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1.
HPB (Oxford) ; 26(5): 711-716, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38431512

RESUMO

INTRODUCTION: The anatomic location of the pancreas can result in involvement of major vasculature, which may act as a contraindication to resection. Several classification systems have been developed. We sought to discover the variations in the HPB community determining PDAC resectability. METHODS: The multiple-choice survey was distributed to all full members of the IHPBA. Questions were asked regarding demographics and clinical scenarios regarding tumor resectability. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. Most practiced in either Asia (n = 57,35.9%), North America (n = 52,32.7%), or Europe (n = 32,20.1%). Classification systems used to determine resectability were: NCCN (n = 42,26.3%), JPS (n = 35,21.9%), International consensus (n = 33,20.6%), AHPBA/SSO (n = 23,14.4%), Alliance (n = 3,1.9%), and other/no-classification (n = 23,14.5%). There was significant variation in the frequency of the most common answer within the scenarios (84.7%-33.5%). Participant concordance with their stated classification system found a median rate of 62.5%. Participant decision of tumor resectability was not dependent on their adopted classification system. CONCLUSION: When classifying PDAC resectability, there is significant variation between surgeons as to how they would classify a specific tumour, independent of the classification system they use. In addition, surgeons do not show high concordance with the definitions within that classification system.


Assuntos
Neoplasias Pancreáticas , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/classificação , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/classificação , Carcinoma Ductal Pancreático/patologia , Pancreatectomia , Padrões de Prática Médica , Inquéritos e Questionários , Invasividade Neoplásica , Tomada de Decisão Clínica , Seleção de Pacientes , Valor Preditivo dos Testes , Pesquisas sobre Atenção à Saúde
2.
HPB (Oxford) ; 26(3): 436-443, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38143165

RESUMO

BACKGROUND: The surgical decision making for pancreatic adenocarcinoma is complex. Although practice guidelines exist for many scenarios, these do not cover many common eventualities that may be encountered during these cases. We sought to identify the practice pattern variations amongst pancreatic surgeons in response to commonly experienced clinical scenarios. METHODS: A multiple-choice questionnaire was distributed to all full members of the IHPBA. Participant demographics, training history, and clinical practice information were obtained. The survey provided various operative scenarios and participants were asked how they would likely proceed. Responses were collected and stored anonymously in a secure database. Statistical analysis was performed using Stata 16.0. RESULTS: 164 responses were submitted. Most of the respondents were male and had been in practice for over 10 years. The median age range was 40-50 years old. When asked about staging laparoscopy, the majority performed it selectively. For most respondents a pathological aorto-caval nodes was a reason to abort the procedure but most would have continued in the setting of a positive hepatic artery node. When encountering a single Segment 2 liver metastasis, participants who practiced in Europe were significantly more likely to resect and proceed compared to those in Asia and North America. Participants who had undergone only a Surgical Oncology fellowship were most likely to abort. With respect to direct colonic invasion, most participants would resect the specimen en bloc. Respondents who participated in fewer that 20 PDAC operations/year were most likely to abort. CONCLUSIONS: Surgical decision making in PDAC surgery is complex and there is significant disagreement on the correct management. While formal guidelines cannot exist for all situations, this survey highlights the need for consensus on commonly encountered operative scenarios.


Assuntos
Adenocarcinoma , Laparoscopia , Neoplasias Pancreáticas , Cirurgiões , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Neoplasias Pancreáticas/cirurgia , Inquéritos e Questionários , Cirurgiões/educação , Padrões de Prática Médica
3.
Lancet Oncol ; 24(12): e472-e518, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37924819

RESUMO

The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.


Assuntos
Neoplasias , Cirurgiões , Humanos , Neoplasias/cirurgia , Saúde Global , Política de Saúde
4.
J Surg Res ; 284: 312-317, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36634411

RESUMO

INTRODUCTION: Drain fluid amylase (DFA) levels have been used to predict clinically relevant postoperative pancreatic fistula (CR-POPF) and guide postoperative drain management. Optimal DFA cutoff thresholds vary between studies, thereby prompting investigation of an alternative assessment technique. As DFA measurements could, in theory, be distorted by variations in ascites fluid production, we hypothesized that adjusting DFA for volume corrected drain fluid amylase (vDFA) would improve CR-POPF predictive models. METHODS: A single-institution retrospective cohort study of patients, who underwent pancreatoduodenectomies (PD) and distal pancreatectomies (DP) between 2013 and 2019, was performed. DFAs and vDFAs were measured on postoperative day (POD) 3. Clinicopathologic variables were compared between cohorts by univariable and multivariable analyses and Receiver operating characteristic (ROC) curves. RESULTS: Patients developing a CR-POPF were more likely to be male and have elevated DFA, vDFA, and body mass index (BMI). vDFA use did not contribute to a superior CR-POPF predictive model compared to DFA-a finding consistent on subanalysis of surgery type PD versus DP. In CR-POPF predictive models, DFA, vDFA, and male sex significantly improved CR-POPF predictive models when considering both surgery subtypes, while only DFA and vDFA significantly improved models when cohorts were segregated by surgery type. CONCLUSIONS: Postoperative DFA remains a preferred method of predicting CR-POPF as the proposed vDFA assessment technique only adds complexity without increased discriminability.


Assuntos
Amilases , Fístula Pancreática , Humanos , Masculino , Feminino , Fístula Pancreática/diagnóstico , Fístula Pancreática/etiologia , Fístula Pancreática/prevenção & controle , Estudos Retrospectivos , Amilases/análise , Pancreatectomia , Pancreaticoduodenectomia/efeitos adversos , Drenagem/efeitos adversos , Drenagem/métodos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Risco
5.
J Surg Res ; 284: 143-150, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36571869

RESUMO

INTRODUCTION: Despite aggressive surgical care and systemic therapy, patients with pancreatic ductal adenocarcinoma (PDAC) have a poor prognosis. Recent studies show that racial disparities in outcome also exist. We sought to investigate the association lymph node (LN) metastases had with survival between Black and White patients with PDAC after resection. METHODS: Retrospective analysis of 226 PDAC patients who underwent resection at a single institution from 2010 to 2018 was performed with attention to LN metastasis and patient race. The number of patients who received chemotherapy was also evaluated. RESULTS: One Hundred Seventy Five (77.4%) PDAC patients were White and 51 (22.6%) were Black. 130 (59.3%) patients had LN metastasis (LN+). LN+ and LN- groups were similar in race (P = 0.93), sex (P = 0.10) and age at the time of diagnosis (P = 0.45). Patients with LN + disease were more likely to present with larger tumors (3.4 versus 2.8 cm, P = 0.02) and higher T status (P = 0.001). White and Black patients had similar rates of LN metastasis (59% versus 58.8%, P = 1.0). The median survival for LN- Black and White patients were similar (43.2 versus 30.2 mo, P = 0.82). LN + Black patients trended towards receiving more systemic therapy than White LN + patients (55% versus 42%, P = 0.10). The median survival for LN + Black patients was significantly less than LN + White patients (17.5 versus 24.6 mo, P = 0.04). CONCLUSIONS: Black LN + PDAC patients have an inferior survival rate after resection when compared to their White counterparts. Our disparity in outcome cannot be solely explained by a difference in systemic treatment. Further investigation is warranted to determine racial differences in tumor biology or response to chemotherapy.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Metástase Linfática/patologia , Neoplasias Pancreáticas/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Linfonodos/cirurgia , Linfonodos/patologia , Prognóstico , Estadiamento de Neoplasias , Taxa de Sobrevida , Neoplasias Pancreáticas
6.
Pancreatology ; 22(1): 168-172, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34916141

RESUMO

Digestive capacity of the gastrointestinal tract, largely but not wholly, depends on exocrine pancreatic function to achieve near complete digestion and absorption of ingested food. Coefficient of fat absorption (CFA), the proportion of ingested fat absorbed (normal >93%), reflects digestive capacity. Exocrine pancreatic insufficiency (EPI) is the state of insufficient digestive capacity (CFA <93%) caused by severe loss of pancreatic exocrine function despite variable compensation by upregulation of extra-pancreatic lipolysis. Fecal elastase 1 (FE1) level is the most widely used, though imperfect, non-invasive test of pancreatic enzyme output. Decline in pancreas enzyme output, or pancreatic exocrine dysfunction (EPD), has a variable correlation with measurable decline in CFA. EPI results in steatorrhea, weight loss and nutrient deficiency, which are mitigated by pancreatic enzyme replacement therapy (PERT). We propose a staging system for EPD, based on measurement of fecal elastase (FE1) and, if necessary, CFA and serum fat-soluble vitamin levels. In Stage I (Mild) EPD, FE1 is 100-200 mcg/gm; if steatorrhea is present, non-pancreatic causes are likely. In Stage II (Moderate) EPD), FE1 is < 100 mcg/gm without clinical and/or laboratory evidence of steatorrhea. In Stage III, there are marked reductions in FE1 and CFA, but vitamin levels remain normal (Severe EPD or EPI without nutritional deficiency). In Stage IV all parameters are abnormal (Severe EPD or EPI with nutritional deficiency). EPD stages I and II are pancreas sufficient and PERT may not be the best or first approach in management of early-stage disease; it needs further study to determine clinical utility. The term EPI refers strictly to EPD Stages III and IV which should be treated with PERT, with Stage IV requiring micronutrient supplementation as well.


Assuntos
Insuficiência Pancreática Exócrina/diagnóstico , Fezes/enzimologia , Elastase Pancreática/metabolismo , Testes de Função Pancreática/métodos , Esteatorreia/diagnóstico , Biomarcadores/metabolismo , Terapia de Reposição de Enzimas , Insuficiência Pancreática Exócrina/sangue , Humanos , Desnutrição , Índice de Gravidade de Doença , Esteatorreia/sangue , Vitaminas/sangue
7.
Pancreatology ; 22(5): 553-563, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35570091

RESUMO

Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.


Assuntos
Ceruletídeo , Pancreatite Crônica , Doença Aguda , Animais , Arginina , Colágeno/efeitos adversos , Citocinas , Modelos Animais de Doenças , Fibrose , Humanos , Camundongos , Pancreatite Crônica/patologia , Piridonas
8.
J Surg Res ; 279: A1-A7, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817604

RESUMO

Surgeon-scientists are uniquely positioned to contribute to our understanding of the fundamental biology of surgical disease and to bring a unique perspective that leads to innovation in the diagnosis and treatment of many conditions. However, it is broadly recognized that due to the changing landscape of surgery and science, the surgeon-scientists of today face multiple challenges in this pursuit. Today, surgeon-scientists face an increased pressure from their department and hospital to generate clinical revenue, decreased availability of grant funding, greater administrative burden, rising complexity of fundamental research, increased medical school debt, and a growing desire for work-life balance. Given that survival of surgeon-scientists is critical for the progress of not only surgery but medical innovation at large, many surgical societies, notably the Association for Academic Surgery (AAS) and the Society of University Surgeons (SUS) have focused on the issues faced by surgeon-scientists. In this regard, the Basic and Translational Research Committee of the AAS and the Research Committee of the SUS organized a hot topic session at the 2021 Academic Surgical Congress in which experts discussed and addressed many issues concerning the surgeon-scientist pathway. This manuscript provides an overview of the issues discussed at this session.


Assuntos
Pesquisa Biomédica , Cirurgiões , Humanos , Pesquisadores , Pesquisa Translacional Biomédica
9.
HPB (Oxford) ; 24(10): 1729-1737, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35717430

RESUMO

BACKGROUND: Exocrine pancreatic insufficiency (EPI) is frequently seen in patients with pancreatic cancer (PDAC) and is thought to contribute to nutritional complications. While EPI can be pharmacologically temporized with pancreatic enzyme replacement therapy (PERT), there is lack of clear evidence informing its use in PDAC. Here we aim to survey pancreatic surgeons regarding their utilization of PERT in the management of EPI for PDAC. METHODS: An online survey was distributed to the members of The Americas Hepato-Pancreato-Biliary Association (AHPBA) and The Pancreas Club. RESULTS: 86.5% (180/208) of surgeons prescribe PERT for at least some resectable/borderline resectable PDAC cases. Only a minority of surgeons order investigations to confirm EPI before starting PERT (28.1%) or test for adequacy of therapy (28.3%). Few surgeons believe that PERT has an effect on overall survival (19.7%) or disease-free survival (6.25%) in PDAC. CONCLUSION: PERT is widely prescribed in patients with resectable/borderline resectable PDAC, but investigations establishing EPI and assessing PERT adequacy are underutilized. A substantial proportion of surgeons are unclear as to the effect of PERT on survival outcomes in PDAC. These data call for prospective studies to establish guidelines for optimal use of PERT and its effects on survival outcomes in PDAC.


Assuntos
Insuficiência Pancreática Exócrina , Neoplasias Pancreáticas , Humanos , Estados Unidos , Terapia de Reposição de Enzimas/efeitos adversos , Estudos Prospectivos , Pâncreas , Insuficiência Pancreática Exócrina/tratamento farmacológico , Neoplasias Pancreáticas/terapia , Prescrições , Neoplasias Pancreáticas
10.
Oncologist ; 26(4): e608-e621, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33284507

RESUMO

Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.


Assuntos
Antineoplásicos , Neoplasias , Secretases da Proteína Precursora do Amiloide/farmacologia , Secretases da Proteína Precursora do Amiloide/uso terapêutico , Antineoplásicos/uso terapêutico , Apoptose , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Receptores Notch/uso terapêutico
11.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948209

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.


Assuntos
Fibroblastos Associados a Câncer/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Animais , Matriz Extracelular/patologia , Humanos , Microambiente Tumoral/fisiologia , Neoplasias Pancreáticas
12.
Gastroenterology ; 156(7): 1979-1993, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30776339

RESUMO

Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.


Assuntos
Células Acinares/enzimologia , Pâncreas Exócrino/enzimologia , Pancreatite/enzimologia , Tripsina/metabolismo , Tripsinogênio/metabolismo , Células Acinares/patologia , Animais , Morte Celular , Ativação Enzimática , Predisposição Genética para Doença , Humanos , Mediadores da Inflamação/metabolismo , Mutação , Pâncreas Exócrino/patologia , Pancreatite/genética , Pancreatite/patologia , Fenótipo , Transdução de Sinais , Tripsina/genética , Tripsinogênio/genética
13.
Gastroenterology ; 156(7): 2097-2115.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30768986

RESUMO

Our understanding of the microbiome and its role in immunity, cancer initiation, and cancer progression has evolved significantly over the past century. The "germ theory of cancer" was first proposed in the early 20th century, and shortly thereafter the bacterium Helicobacter pylori, and later Fusobacterium nucleatum, were implicated in the development of gastric and colorectal cancers, respectively. However, with the development of reliable mouse models and affordable sequencing technologies, the most fascinating aspect of the microbiome-cancer relationship, where microbes undermine cancer immune surveillance and indirectly promote oncogenesis, has only recently been described. In this review, we highlight the essential role of the microbiome in immune system development and maturation. We review how microbe-induced immune activation promotes oncogenesis, focusing particularly on pancreatic carcinogenesis, and show that modulation of the microbiome augments the anti-cancer immune response and enables successful immunotherapy against pancreatic cancer.


Assuntos
Bactérias/imunologia , Imunoterapia/métodos , Microbiota/imunologia , Neoplasias Pancreáticas/microbiologia , Neoplasias Pancreáticas/terapia , Imunidade Adaptativa , Animais , Bactérias/efeitos dos fármacos , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Microbiota/efeitos dos fármacos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Evasão Tumoral , Microambiente Tumoral
14.
Ann Surg Oncol ; 27(7): 2498-2505, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31919713

RESUMO

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality following distal pancreatectomy (DP). However, the influence of operative technique on VTE risk after DP is unknown. OBJECTIVE: The purpose of this study was to examine the association between the MIS technique versus the open technique and the development of postoperative VTE after DP. METHODS: Patients who underwent DP from 2014 to 2015 were identified in the American College of Surgeons National Surgical Quality Improvement Program pancreas-specific database. Multivariable logistic regression was then used to identify independent associations with the development of postoperative VTE after DP. RESULTS: A total of 3558 patients underwent DP during this time period. Of these cases, 47.8% (n = 1702) were performed via the MIS approach. After adjusting for significant covariates, the MIS approach was independently associated with the development of any VTE (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.06-2.40; p = 0.025), as well as increasing the risk of developing a postdischarge VTE (OR 1.80, 95% CI 1.05-3.08; p = 0.033) when compared with the open approach. There was an association between VTE and the development of numerous postoperative complications, including pneumonia, unplanned intubation, need for prolonged mechanical ventilation, and cardiac arrest. CONCLUSION: Compared with the open approach, the MIS approach is associated with higher rates of postoperative VTE in patients undergoing DP. The majority of these events are diagnosed after hospital discharge.


Assuntos
Pancreatectomia , Tromboembolia Venosa , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/efeitos adversos , Procedimentos Cirúrgicos Minimamente Invasivos/estatística & dados numéricos , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Alta do Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
15.
Pancreatology ; 20(4): 762-771, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32327370

RESUMO

BACKGROUND: Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT. METHODS: Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review. RESULTS: Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery. CONCLUSIONS: Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.


Assuntos
Transplante das Ilhotas Pancreáticas , Ilhotas Pancreáticas/metabolismo , Pancreatectomia/métodos , Pancreatite Crônica/cirurgia , Guias de Prática Clínica como Assunto , Humanos , Internacionalidade
16.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G463-G475, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31433214

RESUMO

In the current study, we explored the role of extracellular ATP (eATP) in promoting systemic inflammation during development of acute pancreatitis (AP). Release of extracellular (e)ATP was evaluated in plasma and bronchoalveolar lavage fluid (BALF) of mice with experimental acute pancreatitis (AP). Prophylactic intervention using apyrase or suramin was used to understand the role and contribution of eATP in pancreatitis-associated systemic injury. AP of varying severity was induced in C57BL/6 mice using 1-day or 2-day caerulein, caerulein + LPS and l-arginine models. eATP was measured in plasma and BALF. Mice were treated with suramin or apyrase in the caerulein and l-arginine models of AP. Plasma cytokines, lung, and pancreatic myeloperoxidase, and morphometric analysis of pancreatic and lung histology, were used to assess the severity of pancreatitis. Plasma eATP and purinergic 2 (P2) receptors in the pancreas and lungs were significantly elevated in the experimental models of AP. Blocking the effect of eATP by suramin led to reduced levels of plasma IL-6 and TNFα as well as reduced lung, and pancreatic injury. Neutralizing eATP with apyrase reduced systemic injury but did not ameliorate local injury. The results of this study support the role of eATP and P2 receptors in promoting systemic inflammation during AP. Modulating purinergic signaling during AP can be an important therapeutic strategy in controlling systemic inflammation and, thus, systemic inflammatory response syndrome during AP.NEW & NOTEWORTHY Released ATP from injured cells promotes systemic inflammation in acute pancreatitis.


Assuntos
Trifosfato de Adenosina/metabolismo , Inflamação/metabolismo , Pancreatite/metabolismo , Doença Aguda , Trifosfato de Adenosina/sangue , Animais , Apirase/farmacologia , Arginina , Líquido da Lavagem Broncoalveolar/química , Ceruletídeo , Citocinas/sangue , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/prevenção & controle , Peroxidase/metabolismo , Receptores Purinérgicos/metabolismo , Transdução de Sinais , Suramina/farmacologia
17.
Ann Surg ; 270(3): 400-413, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283563

RESUMO

OBJECTIVE: To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy. BACKGROUND: Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown. METHODS: Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC. RESULTS: Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP. CONCLUSION: This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Pancreatectomia/métodos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Centros Médicos Acadêmicos , Adulto , Idoso , Carcinoma Ductal Pancreático/patologia , Causas de Morte , Terapia Combinada , Bases de Dados Factuais , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Gencitabina
18.
Gastroenterology ; 155(1): 33-37.e6, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29630898

RESUMO

We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy.


Assuntos
Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antibacterianos/farmacologia , Carcinoma/secundário , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Melanoma/imunologia , Melanoma/secundário , Melanoma Experimental/imunologia , Melanoma Experimental/secundário , Camundongos , Camundongos Knockout , Transplante de Neoplasias , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/secundário , Linfócitos T/imunologia , Microambiente Tumoral/imunologia
19.
Gastroenterology ; 155(3): 880-891.e8, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29909021

RESUMO

BACKGROUND & AIMS: Immunotherapies are ineffective against pancreatic cancer. We investigated whether the activity of nuclear factor (NF)κB in pancreatic stromal cells contributes to an environment that suppresses antitumor immune response. METHODS: Pancreata of C57BL/6 or Rag1-/- mice were given pancreatic injections of a combination of KrasG12D/+; Trp53 R172H/+; Pdx-1cre (KPC) pancreatic cancer cells and pancreatic stellate cells (PSCs) extracted from C57BL/6 (control) or mice with disruption of the gene encoding the NFκB p50 subunit (Nfkb1 or p50-/- mice). Tumor growth was measured as an endpoint. Other mice were given injections of Lewis lung carcinoma (LLC) lung cancer cells or B16-F10 melanoma cells with control or p50-/- fibroblasts. Cytotoxic T cells were depleted from C57BL/6 mice by administration of antibodies against CD8 (anti-CD8), and growth of tumors from KPC cells, with or without control or p50-/- PSCs, was measured. Some mice were given an inhibitor of CXCL12 (AMD3100) and tumor growth was measured. T-cell migration toward cancer cells was measured using the Boyden chamber assay. RESULTS: C57BL/6 mice coinjected with KPC cells (or LLC or B16-F10 cells) and p50-/- PSCs developed smaller tumors than mice given injections of the cancer cells along with control PSCs. Tumors that formed when KPC cells were injected along with p50-/- PSCs had increased infiltration by activated cytotoxic T cells along with decreased levels of CXCL12, compared with tumors grown from KPC cells injected along with control PSCs. KPC cells, when coinjected with control or p50-/- PSCs, developed the same-size tumors when CD8+ T cells were depleted from C57BL/6 mice or in Rag1-/- mice. The CXCL12 inhibitor slowed tumor growth and increased tumor infiltration by cytotoxic T cells. In vitro expression of p50 by PSCs reduced T-cell migration toward and killing of cancer cells. When cultured with cancer cells, control PSCs expressed 10-fold higher levels of CXCL12 than p50-/- PSCs. The CXCL12 inhibitor increased migration of T cells toward KPC cells in culture. CONCLUSIONS: In studies of mice and cell lines, we found that NFκB activity in PSCs promotes tumor growth by increasing expression of CXCL12, which prevents cytotoxic T cells from infiltrating the tumor and killing cancer cells. Strategies to block CXCL12 in pancreatic tumor cells might increase antitumor immunity.


Assuntos
Quimiocina CXCL12/fisiologia , Linfócitos do Interstício Tumoral/fisiologia , NF-kappa B/fisiologia , Neoplasias Pancreáticas/metabolismo , Células Estreladas do Pâncreas/metabolismo , Linfócitos T Citotóxicos/fisiologia , Animais , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Imunidade Celular , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/imunologia , Células Estreladas do Pâncreas/imunologia , Regulação para Cima
20.
J Transl Med ; 17(1): 163, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109340

RESUMO

BACKGROUND: There is an urgent need for novel and effective treatment options for acute myeloid leukemia (AML). Triptolide, a diterpenoid tri-epoxide compound isolated from the herb Tripterygium wilfordii and its water-soluble pro-drug-Minnelide have shown promising anti-cancer activity. A recent clinical trial for patients with solid tumors confirmed the safety and efficacy at biologically equivalent doses of 0.2 mg/kg/day and lower. METHODS: Cell viability of multiple AML cell lines as well as patient apheresis samples were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) based assay. Apoptosis was evaluated by estimating the amount of cleaved caspase. AML cell line (THP1-Luc) was implanted in immunocompromised mice and treated with indicated doses of Minnelide. Leukemic burden before and after treatment was evaluated by imaging in an In Vivo Imaging System (IVIS). RESULTS: In the current study, we show that Minnelide, at doses below maximum tolerated dose (MTD) demonstrates leukemic clearance of both primary AML blasts and luciferase expressing THP-1 cells in mice. In vitro, multiple primary AML apheresis samples and AML cell lines (THP-1, KG1, Kasumi-1, HL-60) were sensitive to triptolide mediated cell death and apoptosis in low doses. Treatment with triptolide led to a significant decrease in the colony forming ability of AML cell lines as well as in the expression of stem cell markers. Additionally, it resulted in the cell cycle arrest in the G1/S phase with significant downregulation of c-Myc, a major transcriptional regulator mediating cancer cell growth and stemness. CONCLUSION: Our results suggest that Minnelide, with confirmed safety and activity in the clinic, exerts a potent anti-leukemic effect in multiple models of AML at doses easily achievable in patients.


Assuntos
Diterpenos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Organofosfatos/uso terapêutico , Fenantrenos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Diterpenos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos de Epóxi , Humanos , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Organofosfatos/farmacologia , Fenantrenos/farmacologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco
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