentéricas/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Assistência Perioperatória/métodos , Veia Porta/cirurgia , Procedimentos Cirúrgicos Vasculares , Fatores Etários , Idoso , Carcinoma Ductal Pancreático/patologia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Bases de Dados Factuais , Feminino , Humanos , Masculino , Veias Mesentéricas/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Assistência Perioperatória/efeitos adversos , Veia Porta/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos
17.
Clin Cancer Res ; 25(7): 2194-2205, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30385653

RESUMO

PURPOSE: Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC. EXPERIMENTAL DESIGN: Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected). RESULTS: Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although HGD-IPMNs expressed many core signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a proinflammatory immune component was readily seen in low-grade IPMNs, composed of cytotoxic T cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis. CONCLUSIONS: This study demonstrates the ability to perform high-resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single-cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception.See related commentary by Hernandez-Barco et al., p. 2027.


Assuntos
Adenocarcinoma Mucinoso/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Progressão da Doença , Humanos , Fenótipo , Microambiente Tumoral
18.
HPB (Oxford) ; 21(6): 662-668, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30522947

RESUMO

BACKGROUND: With the increasing use of biliary stents for neoadjuvant therapy (NT) for pancreatic adenocarcinoma (PDAC), the risk of post-pancreaticoduodenectomy (PD) infection remains relevant. This study documents the contemporary incidence of stent-related complications (SRC) during NT and to analyze their impact on surgical infections. METHODS: Consecutive patients from a single institution (2011-15) with resected PDAC treated with biliary decompression, NT, and PD were analyzed. Stent-related complications (SRC) were compared among patients with/without prospectively documented composite pre- and post-operative infections (surgical site infection [SSI], organ space infection [OSI], and cholangitis). RESULTS: Of 114 total patients, (median 164 days, initial stent to surgery), 95% had initial endoscopic (vs. percutaneous) stenting. Initial stents were often plastic (80/114, 70%), with 43/114 (38%) undergoing routine exchange to metal stent before NT. Fifteen (13%) patients had stent cholangitis during NT requiring antibiotics and/or stent exchange. There were 33/114 (29%) patients with SRC, requiring 66 exchanges. Post-PD rates of SSI, OSI, and cholangitis were 23%, 5%, and 4%, respectively [composite rate 30%]. On multivariate analysis, SRC were not associated with composite surgical infections (p > 0.05). CONCLUSIONS: Although SRC occurred in almost one-third of PDAC patients during NT, with appropriate intervention, there was no association with increased surgical infections.


Assuntos
Adenocarcinoma/terapia , Ductos Biliares/cirurgia , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia/efeitos adversos , Infecções Relacionadas à Prótese/epidemiologia , Stents/efeitos adversos , Adenocarcinoma/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Colangiopancreatografia Retrógrada Endoscópica , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Neoplasias Pancreáticas/diagnóstico , Prognóstico , Estudos Retrospectivos , Texas/epidemiologia
19.
Ann Surg Oncol ; 26(2): 652, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30539487

RESUMO

INTRODUCTION: Patients with locally advanced pancreatic cancer (LAPC) represent a challenging group to treat, given the involvement of major vascular structures. In selected patients with favorable biology, temporary mesocaval shunt can facilitate the resection and allow for a safer procedure with enhanced exposure to the superior mesenteric vessels. METHODS: We present a video of a pancreaticoduodenectomy (PD) with temporary mesocaval shunt with left internal jugular (LIJ) vein conduit. RESULTS: A 65-year-old woman presented with LAPC in the uncinate, causing total occlusion of the superior mesenteric vein (SMV) and encasement of the first jejunal artery. After neoadjuvant therapy and evidence of disease stability, a decision was made to perform a PD with a temporary mesocaval shunt to divert mesenteric flow to reduce blood loss and prevent bowel ischemia. During the procedure, the main mesenteric collateral (ileocolic vein) was divided to create the shunt to the inferior vena cava (IVC) with LIJ interposition. The remaining mesenteric tributaries involved by the tumor were divided. The uncinate dissection was performed using a superior mesenteric artery-first approach. Once the resection was completed, the shunt was stapled from the IVC and the graft transposed to the upper SMV. Standard reconstruction was performed. Total operative time was 536 min, and estimated blood loss was 250 cc without transfusions. No perioperative complications occurred. CONCLUSION: In selected patients with LAPC, PD with temporary mesocaval shunt can facilitate resection and venous reconstruction in patients with complete portal vein/SMV occlusion.


Assuntos
Adenocarcinoma/cirurgia , Veias Mesentéricas/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia , Procedimentos Cirúrgicos Vasculares , Veia Cava Inferior/cirurgia , Adenocarcinoma/patologia , Idoso , Anastomose Cirúrgica , Feminino , Humanos , Veias Mesentéricas/patologia , Neoplasias Pancreáticas/patologia , Prognóstico , Veia Cava Inferior/patologia
20.
Ann Surg ; 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30499795

RESUMO

OBJECTIVE: To characterize opioid discharge prescriptions for pancreatectomy patients. BACKGROUND: Wide variation in and over-prescription of opioids after surgery contribute to the United States opioid epidemic through persistent use past the postoperative period. Objective strategies guiding discharge opioid prescriptions for oncologic surgery are lacking, and factors driving prescription amount are not fully delineated. METHODS: Characteristics of pancreatectomy patients (March 2016-August 2017) were retrospectively abstracted from a prospective database. Discharge opioids prescriptions were converted to oral morphine equivalents (OME). Regression models identified variables associated with discharge OME. RESULTS: In 158 consecutive patients, median discharge OME was 250 mg (range 0-3950). Discharge OME was labeled "low" (<200 mg) for 33 patients (21%) and "high" (>400 mg) for 38 (24%). Only shorter operative time (odds ratio [OR]-0.14, P = 0.004) and inpatient team (OR-15.39, P < 0.001) were independently associated with low discharge OME. Older age was the only variable associated with high discharge OME. Fifty-seven patients (36%) used zero opioids in the last 24-hours predischarge, yet 52 of 57 (91%) still received discharge opioids. Older age (OR-1.07), grade B/C pancreatic fistula (OR-3.84), and epidural use (OR-3.12) were independently associated with zero last-24-hours OME (all P ≤ 0.040). CONCLUSIONS: The wide variation in discharge opioid prescriptions is heavily influenced by provider routine/bias and not by objective criteria such as last-24-hours OME. Quality improvement strategies could include aggressive weaning protocols to increase the proportion of patients with zero/near-zero last-24-hour OME and limiting prescriptions to a conservative multiplier of the last-24-hour OME.

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