RESUMEN
OBJECTIVE: The objective of this study was to assess the association of survival with neoadjuvant chemotherapy (NAC) in resectable pancreatic adenocarcinoma (PDAC). BACKGROUND: The early control of potential micrometastases and patient selection using NAC has been advocated for patients with PDAC. However, the role of NAC for resectable PDAC remains unclear. METHODS: Patients with clinical T1 and T2 PDAC were identified in the National Cancer Database from 2010 to 2017. Kaplan-Meier estimates, and Cox regression models were used to compare survival. To address immortal time bias, landmark analysis was performed. Interactions between preoperative factors and NAC were investigated in subgroup analyses. A propensity score analysis was performed to compare survival between multiagent NAC and upfront surgery. RESULTS: In total, 4041 patients were treated with upfront surgery and 1,175 patients were treated with NAC (79.4% multiagent NAC, 20.6% single-agent NAC). Using a landmark time of 6 months after diagnosis, patients treated with multiagent NAC had longer median overall survival compared with upfront surgery and single-agent NAC. (35.8 vs 27.1 vs 27.4 mo). Multiagent NAC was associated with lower mortality rates compared with upfront surgery (adjusted hazard ratio, 0.77; 95% CI, 0.70-0.85), whereas single-agent NAC was not. The association of survival with multiagent NAC were consistent in analyses using the matched data sets. Interaction analysis revealed that the association between multiagent NAC and a lower mortality rate did not significantly differ across age, facility type, tumor location, CA 19-9 levels, and clinical T/N stages. CONCLUSIONS: The findings suggest that multiagent NAC followed by resection is associated with improved survival compared with upfront surgery.
Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Terapia Neoadyuvante , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Quimioterapia Adyuvante , Pancreatectomía , Estudios RetrospectivosRESUMEN
OBJECTIVE: The aim of this study was to clarify the role of pancreatic surgery during the COVID-19 pandemic to optimize patients' and clinicians' safety and safeguard health care capacity. SUMMARY BACKGROUND DATA: The COVID-19 pandemic heavily impacts health care systems worldwide. Cancer patients appear to have an increased risk for adverse events when infected by COVID-19, but the inability to receive oncological care seems may be an even larger threat, particularly in case of pancreatic cancer. METHODS: An online survey was submitted to all members of seven international pancreatic associations and study groups, investigating the impact of the COVID-19 pandemic on pancreatic surgery using 21 statements (April, 2020). Consensus was defined as >80% agreement among respondents and moderate agreement as 60% to 80% agreement. RESULTS: A total of 337 respondents from 267 centers and 37 countries spanning 5 continents completed the survey. Most respondents were surgeons (n = 302, 89.6%) and working in an academic center (n = 286, 84.9%). The majority of centers (n = 166, 62.2%) performed less pancreatic surgery because of the COVID-19 pandemic, reducing the weekly pancreatic resection rate from 3 [interquartile range (IQR) 2-5] to 1 (IQR 0-2) (P < 0.001). Most centers screened for COVID-19 before pancreatic surgery (n = 233, 87.3%). Consensus was reached on 13 statements and 5 statements achieved moderate agreement. CONCLUSIONS: This global survey elucidates the role of pancreatic surgery during the COVID-19 pandemic, regarding patient selection for the surgical and oncological treatment of pancreatic diseases to support clinical decision-making and creating a starting point for further discussion.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Internacionalidad , Neoplasias Pancreáticas/cirugía , Neumonía Viral/epidemiología , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Betacoronavirus , COVID-19 , Toma de Decisiones Clínicas , Consenso , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Seguridad del Paciente , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
OBJECTIVE: To compare short-term and oncologic outcomes of patients with cancer who underwent open pancreaticoduodenectomy (OPD) versus minimally invasive pancreaticoduodenectomy (MIPD) using the National Cancer Database. SUMMARY BACKGROUND DATA: MIPD, including laparoscopic and robotic approaches, has continued to gain acceptance despite prior reports of increased short-term mortality when compared with OPD. METHODS: Patients with pancreatic cancer diagnosed from 2010 to 2015 undergoing curative intent resection were selected from the National Cancer Database. Patients submitted to OPD were compared with those submitted to MIPD. Laparoscopic and robotic approaches were included in the MIPD cohort. The primary outcome was 90-day mortality; secondary outcomes included 30-day mortality, hospital length of stay, unplanned 30-day readmission, surgical margins, number of lymph nodes harvested, and receipt of adjuvant chemotherapy. Propensity score-weighted random effects logistic regression models were used to examine the adjusted association between surgical approach and the specified outcomes. RESULTS: Between 2010 and 2015, 22,013 patients underwent OPD or MIPD for pancreatic cancer and 3754 (17.1%) were performed minimally invasively. On multivariable analysis, there was no difference in 90-day mortality between MIPD and OPD (OR, 0.92; 95% CI, 0.75-1.14). Patients undergoing MIPD were less likely to stay in the hospital for a prolonged time (OR, 0.75; 95% CI, 0.68-0.82). 30-day mortality, unplanned readmissions, margins, lymph nodes harvested, and receipt of adjuvant chemotherapy were equivalent between groups. Regardless of surgical approach, patients operated on at high volume centers had reduced 90-day mortality. CONCLUSION: Patients selected to receive MIPD for cancer have equivalent short-term and oncologic outcomes, when compared with patients who undergo OPD.
Asunto(s)
Adenocarcinoma/cirugía , Laparoscopía/estadística & datos numéricos , Neoplasias Pancreáticas/cirugía , Pancreaticoduodenectomía/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Procedimientos Quirúrgicos Robotizados/estadística & datos numéricos , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pancreaticoduodenectomía/efectos adversos , Utilización de Procedimientos y Técnicas , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Tasa de Supervivencia , Resultado del TratamientoAsunto(s)
Pancreatectomía , Neoplasias Pancreáticas/cirugía , Arterias , Humanos , PancreaticoduodenectomíaRESUMEN
CONTEXT: Neoadjuvant chemotherapy is increasingly used in borderline resectable and locally advanced pancreatic cancer to facilitate surgical resection. OBJECTIVE: To compare progression free survival and overall survival in patients receiving neoadjuvant FOLFIRINOX with those receiving gemcitabine/abraxane. DESIGN: Retrospective cohort study. SETTING: University of Colorado Hospital from 2012-2016. PARTICIPANTS: Patients with pancreatic adenocarcinoma. INTERVENTIONS: Neoadjuvant FOLFIRINOX or gemcitabine/abraxane. OUTCOME MEASURES: Perioperative outcomes, progression free survival, and overall survival were compared between groups. A multivariate Cox proportional hazard model was applied to evaluate survival outcomes. RESULTS: We identified 120 patients: 83 (69.2%) FOLFIRINOX and 37 (30.8%) gemcitabine/abraxane. The FOLIFRINOX group was younger and had a lower ECOG performance status (p<0.05). Patients in the FOLFIRINOX group were more likely to undergo surgical resection compared to gemcitabine/abraxane (66.3% vs. 32.4%, p=0.002). Among all patients, median follow up was 16.9 months and FOLFIRINOX was associated with improved PFS (15.3 vs. 8.2 months, p=0.006), but not overall survival (23.5 vs. 18.7 months, p=0.228). In these patients, insulin-dependent diabetes was associated with a worse progression free survival and overall survival and surgical resection was protective. Among surgically resected patients, median follow up was 21.1 months and there was no difference in progression free survival (19.5 vs. 15.1 months) or overall survival (27.4 vs. 19.8 months) between the FOLFIRINOX and gemcitabine/abraxane groups, respectively (p>0.05). Insulin-dependent diabetes and a poor-to-moderate pathologic response was associated with worse progression free survival and overall survival. CONCLUSION: Neoadjuvant FOLFIRINOX may improve progression free survival by increasing the proportion of patients undergoing surgical resection. Improved understanding of the role for selection bias and longer follow up are needed to better define the impact of neoadjuvant FOLFIRINOX on overall survival.
RESUMEN
BACKGROUND AND OBJECTIVES: To compare outcomes in patients receiving neoadjuvant stereotactic body radiation therapy (SBRT) with those receiving intensity-modulated radiation therapy (IMRT) for pancreatic adenocarcinoma. METHODS: We analyzed patients receiving neoadjuvant SBRT for borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) (2012-2016). Differences in baseline characteristics, perioperative outcomes, progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: Seventy-five (82.4%) patients received SBRT and 16 (17.6%) received IMRT. There were no differences in surgical resection rates in the SBRT (n = 38, 50.7%) and IMRT (n = 11, 68.8%) groups (P = 0.188). Among resected patients, there was no difference in postoperative outcomes or pathologic outcomes including lymph node status, margin status, lymphovascular and perineural invasion, or pathologic response to neoadjuvant treatment (P > 0.05). Among all patients, median PFS and OS were 9.9 and 23.5 months in the SBRT group, respectively, and 15.3 and 21.8 months in the IMRT group, respectively (P > 0.05). Similarly, there was no difference in PFS or OS between groups when stratified by BRPC, LAPC, and surgically resected patients (P > 0.05). CONCLUSIONS: In the neoadjuvant setting, SBRT and IMRT appear to have similar rates of resection, perioperative outcomes, and survival outcomes, but additional studies with increased sample size and longer follow up are needed.
Asunto(s)
Adenocarcinoma/mortalidad , Terapia Neoadyuvante/mortalidad , Neoplasias Pancreáticas/mortalidad , Radiocirugia/mortalidad , Radioterapia de Intensidad Modulada/mortalidad , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Anciano , Anciano de 80 o más Años , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/cirugía , Atención Perioperativa , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias PancreáticasRESUMEN
BACKGROUND: Previous studies have demonstrated improved in-hospital mortality after hepatic resection for hepatocellular carcinoma (HCC) at teaching hospitals. The objective of this study was to evaluate if resection of HCC at academic cancer programs (ACP) is associated with improved 10-year survival. STUDY DESIGN: Using the National Cancer Data Base (NCDB) (1998 to 2011), we evaluated patients undergoing hepatic resection for HCC at ACPs, comprehensive community cancer programs (CCCPs), and community cancer programs (CCPs). High volume cancer programs (HVCPs) were defined as performing 10 or more hepatectomies per year. Multivariate Cox proportional hazard models by stepwise selection were applied to estimate hazard ratios (HR) of predictors of survival. The Kaplan-Meier method was used to generate survival curves at each facility type, and survival rates were compared using the log-rank test. RESULTS: We identified 12,757 patients undergoing hepatic resection for HCC at ACPs (n = 8,404), CCPs (n = 483), and CCCPs (n = 3,870). Sixty-two percent (n = 5,191) of patients treated at ACPs were at high volume institutions compared with 11.6% (n = 446) and 0% of CCCPs and CCPs, respectively (p < 0.0001). On multivariable analysis, patients undergoing hepatic resection at transplant centers (p < 0.0001) and HVCPs had significantly improved survival (p < 0.0001). Adjusted 10-year survival rates were 28.7% at high volume ACPs, 28.2% at high volume CCCPs, 24.9% at low volume CCCPs, 25.1% at low volume ACPs, and 21.3% at CCPs (p ≤ 0.0001). CONCLUSIONS: Patients undergoing hepatic resection for HCC at HVCPs had a significantly improved 10-year survival. Regionalization of HCC treatment to HVCPs may improve long-term survival.
Asunto(s)
Instituciones Oncológicas , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/cirugía , Hospitales de Alto Volumen , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Anciano , Anciano de 80 o más Años , Femenino , Hepatectomía , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Estados UnidosRESUMEN
BACKGROUND: Anaplastic pancreatic carcinoma (APC) is a rare and poorly characterized disease. We sought to compare the clinical characteristics and outcomes of APC to pancreatic adenocarcinoma (PDAC). METHODS: The American National Cancer Data Base was queried for patients with resected APC and PDAC using histologic and operative codes. APC cases were matched 1:5 with PDACs based on age, sex, pathologic tumor stage, operative margin status, lymph node positivity ratio, and use of adjuvant chemotherapy. RESULTS: After 1:5 matching, 192 APCs and 960 PDACs were analyzed. When comparing APC vs PDAC the median tumor size was 45 mm (interquartile range, 33-60) vs 30 mm (interquartile range, 23-40; P < .001), and metastatic nodal disease was present in 40.6% and 38.0% of the cases (P = .25), respectively. APC cases were distributed equally between the head and the body/tail region of the pancreas (50%), while PDAC cases were located mainly in the head of the pancreas (75%; P < .001). Although the resected APC group had a lesser survival during the first year after the diagnosis (51% vs 69%; P = .029), the overall survival was similar in the 2 groups, with 21.6% vs 17.4% alive at 5 years, respectively for APC and PDAC (P = .32). Subgroup analysis of patients with APC with (n = 18) versus those without (n = 80) osteoclastlike giant cells showed a greater 5-year survival (50% versus 15%, P < .001). CONCLUSION: Patients with resected APC tend to present with large tumors equally distributed between the head and body/tail of the pancreas. While APC is thought to have a more aggressive biology, our matched analysis showed similar overall survival compared with PDAC. The presence of osteoclastlike giant cells portends a significantly better prognosis compared with other histologic features of APCs.
Asunto(s)
Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Adenocarcinoma/terapia , Anciano , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Células Gigantes/patología , Humanos , Masculino , Análisis por Apareamiento , Persona de Mediana Edad , Estadificación de Neoplasias , Pancreatectomía , Neoplasias Pancreáticas/terapia , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos , Neoplasias PancreáticasRESUMEN
Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-γ production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Vacunas contra el Cáncer/inmunología , Carcinoma Ductal Pancreático/inmunología , Neoplasias Pancreáticas/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
5-Fluorouracile, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) has not been extensively used in the neoadjuvant setting because of concerns with safety and toxicity. We evaluated our institutional experience with neoadjuvant FOLFIRINOX in borderline resectable pancreatic adenocarcinoma (BRPAC). The primary endpoints were completion of therapy to surgery and negative resection margin (R0) rate. Patients with BRPAC treated with neoadjuvant FOLFIRINOX were retrospectively analyzed. Between August 2011 and September 2013, 20 patients with BRPAC treated with neoadjuvant FOLFIRINOX were identified. Most patients (88.8%) completed FOLFIRINOX therapy and underwent resection. Abutment of venous structures was identified in 13 cases (72.2%), while short segment portal vein encasement in 3 cases (16.6%) with concomitant arterial involvement in 3 cases (16.6%). Isolated superior mesenteric artery abutment was identified in 2 cases (11.2%). Patients received a median of 4 cycles of FOLFIRINOX. There was 1 case of progression. Vascular resection was performed in 9 cases (52.9%). Preoperative radiation therapy was used in 8 patients (44%). All patients underwent margin negative resection (R0). Histopathologic treatment response was evident in 10 cases (58.8%). Neoadjuvant FOLFIRINOX was generally safe and the expected toxicity did not prevent surgery allowing for a high rate of R0 resection.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Leucovorina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Complejo Vitamínico B/uso terapéutico , Adenocarcinoma/cirugía , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neoplasias Pancreáticas/cirugía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92%-100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms.
Asunto(s)
Tumores Neuroendocrinos/patología , Nomogramas , Neoplasias Pancreáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Técnicas de Apoyo para la Decisión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Estadificación de Neoplasias , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Reproducibilidad de los Resultados , Análisis de Supervivencia , Carga TumoralRESUMEN
The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.
Asunto(s)
Diferenciación Celular , Proliferación Celular , Antígeno Ki-67/análisis , Índice Mitótico , Tumores Neuroendocrinos/química , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/secundario , Tumores Neuroendocrinos/cirugía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
BACKGROUND: Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. METHODS: Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. RESULTS: Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P =.028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P =.034). CONCLUSIONS: The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.