RESUMEN
Importance: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed. Objective: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US. Design, Setting, and Participants: This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19â¯289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023. Main Outcomes and Measures: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation. Results: The study included 19â¯289 patients (median age, 71 years [IQR, 59-80 years]; 10â¯506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1â¯000â¯000 person-years (95% CI, 3.1-3.5 cases per 1â¯000â¯000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1â¯000â¯000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13â¯955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001). Conclusions and Relevance: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.
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Neoplasias de la Mama , Hemangiosarcoma , Masculino , Humanos , Femenino , Anciano , Incidencia , Hemangiosarcoma/epidemiología , Estudios Transversales , Estudios RetrospectivosRESUMEN
Robotic pancreaticoduodenectomy (RPD) has a learning curve of approximately 30-250 cases to reach proficiency. The learning curve for laparoscopic pancreaticoduodenectomy (LPD) at Duke University was previously defined as 50 cases. This study describes the RPD learning curve for a single surgeon following experience with LPD. LPD and RPD were retrospectively analyzed. Continuous pathologic and perioperative metrics were compared and learning curve were defined with respect to operative time using CUSUM analysis. Seventeen LPD and 69 RPD were analyzed LPD had an inverted learning curve possibly accounting for proficiency attained during the surgeon's fellowship and acquisition of new skills coinciding with more complex patient selection. The learning curve for RPD had three phases: accelerated early experience (cases 1-10), skill consolidation (cases 11-40), and improvement (cases 41-69), marked by reduction in operative time. Compared to LPD, RPD had shorter operative time (379 vs 479 min, p < 0.005), less EBL (250 vs 500, p < 0.02), and similar R0 resection. RPD also had improved LOS (7 vs 10 days, p < 0.007), and lower rates of surgical site infection (10% vs 47%, p < 0.002), DGE (19% vs 47%, p < 0.03), and readmission (13% vs 41%, p < 0.02). Experience in LPD may shorten the learning curve for RPD. The gap in surgical quality and perioperative outcomes between LPD and RPD will likely widen as exposure to robotics in General Surgery, Hepatopancreaticobiliary, and Surgical Oncology training programs increase.
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Laparoscopía , Neoplasias Pancreáticas , Procedimientos Quirúrgicos Robotizados , Cirujanos , Humanos , Pancreaticoduodenectomía/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Curva de Aprendizaje , Estudios Retrospectivos , Laparoscopía/métodos , Neoplasias Pancreáticas/cirugía , Complicaciones Posoperatorias/cirugíaRESUMEN
PURPOSE: Intrahepatic cholangiocarcinoma (ICCA) is characterized by significant phenotypic and clinical heterogeneities and poor response to systemic therapy, potentially related to underlying heterogeneity in oncogenic alterations. We aimed to characterize the genomic heterogeneity between primary tumors and advanced disease in patients with ICCA. METHODS: Biopsy-proven CCA specimens (primary tumor and paired advanced disease [metastatic disease, progressive disease on systemic therapy, or postoperative recurrence]) from two institutions were subjected to targeted next-generation sequencing. Overall concordance (oncogenic driver mutations, copy number alterations, and fusion events) and mutational concordance (only oncogenic mutations) were compared across paired samples. A subgroup analysis was performed on the basis of exposure to systemic therapy. Patients with extrahepatic CCA (ECCA) were included as a comparison group. RESULTS: Sample pairs from 65 patients with ICCA (n = 54) and ECCA (n = 11) were analyzed. The median time between sample collection was 19.6 months (range, 2.7-122.9). For the entire cohort, the overall oncogenic concordance was 49% and the mutational concordance was 62% between primary and advanced disease samples. Subgroup analyses of ICCA and ECCA revealed overall/mutational concordance rates of 47%/58% and 60%/84%, respectively. Oncogenic concordance was similarly low for pairs exposed to systemic therapy between sample collections (n = 50, 53% overall, 68% mutational). In patients treated with targeted therapy for IDH1/2 alterations (n = 6) or FGFR2 fusions (n = 3), there was 100% concordance between the primary and advanced disease specimens. In two patients, FGFR2 (n = 1) and IDH1 (n = 1) alterations were detected de novo in the advanced disease specimens. CONCLUSION: The results reflect a high degree of heterogeneity in ICCA and argue for reassessment of the dominant driver mutations with change in disease status.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Colangiocarcinoma/tratamiento farmacológico , Mutación , Conductos Biliares Intrahepáticos/patología , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patologíaRESUMEN
OBJECTIVES: Angiosarcoma is a rare complication of breast-conserving therapy. This study evaluated the change in incidence between 1992 and 2016 of secondary breast angiosarcoma (SBA) in patients with a history of breast cancer and the impact of management strategies for the original breast carcinoma on angiosarcoma treatment. METHODS: Breast cancer and angiosarcoma cases were abstracted from the Surveillance, Epidemiology, and End Result (SEER) database. SBAs were defined as angiosarcomas located in the breast occurring after a prior breast cancer diagnosis. Primary breast angiosarcomas (PBAs) were defined as an angiosarcoma diagnosis listed as "one primary only." Incidence rates were estimated using a proportion of the US total population. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazard models were used to assess the association of clinicopathologic characteristics on overall survival. RESULTS: Between 1992 and 2016, 193 cases of SBA were reported in the SEER dataset in patients with a prior history of breast cancer. The incidence of breast angiosarcoma in patients with a prior diagnosis of breast cancer increased 3-fold from about 10 cases per 100,000 person-years to about 30 cases per 100,000 person-years over this same period ( P =0.0037). For treatment of SBA (n=193), almost all (95%) had surgery. Nine percent received radiation (compared with 35% of patients with PBA, P <0.001) and 23% received chemotherapy (vs. 45% for PBA, P =0.11). CONCLUSIONS: We demonstrate an increasing incidence of SBA over the study period. These data can help inform shared decision-making for optimal management of locoregional breast cancer and raise awareness of secondary angiosarcoma.
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Neoplasias de la Mama , Hemangiosarcoma , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Hemangiosarcoma/epidemiología , Hemangiosarcoma/terapia , Hemangiosarcoma/patología , Estudios Retrospectivos , Mastectomía SegmentariaRESUMEN
Surgery is considered for patients without metastatic disease and with resectable primary tumor. Pre-operatively, high quality imaging is reviewed to determine the likely extent of resection, specifically including the need for potential en-bloc resection of adjacent organs. In cases where up-front surgical approach would expose the patient to excessive morbidity (such as bilateral nephrectomy, multi-visceral resection, or prohibitively high risk of positive margins), neoadjuvant chemotherapy and/or chemoradiotherapy is considered. Though data are sparse in LMS, a neoadjuvant regimen of doxorubicin and dacarbazine is typically considered for borderline resectable tumors at our institution; patients may be treated for up to 4 months with interval imaging every 2 months to evaluate for tumor response. Postoperatively, adjuvant systemic therapy or radiation may be considered for patients with positive surgical margins or high-grade tumors.
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Leiomiosarcoma , Procedimientos de Cirugía Plástica , Humanos , Vena Cava Inferior/cirugía , Vena Cava Inferior/patología , Leiomiosarcoma/cirugía , Nefrectomía , Terapia CombinadaRESUMEN
BACKGROUND: Hepatic artery infusion (HAI) is a liver-directed therapy that delivers high-dose chemotherapy to the liver through the hepatic arterial system for colorectal liver metastases and intrahepatic cholangiocarcinoma. Utilization of HAI is rapidly expanding worldwide. OBJECTIVE AND METHODS: This review describes the conduct of HAI pump implantation, with focus on common technical pitfalls and their associated solutions. Perioperative identification and management of common postoperative complications is also described. RESULTS: HAI therapy is most commonly performed with the surgical implantation of a subcutaneous pump, and placement of its catheter into the hepatic arterial system for inline flow of pump chemotherapy directly to the liver. Intraoperative challenges and abnormal hepatic perfusion can arise due to aberrant anatomy, vascular disease, technical or patient factors. However, solutions to prevent or overcome technical pitfalls are present for the majority of cases. Postoperative HAI-specific complications arise in 22% to 28% of patients in the form of pump pocket (8%-18%), catheter (10%-26%), vascular (5%-10%), or biliary (2%-8%) complications. The majority of patients can be rescued from these complications with early identification and aggressive intervention to continue to deliver safe and effective HAI therapy. CONCLUSIONS: This HAI toolkit provides the HAI team a reference to manage commonly encountered HAI-specific perioperative obstacles and complications. Overcoming these challenges is critical to ensure safe and effective pump implantation and delivery of HAI therapy, and key to successful implementation of new programs and expansion of HAI to patients who may benefit from such a highly specialized treatment strategy.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Arteria Hepática/cirugía , Arteria Hepática/patología , Infusiones Intraarteriales/efectos adversos , Neoplasias Colorrectales/patología , Bombas de Infusión Implantables/efectos adversos , Neoplasias Hepáticas/cirugía , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
ABSTRACT: Pancreatic myoepithelial hamartoma is a rare, benign solid and cystic lesion of the pancreas. We present the first case of an adult with a giant myoepithelial hamartoma extending throughout the pancreas in a patient with diabetes in 4 immediate family members. The patient is a 46-year-old man presented with recurrent acute pancreatitis. Computed tomographic imaging showed that the head and body of the pancreas were replaced by a solid-cystic mass with focal calcification. Medical history includes insulin-dependent diabetes mellitus (IDDM) diagnosed at age 30. Endoscopic ultrasound-guided fine-needle aspiration showed pancreatic acinar tissue and smooth muscle without evidence of malignancy. Total pancreatectomy was performed because of the diffuse nature of the cystic disease and preexisting IDDM. The histopathologic diagnosis was consistent with myoepithelial hamartoma. In addition, there was a family history of IDDM and hamartomatous cyst resection in the paternal grandmother. We report the first case of diffuse pancreatic myoepithelial hamartoma with near total replacement of the entire pancreatic parenchyma, and the first reported case associated with a family history of heritable IDDM. Improved knowledge of the genetics, development, and malignant potential of such rare diseases is critical to determine appropriate management for patients.
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Diabetes Mellitus Tipo 1 , Hamartoma , Neoplasias Pancreáticas , Pancreatitis , Masculino , Adulto , Humanos , Persona de Mediana Edad , Diabetes Mellitus Tipo 1/patología , Enfermedad Aguda , Neoplasias Pancreáticas/patología , Pancreatitis/patología , Páncreas/diagnóstico por imagen , Páncreas/cirugía , Páncreas/patología , Hamartoma/diagnóstico por imagen , Hamartoma/genéticaRESUMEN
BACKGROUND: Colorectal liver metastases (CRLM) are the most common cause of disease-specific mortality in patients with colorectal cancer. Hepatic artery infusion (HAI) combined with systemic chemotherapy improves survival for these patients. The safety of colorectal resection at the time of HAI pump placement has not been well established. METHODS: Patients with CRLM who underwent combined HAI pump placement and colorectal (primary) resection or HAI pump placement alone were evaluated for perioperative outcomes, pump-specific complications, infectious complications, and time to treatment initiation. These outcomes were compared using comparative statistics. RESULTS: Patients who underwent combined HAI pump placement and primary resection (n = 19) vs HAI pump placement alone (n = 13) had similar demographics and rates of combined hepatectomy. Combined HAI pump placement and primary resection group had similar operative time and blood loss (both p = NS), but longer length of stay (6 vs 4 days, p = 0.02) compared to pump placement alone. Overall postoperative complications (21% vs 8%) and pump-specific complications (16% vs 31%) were similar (both p = NS). Infection rates were not different between groups, nor was time to initiation of HAI therapy (19 vs 16 days p = NS), or systemic therapy (34 vs 35 days p = NS). CONCLUSION: Combining colorectal resection with HAI pump implantation is a safe surgical approach for management of unresectable CRLM. Postoperative complications, specifically infectious complications, were not increased, nor was there a delay to initiation of HAI or systemic chemotherapy. Investigation of long-term oncologic outcomes for HAI pump placement and primary tumor resection in patients with unresectable CRLM is ongoing.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Fluorouracilo/uso terapéutico , Arteria Hepática/patología , Humanos , Bombas de Infusión , Infusiones Intraarteriales , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
Since the observation that clearance of all visible and microscopic tumors from cutaneous melanoma is critical to prevent a recurrence, wide surgical margins have been central to surgical dogma. In the last several decades, more conservative margin widths have been vigorously studied by surgical investigators to lessen wound complications, the need for reconstruction, and healthcare costs. This review summarizes surgeon-led clinical trials that define current guidelines and highlights the challenges to initiate and perform trials today.
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Ensayos Clínicos como Asunto/métodos , Procedimientos Quirúrgicos de Citorreducción/métodos , Melanoma/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Neoplasias Cutáneas/cirugía , Ensayos Clínicos como Asunto/historia , Ensayos Clínicos como Asunto/normas , Procedimientos Quirúrgicos de Citorreducción/historia , Procedimientos Quirúrgicos de Citorreducción/normas , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Márgenes de Escisión , Melanoma/historia , Melanoma/patología , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto/historia , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Neoplasias Cutáneas/historia , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Detection of cystic lesions of the pancreas has outpaced our ability to stratify low-grade cystic lesions from those at greater risk for pancreatic cancer, raising a concern for overtreatment. METHODS: We developed a Markov decision model to determine the cost-effectiveness of guideline-based management for asymptomatic pancreatic cysts. Incremental costs per quality-adjusted life year gained and survival were calculated for current management guidelines. A sensitivity analysis estimated the effect on cost-effectiveness and mortality if overtreatment of low-grade cysts is avoided, and the sensitivity and specificity thresholds required of methods of cyst stratification to improve costs expended. RESULTS: "Surveillance" using current management guidelines had an incremental cost-effectiveness ratio of $171,143/quality adjusted life year compared with no surveillance or operative treatment ("do nothing"). An incremental cost-effectiveness ratio for surveillance decreases to $80,707/quality adjusted life year if the operative overtreatment of low-grade cysts was avoided. Assuming a societal willingness-to-pay of $100,000/quality adjusted life year, the diagnostic specificity for high-risk cysts must be >67% for surveillance to be preferred over surgery and "do nothing." Changes in sensitivity alone cannot make surveillance cost-effective. Most importantly, survival in surveillance is worse than "do nothing" for 3 years after cyst diagnosis, although long-term survival is improved. The disadvantage is eliminated when overtreatment of low-grade cysts is avoided. CONCLUSION: Current management of pancreatic cystic lesions is not cost-effective and may increase mortality owing to overtreatment of low-grade cysts. The specificity for risk stratification for high-risk cysts must be greater than 67% to make surveillance cost-effective.
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Análisis Costo-Beneficio , Quiste Pancreático/economía , Quiste Pancreático/cirugía , Guías de Práctica Clínica como Asunto , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Asintomáticas , Técnicas de Apoyo para la Decisión , Diagnóstico por Imagen/economía , Humanos , Hallazgos Incidentales , Cadenas de Markov , Persona de Mediana Edad , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/mortalidad , Años de Vida Ajustados por Calidad de Vida , Medición de Riesgo/economía , Sensibilidad y Especificidad , Análisis de Supervivencia , Procedimientos InnecesariosAsunto(s)
Reproductor MP3 , Pancreaticoduodenectomía , Anastomosis Quirúrgica , Descompresión , Humanos , PancreatectomíaRESUMEN
PURPOSE: The recent emergence of radioligand therapies for cancer treatment has increased enthusiasm for developing new theranostic strategies coupling both imaging and cytotoxicity in the same entity. In this study, we evaluated whether CUB domain containing protein 1 (CDCP1), a single-pass transmembrane protein highly overexpressed in diverse human cancers, might be a target for cancer theranostics. EXPERIMENTAL DESIGN: The ectodomain of CDCP1 was targeted using radiolabeled forms of 4A06, a potent and specific recombinant human antibody that we developed. Imaging and antitumor assessment studies were performed in animal models of pancreatic cancer, including two patient-derived xenograft models we developed for this study. For antitumor assessment studies, the endpoints were death due to tumor volume >3,000 mm3 or ≥20% loss in body weight. Specific tracer binding or antitumor effects were assessed with an unpaired, two-tailed Student t test and survival advantages were assessed with a log rank (Mantel-Cox) test. Differences at the 95% confidence level were interpreted to be significant. RESULTS: 89Zr-4A06 detected a broad dynamic range of full length or cleaved CDCP1 expression on seven human pancreatic cancer tumors (n = 4/tumor). Treating mice with single or fractionated doses of 177Lu-4A06 significantly reduced pancreatic cancer tumor volume compared with mice receiving vehicle or unlabeled 4A06 (n = 8; P < 0.01). A single dose of 225Ac-4A06 also inhibited tumor growth, although the effect was less profound compared with 177Lu-4A06 (n = 8; P < 0.01). A significant survival advantage was imparted by 225Ac-4A06 (HR = 2.56; P < 0.05). CONCLUSIONS: These data establish that CDCP1 can be exploited for theranostics, a finding with widespread implications given its breadth of overexpression in cancer.
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Antineoplásicos Inmunológicos/administración & dosificación , Moléculas de Adhesión Celular/antagonistas & inhibidores , Páncreas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Medicina de Precisión/métodos , Animales , Antígenos de Neoplasias/genética , Antineoplásicos Inmunológicos/farmacocinética , Moléculas de Adhesión Celular/genética , Humanos , Masculino , Ratones , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Direct-to-consumer BRCA testing will increase BRCA diagnoses and subsequent abdominal imaging. It is unclear whether BRCA carriers are at higher risk of developing pancreatic cysts (PCs) or cyst-associated pancreatic ductal adenocarcinoma (PDAC). We investigated the prevalence of PCs in BRCA-tested patients, and whether BRCA-carriers have higher rates of PDAC when PCs are found. STUDY DESIGN: This is a retrospective cross-sectional study of patients with BRCA testing and abdominal imaging between 1996 and 2018. Pancreatic cysts were identified on original imaging reports. Prevalence and risk characteristics of PCs, as well as incidence of PDAC, were compared between BRCA+, BRCA-, and BRCA-untested patients. RESULTS: Pancreatic cysts were identified in 4,045 patients among 128,164 unique patients with abdominal imaging, including 33 patients with PCs in 1,113 BRCA-tested patients. There was no difference in PC prevalence between BRCA+, BRCA-, and untested patients (3.6%, 2.6%, 3.2%, respectively; p = 0.64). Pancreatic cysts were diagnosed in BRCA+ patients at a younger age (57.1 vs 65.3 years, p < 0.001); however, there was no difference in risk stratification compared with BRCA- or untested patients by consensus criteria. Across the population of imaged patients, patients with PCs had significantly higher rates of PDAC compared with those without PCs (18.2% vs 2.4%, p < 0.001). Incidence of cyst-associated PDAC was similar in BRCA+ and BRCA- patients (13.3% vs 22.2%, p = 0.84). CONCLUSIONS: BRCA+ patients have similar rates of PCs, high-risk features in their cysts, and PDAC as BRCA- and untested patients. BRCA+ patients likely do not require dedicated abdominal imaging to evaluate for PCs and should follow management guidelines similar to those as the untested general population if an incidental PC is identified.
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Abdomen/diagnóstico por imagen , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/genética , Genes BRCA1 , Genes BRCA2 , Mutación , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/genética , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/genética , Adulto , Anciano , Carcinoma Ductal Pancreático/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quiste Pancreático/epidemiología , Neoplasias Pancreáticas/epidemiología , Estudios Retrospectivos , Medición de RiesgoRESUMEN
KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Factor Inhibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Femenino , Técnicas de Inactivación de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Factor Inhibidor de Leucemia/antagonistas & inhibidores , Factor Inhibidor de Leucemia/genética , Ratones , Mutación , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal/genética , Factores de Transcripción , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP , GemcitabinaRESUMEN
Incidental detection of pancreatic cysts has increased dramatically over the last decade, but risk stratification and clinical management remain a challenge. Mucinous cysts are precursor lesions to pancreatic cancer, however, the majority are indolent. Current diagnostics cannot identify mucinous cysts that harbor cancer or reliably differentiate these lesions from nonmucinous cysts, which present minimal risk of malignant progression. We previously determined that activity of two aspartyl proteases was increased in mucinous cysts. Using a global protease activity profiling technology, termed multiplex substrate profiling by mass spectrometry (MSP-MS), we now show that aminopeptidase activity is also elevated in mucinous cysts. The serine aminopeptidase, tripeptidyl peptidase 1 (TPP1), was detected by proteomic analysis of cyst fluid samples and quantitation using targeted MS demonstrated that this protease was significantly more abundant in mucinous cysts. In a cohort of 110 cyst fluid samples, TPP1 activity was increased more than 3-fold in mucinous cysts relative to nonmucinous cysts. Moreover, TPP1 activity is primarily associated with mucinous cysts that harbor high-grade dysplasia or invasive carcinoma. Although only 59% accurate for differentiating these lesions, measurement of TPP1 activity may improve early detection and treatment of high-risk pancreatic cysts when used in conjunction with other promising biomarkers.
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Aminopeptidasas/metabolismo , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/metabolismo , Lisosomas/enzimología , Quiste Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Serina Proteasas/metabolismo , Humanos , Lisosomas/metabolismo , Quiste Pancreático/patología , Neoplasias Pancreáticas/patología , Proteómica , Tripeptidil Peptidasa 1RESUMEN
BACKGROUND: Significant overtreatment of intraductal papillary mucinous neoplasms can be attributed to low specificity of the current International Consensus Guidelines as well as nonconformity with the guidelines. We compare the ability of the 2012 and revised 2017 intraductal papillary mucinous neoplasms International Consensus Guidelines to predict high-grade dysplasia/invasive cancer and to determine the preoperative variables that predict resection of benign or low-grade dysplasia in tertiary care centers. METHODS: Clinical, radiographic, and pathologic data for resected intraductal papillary mucinous neoplasms at 3 high-volume National Cancer Institute Cancer Centers were reviewed and the 2012 and 2017 consensus criteria were retrospectively applied. When International Consensus Guidelines were not met, clinical decision analysis was used to determine the primary indication for resection. Logistic regression identified variables associated with pathologic grade. RESULTS: Records for a total of 251 patients were reviewed, 129 of whom (52%) had low-grade dysplasia. The revised 2017 International Consensus Guidelines had high sensitivity (98.4%) and negative predicted value (96.1%), and all high-risk stigmata predicted high-grade dysplasia/invasive cancer; however, specificity remained low (14.8%). Nonconformity with International Consensus Guidelines was the most powerful predictor of low-grade dysplasia on final pathologic examination (9.5; 2.12-40.78). Independent predictors of low-grade dysplasia included age younger than 50 (2.46; 1.08-5.62), fine-needle aspiration without epithelial cells (2.6; 1.43-4.72), and normal duct diameter (3.07; 1.99-4.75). Diabetes developed in 30% of patients after resection. CONCLUSION: Management of intraductal papillary mucinous neoplasms remains clinically challenging. Low specificity of the International Consensus Guidelines and nonconformity with the guidelines continue to contribute to unnecessary pancreatic resections. Improved tools for disease classification as well as a better understanding of the natural history, biology, and rates of progression of intraductal papillary mucinous neoplasms are needed to avoid surgical overtreatment of low-grade intraductal papillary mucinous neoplasms.
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Uso Excesivo de los Servicios de Salud , Neoplasias Intraductales Pancreáticas/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Páncreas/patología , Neoplasias Intraductales Pancreáticas/patología , Guías de Práctica Clínica como Asunto , Estudios Retrospectivos , Adulto JovenRESUMEN
Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 µL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR.
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Líquido Quístico/enzimología , Quiste Pancreático/enzimología , Neoplasias Pancreáticas/enzimología , Péptido Hidrolasas/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Antígeno Carcinoembrionario/metabolismo , Catepsina E/metabolismo , Diagnóstico Diferencial , Colorantes Fluorescentes/metabolismo , Humanos , Ratones Noqueados , Ratones Transgénicos , Neoplasias Quísticas, Mucinosas y Serosas/diagnóstico , Neoplasias Quísticas, Mucinosas y Serosas/enzimología , Quiste Pancreático/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Seudoquiste Pancreático/diagnóstico , Seudoquiste Pancreático/enzimología , Pepsina A/metabolismo , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Purpose To compare the agreement of three-dimensional (3D) tumor measurements for therapeutic response assessment of Ewing sarcoma according to the Children's Oncology Group (COG) criteria, one-dimensional (1D) Response Evaluation Criteria in Solid Tumors (RECIST), and two-dimensional (2D) measurements defined by the World Health Organization (WHO) with tumor volume measurements as the standard of reference and to determine which method correlates best with clinical outcomes. Materials and Methods This retrospective study was approved by the institutional review board of three institutions. Seventy-four patients (mean age ± standard deviation, 14.5 years ± 6.5) with newly diagnosed Ewing sarcoma treated at three medical centers were evaluated. Primary tumor size was assessed on pre- and posttreatment magnetic resonance images according to 1D RECIST, 2D WHO, and 3D COG measurements. Tumor responses were compared with the standard of reference (tumor volume) on the basis of RECIST, COG, and WHO therapeutic response thresholds. Agreement between the percentage reduction measurements of the methods was assessed with concordance correlation, Bland-Altman analysis, and Spearman rank correlation. Agreement between therapeutic responses was assessed with Kendall tau and unweighted κ statistics. Tumor responses were compared with patient survival by using the log-rank test, Kaplan-Meier plots, and Cox regression. Results Agreement with the reference standard was significantly better for 3D measurement than for 1D and 2D measurements on the basis of RECIST and COG therapeutic response thresholds (concordance correlation of 0.41, 0.72, and 0.84 for 1D, 2D, and 3D measurements, respectively; P < .0001). Comparison of overall survival of responders and nonresponders demonstrated P values of .4133, .0112, .0032, and .0027 for 1D, 2D, 3D, and volume measurements, respectively, indicating that higher dimensional measurements were significantly better predictors of overall survival. Conclusion The 3D tumor measurements according to COG are better predictors of therapeutic response of Ewing sarcoma than 1D RECIST or 2D WHO measurements and show a significantly higher correlation with clinical outcomes. (©) RSNA, 2016 Online supplemental material is available for this article.
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Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Sarcoma de Ewing/diagnóstico por imagen , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/patología , Niño , Preescolar , Femenino , Humanos , Imagenología Tridimensional , Lactante , Estimación de Kaplan-Meier , Masculino , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Sarcoma de Ewing/patología , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. METHODS: Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. RESULTS: Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). CONCLUSION: Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients.