RESUMO
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology1,2. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance3-7. Furthermore, PSC activation occurs very early during PDAC tumorigenesis8-10, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Comunicação Parácrina , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Carcinogênese/genética , Carcinoma Ductal Pancreático/diagnóstico , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Humanos , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/sangue , Masculino , Espectrometria de Massas , Camundongos , Neoplasias Pancreáticas/diagnóstico , Comunicação Parácrina/efeitos dos fármacos , Receptores de OSM-LIF/deficiência , Receptores de OSM-LIF/genética , Receptores de OSM-LIF/metabolismo , Microambiente TumoralRESUMO
Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT). Accordingly, IFN treatment up-regulates cancer cell [18F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression.
Assuntos
Didesoxinucleosídeos/administração & dosagem , Radioisótopos de Flúor/administração & dosagem , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Neoplasias Pancreáticas/patologia , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/patologia , Citocinas/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Interferon Tipo I/metabolismo , NAD/deficiência , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Neoplasias Pancreáticas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Citocinas/genética , Citocinas/metabolismo , Humanos , Interferon Tipo I/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.
Assuntos
Ácido Aspártico/deficiência , Carcinoma Ductal Pancreático , Cloroquina/farmacologia , Lisossomos/metabolismo , Mitocôndrias , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Lisossomos/patologia , Masculino , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Estresse Fisiológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted. METHODS: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 µg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea. CONCLUSIONS: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.
Assuntos
Pancreatectomia/efeitos adversos , Fístula Pancreática/prevenção & controle , Pancreaticoduodenectomia/efeitos adversos , Somatostatina/análogos & derivados , Idoso , Estudos de Casos e Controles , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Fístula Pancreática/diagnóstico por imagem , Fístula Pancreática/etiologia , Estudos Prospectivos , Fatores de Risco , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Historically, stage IV melanoma carried a dismal prognosis and surgical resection was the only potential treatment offering long-term survival or palliation of symptomatic disease. With modern systemic therapies that can provide durable disease control for many patients with metastatic disease, we are actively redefining the role of surgery in metastatic melanoma. Contemporary treatment strategies can employ surgical resection in the upfront setting followed by adjuvant therapy, or used in tailored approach following systemic therapy. The combination of surgical resection and modern therapies has been associated with good long-term survival.
Assuntos
Melanoma , Estadiamento de Neoplasias , Neoplasias Cutâneas , Melanoma/cirurgia , Melanoma/patologia , Melanoma/mortalidade , Humanos , Neoplasias Cutâneas/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidade , PrognósticoRESUMO
Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma that arises from smooth muscle cells, most commonly in the uterus and retroperitoneum. LMS is a heterogeneous disease with diverse clinical and molecular characteristics that have yet to be fully understood. Molecular profiling has uncovered possible targets amenable to treatment, though this has yet to translate into approved targeted therapies in LMS. This review will explore historic and recent findings from molecular profiling, highlight promising avenues of current investigation, and suggest possible future strategies to move toward the goal of molecularly matched treatment of LMS. We focus on targeting the DNA damage response, the macrophage-rich micro-environment, the PI3K/mTOR pathway, epigenetic regulators, and telomere biology.
RESUMO
BACKGROUND OR PURPOSE: The role of extended lymphadenectomy as part of resection for lymph node (LN)-positive gastrointestinal (GI) malignancies remains controversial with no clear clinical guidance. The purpose of this retrospective study is to determine whether the number of LNs examined as part of GI malignancy resections affects overall survival (OS) among patients with node-positive esophageal, gastric, pancreatic, and colon cancers. METHODS: Participants with LN-positive GI cancers who were diagnosed between 2004 and 2015 and underwent oncologic resections were selected from National Cancer Database (NCDB). The primary predictor was the number of examined LNs categorized in tertiles. The effect on OS was measured by hazard ratio (HR) derived from multivariate Cox regression analyses. RESULTS: From 2004 to 2015, 1877, 10,086, 18,193, and 102,500 patients with LN-positive esophageal, gastric, pancreatic, and colon adenocarcinomas who did not receive neoadjuvant treatment and underwent oncologic tumor resection were registered in the NCDB. Using multivariate Cox proportional hazard modeling, greater LNs examined in surgically resected LN-positive GI cancers were found to be associated with increased OS for all histologies. This association was the strongest (as compared to the lowest tertile) for gastric cancer (middle tertile: HR = 0.91, 95% CI, 0.86-0.96, p = 0.001; highest tertile: HR = 0.73, 95% CI, 0.69-0.78, p < 0.001), followed by colon (highest tertile: HR = 0.86, 95% CI, 0.84-0.88, p < 0.001), esophageal (highest tertile: HR = 0.83, 95% CI, 0.72-0.95, p = 0.01), and pancreatic (highest tertile: HR = 0.93, 95% CI, 0.89-0.98, p = 0.002) cancers. DISCUSSION AND CONCLUSION: In patients with surgically resected node-positive GI malignancies who did not receive neoadjuvant systemic therapy, a higher number of examined LNs is associated with increased OS. This association is the strongest for gastric cancer, followed by colon, esophageal, and pancreatic cancers respectively.
Assuntos
Neoplasias do Colo , Neoplasias Gástricas , Humanos , Estudos Retrospectivos , Neoplasias Gástricas/cirurgia , Prognóstico , Linfonodos/cirurgia , Linfonodos/patologia , Excisão de Linfonodo , Neoplasias do Colo/cirurgia , Neoplasias do Colo/patologia , Estadiamento de NeoplasiasRESUMO
We determine that type I interferon (IFN) response biomarkers are enriched in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors; however, actionable vulnerabilities associated with IFN signaling have not been systematically defined. Integration of a phosphoproteomic analysis and a chemical genomics synergy screen reveals that IFN activates the replication stress response kinase ataxia telangiectasia and Rad3-related protein (ATR) in PDAC cells and sensitizes them to ATR inhibitors. IFN triggers cell-cycle arrest in S-phase, which is accompanied by nucleotide pool insufficiency and nucleoside efflux. In combination with IFN, ATR inhibitors induce lethal DNA damage and downregulate nucleotide biosynthesis. ATR inhibition limits the growth of PDAC tumors in which IFN signaling is driven by stimulator of interferon genes (STING). These results identify a cross talk between IFN, DNA replication stress response networks, and nucleotide metabolism while providing the rationale for targeted therapeutic interventions that leverage IFN signaling in tumors.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Interferon Tipo I/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Feminino , Humanos , Interferon Tipo I/farmacologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Nucleotídeos/antagonistas & inibidores , Nucleotídeos/biossíntese , Nucleotídeos/metabolismo , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
Arginine (Arg) deprivation is a promising therapeutic approach for tumors with low argininosuccinate synthetase 1 (ASS1) expression. However, its efficacy as a single agent therapy needs to be improved as resistance is frequently observed. Methods: A tissue microarray was performed to assess ASS1 expression in surgical specimens of pancreatic ductal adenocarcinoma (PDAC) and its correlation with disease prognosis. An RNA-Seq analysis examined the role of ASS1 in regulating the global gene transcriptome. A high throughput screen of FDA-approved oncology drugs identified synthetic lethality between histone deacetylase (HDAC) inhibitors and Arg deprivation in PDAC cells with low ASS1 expression. We examined HDAC inhibitor panobinostat (PAN) and Arg deprivation in a panel of human PDAC cell lines, in ASS1-high and -knockdown/knockout isogenic models, in both anchorage-dependent and -independent cultures, and in multicellular complex cultures that model the PDAC tumor microenvironment. We examined the effects of combined Arg deprivation and PAN on DNA damage and the protein levels of key DNA repair enzymes. We also evaluated the efficacy of PAN and ADI-PEG20 (an Arg-degrading agent currently in Phase 2 clinical trials) in xenograft models with ASS1-low and -high PDAC tumors. Results: Low ASS1 protein level is a negative prognostic indicator in PDAC. Arg deprivation in ASS1-deficient PDAC cells upregulated asparagine synthetase (ASNS) which redirected aspartate (Asp) from being used for de novo nucleotide biosynthesis, thus causing nucleotide insufficiency and impairing cell cycle S-phase progression. Comprehensively validated, HDAC inhibitors and Arg deprivation showed synthetic lethality in ASS1-low PDAC cells. Mechanistically, combined Arg deprivation and HDAC inhibition triggered degradation of a key DNA repair enzyme C-terminal-binding protein interacting protein (CtIP), resulting in DNA damage and apoptosis. In addition, S-phase-retained ASS1-low PDAC cells (due to Arg deprivation) were also sensitized to DNA damage, thus yielding effective cell death. Compared to single agents, the combination of PAN and ADI-PEG20 showed better efficacy in suppressing ASS1-low PDAC tumor growth in mouse xenograft models. Conclusion: The combination of PAN and ADI-PEG20 is a rational translational therapeutic strategy for treating ASS1-low PDAC tumors through synergistic induction of DNA damage.
Assuntos
Arginina/deficiência , Argininossuccinato Sintase/metabolismo , Carcinoma Ductal Pancreático/tratamento farmacológico , Histona Desacetilases/química , Hidrolases/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Panobinostat/farmacologia , Polietilenoglicóis/farmacologia , Animais , Antineoplásicos/farmacologia , Argininossuccinato Sintase/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Feminino , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Prognóstico , Mutações Sintéticas LetaisRESUMO
OBJECTIVES: The aim of this study was to evaluate the impact of epidural analgesia (EA) on postoperative length of stay (LOS), expeditious discharge, and pain relief after pancreaticoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Retrospective reviews of 2014-2015 American College of Surgeons National Surgical Quality Improvement Program databases and our institutional pancreatic surgery database were conducted. RESULTS: On univariate analysis, EA was associated with statistically significant longer lengths of stay for both PD and DP. On comparative analysis at mode LOS, discharged before versus after 7 days for PD and 6 days for DP, EA was a significant predictor for the longer groups for both procedures on multivariable analysis (PD, odds ratio of 1.465, P < 0.001; DP, odds ratio of 1.471, P = 0.004). On review of our institution's pancreatic surgery database, patient-reported pain scores were significantly lower in the EA groups than intravenous narcotics groups on the day of surgery only for both PD and DP. CONCLUSIONS: Epidural analgesia was associated with longer LOS with a most pronounced effect on early discharge after surgery for patients undergoing open PD and DP. It only resulted in superior pain control on the day of surgery.
Assuntos
Analgesia Epidural/estatística & dados numéricos , Tempo de Internação/estatística & dados numéricos , Dor Pós-Operatória/prevenção & controle , Pancreatectomia/métodos , Pancreaticoduodenectomia/métodos , Alta do Paciente/estatística & dados numéricos , Idoso , Analgesia Epidural/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor/métodos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/fisiopatologia , Pancreatectomia/efeitos adversos , Pancreaticoduodenectomia/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: The current (seventh edition) American Joint Commission on Cancer (AJCC) Staging System for pancreatic ductal adenocarcinoma (PDAC) dichotomizes pathologic lymph node (LN) involvement into absence (pN0) or presence (pN1) of disease. The recently announced eighth edition also includes stratification on the number of positive nodes. Furthermore, LNs detected on preoperative imaging (CT, MRI, or endoscopic ultrasound-EUS) are considered to be pathologically involved in other gastrointestinal cancers. However, this is less well defined for PDAC. Therefore, the three aims of this study were to determine (1) whether the new AJCC staging system led to more accurate staging, (2) the number of nodes needed to be examined to detect pathologic involvement, and (3) if pN disease could be reliably detected on preoperative imaging in PDAC. METHODS: A retrospective review of all patients undergoing pancreatectomy at a single US academic center from January 1990 to September 2015. Pathology reports of resected specimens were reviewed to determine the total number of LNs examined and those positive for metastasis. CT, MRI, and/or EUS reports were used to determine the presence or absence of preoperatively detectable LN enlargement. RESULTS: Of the 490 surgical resections for PDAC, pN1 disease was detected in 59.4% (n = 291) and was positively correlated with the number of LNs pathologically examined (P < 0.001). Patients with pN1 disease had a shorter overall survival (OS) than those without nodal involvement (25.1 vs. 44.0 months; P < 0.001); however, OS was not different when stratifying by the number of nodes as on the eighth AJCC system. Pathologic examination of > 20 LNs in treatment naïve patients was optimal to detect pN1 disease and predict longer OS for those without nodal involvement (median survival > 41.1 months, P = 0.03 when compared to < 15 or 15-19 LNs examined). LNs were detected by CT, MRI, or EUS in 30.7% (103/335) of patients. The positive predictive value (PPV) of preoperative LN detection for pathologic involvement was 77.3% for treatment naïve patients and 84.2% for those without biliary obstruction. CONCLUSIONS: Although the LN scoring in the seventh PDAC AJCC Staging System was sufficient to predict OS of our patients, more LNs than previously considered (20 vs. 15) were optimal to detect pathologic involvement. Preoperative LN detection was an accurate predictor of pN1 disease for treatment naïve patients without biliary obstruction.
Assuntos
Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/cirurgia , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Adulto , Idoso , Endossonografia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/métodos , Pancreatectomia , Valor Preditivo dos Testes , Período Pré-Operatório , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
IMPORTANCE: Surgical site infection (SSI) rates are increasingly used as a quality metric. However, risk factors for SSI in pancreatic surgery remain undefined. OBJECTIVE: To stratify superficial and organ-space SSIs after pancreatectomy and investigate their modifiable risk factors. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis included 201 patients undergoing pancreatic surgery at a university-based tertiary referral center from July 1, 2013, through June 30, 2015, and 10â¯371 patients from National Surgical Quality Improvement Program-Hepatopancreaticobiliary (NSQIP-HPB) Collaborative sites from January 1, 2014, through December 31, 2015. MAIN OUTCOMES AND MEASURES: Superficial, deep-incisional, and organ-space SSIs, as defined by NSQIP. RESULTS: Among the 201 patients treated at the single center (108 men [53.7%] and 93 women [46.3%]; median age, 48.6 years [IQR, 41.4-57.3 years]), 58 had any SSI (28.9%); 28 (13.9%), superficial SSI; 8 (4%), deep-incisional SSI; and 24 (11.9%), organ-space SSI. Independent risk factors for superficial SSI were preoperative biliary stenting (odds ratio [OR], 4.81; 95% CI, 1.25-18.56; P = .02) and use of immunosuppressive corticosteroids (OR, 13.42; 95% CI, 1.64-109.72; P = .02), whereas soft gland texture was the only risk factor for organ-space SSI (OR, 4.45; 95% CI, 1.35-14.66; P = .01). Most patients with organ-space infections also had grades B/C fistulae (15 of 24 [62.5%] vs 4 of 143 [2.8%] in patients with no SSI; P < .001). Organ/space but not superficial SSI was associated with an increased rate of sepsis (7 of 24 [29.2%] vs 4 of 143 [2.8%]; P < .001) and prolonged length of hospital stay (12 vs 8 days; P = .04). Among patients in the NSQIP-HPB Collaborative, 2057 (19.8%) had any SSI; 719 (6.9%), superficial SSI; 207 (2%), deep-incisional SSI; and 1287 (12.4%), organ-space SSI. Preoperative biliary stenting was confirmed as an independent risk factor for superficial SSI (OR, 2.07; 95% CI, 1.58-2.71; P < .001). In this larger data set, soft gland texture was an independent risk factor for superficial SSI (OR, 1.45; 95% CI, 1.14-1.85; P = .002) but was more strongly and significantly associated with organ-space SSI (OR, 2.32; 95% CI, 1.88-2.85; P < .001). CONCLUSIONS AND RELEVANCE: Preoperative biliary stenting and coriticosteroid use increase superficial SSI, even in patients receiving perioperative piperacillin-tazobactam. Additional measures, including extended broad-spectrum perioperative antibiotic treatment, should be considered in these patients. Organ/space SSIs appear to be related to pancreatic fistulae, which are not modifiable. Reporting these different subtypes as a single, overall rate may be misleading.
Assuntos
Pancreatopatias/cirurgia , Infecção da Ferida Cirúrgica/etiologia , Adulto , Idoso , Cateterismo/efeitos adversos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sepse/etiologiaRESUMO
Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.