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OBJECTIVES: Large surface area microparticle paclitaxel (LSAM-PTX) provides an intratumoral (IT) chemotherapeutic depot. Safety, tolerability, and tumor response to IT LSAM-PTX delivered by endoscopic ultrasound-fine needle injection were evaluated in subjects with unresectable locally advanced pancreatic cancer (LAPC). METHODS: Ten subjects treated in a dose escalation phase and 22 additional subjects receiving 2 injections, 4 weeks apart, of 15 mg/mL LSAM-PTX were followed for 12 months. Paclitaxel pharmacokinetics were evaluated, imaging at 3 and 6 months determined tumor response, and multiplex immunofluorescence was conducted to characterize local immune response. RESULTS: Most treatment-emergent adverse events were attributed to LAPC. Plasma paclitaxel levels were negligible. Eight subjects' tumors became resectable after IT LSAM-PTX, and 5 of 6 (83%) were resected with R0. Multiplex immunofluorescence of resected tumors demonstrated increased T cells, natural killer cells, and macrophages and decreased myeloid-derived suppressor cells. Six-month disease control rate was 94%, and median overall survival was 19.7 months in the 2-injection subjects. For nonresected and resected groups, overall survival times were 18.9 and 35.2 months, respectively. CONCLUSIONS: Neoadjuvant IT LSAM-PTX, in combination with SOC, was well tolerated and may provide benefits to LAPC patients, evidenced by enhanced immune response, improved disease control rate, restaging leading to surgery, and extended survival.
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Paclitaxel , Neoplasias Pancreáticas , Humanos , Inyecciones Intralesiones , Terapia Neoadyuvante/métodos , Hormonas Pancreáticas , Neoplasias Pancreáticas/patología , Neoplasias PancreáticasRESUMEN
Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with chromosome 1q amplification being associated with HG progression and with cases that harbored co-occurring PDAC. Furthermore, the combined assessment of single-nucleotide variants (SNV) and CNAs identified both linear and branched evolutionary trajectories, underscoring the heterogeneity in the progression of LG lesions to HG and PDAC. At the transcriptome level, upregulation of MYC-regulated targets and downregulation of transcripts associated with the MHC class I antigen presentation machinery as well as pathways related to glycosylation were a common feature of progression to HG. In addition, the established PDAC transcriptional subtypes (basal-like and classical) were readily apparent within IPMNs. Taken together, this work emphasizes the role of 1q copy-number amplification as a putative biomarker of high-risk IPMNs, underscores the importance of immune evasion even in noninvasive precursor lesions, and reinforces that evolutionary pathways in IPMNs are heterogenous, comprised of both SNV and CNA-driven events. SIGNIFICANCE: Integrated molecular analysis of genomic and transcriptomic alterations in the multistep progression of IPMNs, which are bona fide precursors of pancreatic cancer, identifies features associated with progression of low-risk lesions to high-risk lesions and cancer, which might enable patient stratification and cancer interception strategies.
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Carcinoma Ductal Pancreático , Neoplasias Quísticas, Mucinosas y Serosas , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Proyectos Piloto , Neoplasias Intraductales Pancreáticas/genética , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genéticaRESUMEN
Background: The risk of developing invasive cancer in the remnant pancreas after resection of multifocal high-grade pancreatic precursor lesions is not well known. We report three patients who were followed up after resection of multifocal high-grade pancreatic intraepithelial neoplasia (PanIN)-3 or intraductal papillary mucinous neoplasia (IPMN), two of whom eventually developed invasive carcinoma. Presentation: 1) 68-year-old woman who had a laparoscopic distal pancreatectomy for multifocal mixed-type IPMN, identified as high-grade on final pathology, with negative surgical margins. During semiannual monitoring, eight years from the first surgery, the patient developed suspicious features prompting surgical resection of the body with final pathology revealing invasive ductal adenocarcinoma in the setting of IPMN. 2) 48-year-old woman who had a distal pancreatectomy for severe acute/chronic symptomatic pancreatitis, with final pathology revealing multifocal high-grade PanIN-3, with negative surgical margins. Despite semiannual monitoring, two years from the first surgery, the patient developed pancreatic adenocarcinoma with liver metastasis. 3) 55-year-old woman who had a Whipple procedure for symptomatic chronic pancreatitis, with multifocal PanIN-3 on final pathology. The patient underwent completion pancreatectomy due to symptomatology and her high-risk profile, with final pathology confirming multifocal PanIN-3. Conclusion: Multifocal high-grade dysplastic lesions of the pancreas might benefit from surgical resection.
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PURPOSE: The purpose of this study was to describe clinical outcomes of patients with temporary ostomies in 3 Veterans Health Administration hospitals. DESIGN: Retrospective descriptive study, secondary analysis. SAMPLE AND SETTING: Veterans with temporary ostomies from 3 Veterans Health Administration hospitals who were enrolled in a previous study. The sample comprised 36 participants all were male. Their mean age was 67.05 ± 9.8 years (mean ± standard deviation). Twenty patients (55.6%) had ileostomies and 16 patients (44.4%) had colostomies. METHODS: This was a secondary analysis of data collected using medical record data. Variables examined included etiology for creation and type of ostomy, health-related quality of life, time to reversal, reasons for nonreversal, postoperative complications after reversal, and mortality in the follow-up period. RESULTS: Colorectal cancer and diverticular disease were the main reasons for temporary stoma formation. The reversal rate was 50%; the median time to reversal was 9 months in our sample; temporary ileostomies were reversed more often than temporary colostomies (P = .18). Comorbid conditions were identified as the main reason for nonreversal. Mortality was not significantly different between the reversal and nonreversal groups. No significant differences were reported with health-related quality-of-life parameters between reversal and nonreversal groups. CONCLUSIONS: This study identified that the proportion of temporary ostomies was limited to 50%. Complications during the index operation, medical comorbidities, and progression of cancer are the main reasons for nonreversal of temporary stomas. Study findings should be included in the counseling of patients who are likely to get intestinal stomas with temporary intention, and during consideration for later reversal of a stoma.
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Estomía/métodos , Estomía/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Anastomosis Quirúrgica/métodos , Neoplasias Colorrectales/cirugía , Colostomía/métodos , Colostomía/estadística & datos numéricos , Enfermedades Diverticulares/cirugía , Humanos , Ileostomía/métodos , Ileostomía/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Psicometría/instrumentación , Psicometría/métodos , Calidad de Vida , Estudios Retrospectivos , Encuestas y Cuestionarios , Estados Unidos , United States Department of Veterans Affairs/organización & administración , United States Department of Veterans Affairs/estadística & datos numéricosRESUMEN
OBJECTIVE: The objective of this study was to test the hypothesis that distal pancreatectomy (DP) without intraperitoneal drainage does not affect the frequency of grade 2 or higher grade complications. BACKGROUND: The use of routine intraperitoneal drains during DP is controversial. Prior to this study, no prospective trial focusing on DP without intraperitoneal drainage has been reported. METHODS: Patients undergoing DP for all causes at 14 high-volume pancreas centers were preoperatively randomized to placement of a drain or no drain. Complications and their severity were tracked for 60 days and mortality for 90 days. The study was powered to detect a 15% positive or negative difference in the rate of grade 2 or higher grade complications. All data were collected prospectively and source documents were reviewed at the coordinating center to confirm completeness and accuracy. RESULTS: A total of 344 patients underwent DP with (N = 174) and without (N = 170) the use of intraperitoneal drainage. There were no differences between cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, or operative technique. There was no difference in the rate of grade 2 or higher grade complications (44% vs. 42%, P = 0.80). There was no difference in clinically relevant postoperative pancreatic fistula (18% vs 12%, P = 0.11) or mortality (0% vs 1%, P = 0.24). DP without routine intraperitoneal drainage was associated with a higher incidence of intra-abdominal fluid collection (9% vs 22%, P = 0.0004). There was no difference in the frequency of postoperative imaging, percutaneous drain placement, reoperation, readmission, or quality of life scores. CONCLUSIONS: This prospective randomized multicenter trial provides evidence that clinical outcomes are comparable in DP with or without intraperitoneal drainage.
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Drenaje , Pancreatectomía/métodos , Complicaciones Posoperatorias/prevención & control , Anciano , Drenaje/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Estudios ProspectivosAsunto(s)
Adenocarcinoma Mucinoso , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma Mucinoso/clasificación , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/terapia , Carcinoma Ductal Pancreático/clasificación , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/terapia , Humanos , Neoplasias Pancreáticas/clasificación , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/terapiaRESUMEN
BACKGROUND: Patients with adenocarcinoma of the pancreatic body/tail and associated vascular thrombosis or adjacent organ invasion are suboptimal candidates for resection. We hypothesized that extended distal pancreatectomy (EDP) for locally advanced adenocarcinoma is associated with a survival benefit. METHODS: We retrospectively reviewed a prospectively collected database of patients who underwent distal pancreatectomy (DP) for adenocarcinoma at a single academic institution (1996 to 2011) with greater than or equal to 2 years of follow-up. RESULTS: Among 680 DP patients, 93 were indicated for pancreatic adenocarcinoma. Splenic vein thrombosis (n = 26) did not significantly affect morbidity, mortality, or survival. Standard DP was performed in 70 patients and 23 underwent EDP with no difference in morbidity/mortality. Patients with EDP had a survival comparable with patients with standard DP (disease-free survival 18 vs 12 months = .8; overall survival 23 vs 17 months, P =.6). There was no difference in survival between EDP patients with versus without pathologic invasion of adjacent organs, but a trend favored those without. CONCLUSION: EDP is safe and should be considered in fit patients with locally advanced adenocarcinoma.
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Adenocarcinoma/cirugía , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Vena Esplénica/patología , Trombosis de la Vena/etiología , Adenocarcinoma/complicaciones , Adenocarcinoma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/diagnóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Trombosis de la Vena/diagnóstico , Trombosis de la Vena/cirugíaRESUMEN
OBJECTIVES: Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras(G12D);Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored. METHODS: LSL-Kras(G12D);Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed. RESULTS: The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine. CONCLUSIONS: Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras(G12D);Pdx-1-Cre mouse model of pancreatic cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma in Situ/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Carcinoma in Situ/sangre , Carcinoma in Situ/genética , Carcinoma in Situ/patología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/administración & dosificación , Citocinas/sangre , Progresión de la Enfermedad , Genes p53 , Ratones , Ratones Transgénicos , Mutación , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Sesquiterpenos/administración & dosificación , Sulindac/administración & dosificaciónRESUMEN
UNLABELLED: To determine if the level of transforming growth factor α (TGF-α) in the pancreatic fluid (PF) can diagnose intraductal papillary mucinous neoplasm (IPMN) versus other cystic lesions of the pancreas in patients. METHODS: Pancreatic fluid was prospectively obtained from patients during routine endoscopy and/or operation at Indiana University Hospital. Pancreatic fluid TGF-α levels were analyzed by enzyme-linked immunosorbent assay. Intraductal papillary mucinous neoplasm tissue was also analyzed by TGF-α immunohistochemistry. RESULTS: Sixty-nine fluid samples from 58 patients with the following pathologically confirmed pancreatic disorders were analyzed: IPMN (26 patients), serous cystadenoma (6), mucinous cystic neoplasm (9), pseudocysts (5), non-IPMNY associated pancreatic ductal adenocarcinoma (6), and sphincter of Oddi dysfunction (6). There was no significant difference between the mean PF-TGF-α levels in each category or between different dysplastic grades of IPMN. However, of all the diagnoses examined, only IPMN demonstrated PF-TGF-α levels greater than 95 pg/mL. In low-grade IPMN specimens, TGF-α immunohistochemistry correlated with enzyme-linked immunosorbent assay levels. CONCLUSIONS: The mean PF-TGF-α levels are not significantly different in IPMN lesions compared with those in other cystic pancreatic lesions, pancreatic ductal adenocarcinoma, or sphincter of Oddi dysfunction. However, PF-TGF-α levels more than 95 pg/mL may be useful in diagnosing IPMN. This assertion requires prospective validation.
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Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/diagnóstico , Neoplasias Quísticas, Mucinosas y Serosas/diagnóstico , Jugo Pancreático/inmunología , Neoplasias Pancreáticas/diagnóstico , Factor de Crecimiento Transformador alfa/análisis , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunohistoquímica , Indiana , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Quísticas, Mucinosas y Serosas/inmunología , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Regulación hacia Arriba , Adulto JovenRESUMEN
A 68 year-old male with a bifid pancreatic neck is described in the context of a common head during pancreatoduodenectomy.