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1.
J Pathol ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34750813

RESUMO

Primary non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a heterogeneous group of neuroendocrine neoplasms that display highly variable clinical behavior. Therefore, NF-PanNETs often present clinical teams a dilemma: the uncertain metastatic potential of the tumor has to be weighed against the morbidity associated with surgical resection. Thus, rather than utilizing current radiologic thresholds, there is an urgent need for improved prognostic biomarkers. Recent studies aimed at understanding the epigenetic underpinnings of NF-PanNETs have led to the identification of tumor subgroups based on histone modification and DNA methylation patterns. These molecular profiles tend to resemble the cellular origins of PanNETs. Subsequent retrospective analyses have demonstrated that these molecular signatures are of prognostic value and, importantly, may be useful in the pre-operative setting. These studies have highlighted that sporadic NF-PanNETs displaying biomarkers associated with disease progression and poor prognosis, such as alternative lengthening of telomeres (ALT), inactivating ATRX or DAXX gene mutations, or copy number variations, more often display alpha-cell characteristics. Conversely, NF-PanNETs with beta-cell characteristics often lack these unfavorable biomarkers. ALT, transcription factor protein expression, and possibly DNA methylation can be assessed in endoscopic ultrasound-guided tumor biopsies. Prospective studies focusing on cell-of-origin and epigenetic profile driven decision-making prior to surgery are likely to be routinely implemented into clinical practice in the near future. This article is protected by copyright. All rights reserved.

2.
Elife ; 102021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34609282

RESUMO

Expansion of biliary epithelial cells (BECs) during ductular reaction (DR) is observed in liver diseases including cystic fibrosis (CF), and associated with inflammation and fibrosis, albeit without complete understanding of underlying mechanism. Using two different genetic mouse knockouts of ß-catenin, one with ß-catenin loss is hepatocytes and BECs (KO1), and another with loss in only hepatocytes (KO2), we demonstrate disparate long-term repair after an initial injury by 2-week choline-deficient ethionine-supplemented diet. KO2 show gradual liver repopulation with BEC-derived ß-catenin-positive hepatocytes and resolution of injury. KO1 showed persistent loss of ß-catenin, NF-κB activation in BECs, progressive DR and fibrosis, reminiscent of CF histology. We identify interactions of ß-catenin, NFκB, and CF transmembranous conductance regulator (CFTR) in BECs. Loss of CFTR or ß-catenin led to NF-κB activation, DR, and inflammation. Thus, we report a novel ß-catenin-NFκB-CFTR interactome in BECs, and its disruption may contribute to hepatic pathology of CF.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose/genética , Inflamação/genética , NF-kappa B/genética , beta Catenina/genética , Animais , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/metabolismo , Fibrose/imunologia , Inflamação/imunologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , beta Catenina/metabolismo
3.
Dis Colon Rectum ; 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34508015

RESUMO

BACKGROUND: Right hemicolectomy is recommended for appendiceal adenocarcinoma but may not be needed for early-stage disease. OBJECTIVE: This study aimed to determine whether appendectomy offers adequate oncologic outcomes for T1 appendiceal adenocarcinoma from a national cohort of patients. DESIGN: Patients with T1 appendiceal adenocarcinoma (mucinous and non-mucinous histology) treated with either a right hemicolectomy or appendectomy between 2004-2016 were retrieved. Multivariate Cox-regression analysis was used to identify predictors of overall survival. SETTING: National cancer database. PATIENTS: A total 320 patients (median age 62yrs, 47% females) were identified: 69 (22%) underwent an appendectomy and 251 (78%) underwent a right hemicolectomy. MAIN OUTCOME MEASURE: Overall survival. RESULTS: Non-mucinous adenocarcinoma was identified in 194 (61%) while 126 (39%) had mucinous adenocarcinoma. Out of the overall cohort, 43% had well differentiated histology, 39% had moderately differentiated disease and 4% had poorly differentiated tumors. The rate of lymph node metastasis was lower in well differentiated tumors (3%) compared to moderately (10%) or poorly differentiated tumors (25%). On univariate survival analysis, right hemicolectomy was associated with improved 1-,3- and 5-year overall survival in patients with moderately/poorly differentiated disease (P<0.001) but not for well differentiated disease (p=1.000). After adjustment, right hemicolectomy was associated with overall survival improvement for moderately/poorly differentiated T1 adenocarcinoma (HR=0.26, 95% CI: 0.08-0.82, p=0.02) but not for well differentiated disease. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSION: The current analysis from the national cancer database demonstrates that appendectomy is associated with equivalent survival to right hemicolectomy for well differentiated T1 adenocarcinoma, while for moderately and poorly differentiated disease, right hemicolectomy is oncologically superior to appendectomy. See Video Abstract at http://links.lww.com/DCR/B689.

4.
Cancer Med ; 10(20): 7233-7241, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34559451

RESUMO

INTRODUCTION: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort. METHODS: A review of patients enrolled between July 2010 and February 2013 in the completed phase I/II single arm (two doses of fixed-dose gemcitabine (1500 mg/m2 ) in combination with oral hydroxychloroquine administered for 31 consecutive days until the day of surgery for high-risk pancreatic cancer) was undertaken. Progression-free survival (PFS) and overall survival analysis (OS) using Kaplan-Meier estimates were performed. RESULTS: Of 35 patients initially enrolled, 29 patients underwent surgical resection (median age at diagnosis: 62 years, 45% females). Median duration of follow-up was 7.5 years. There was a median 15% decrease in the serum CA19-9 levels following completion of neoadjuvant therapy and 83% of the cohort underwent a pancreaticoduodenectomy, 7 (24%) patients had a concomitant venous resection. On histopathology, 14 (48%) patients had at least a partial treatment response. The median PFS and OS were 11 months (95% Confidence interval [CI]: 7-28) and 31 months (95% CI: 13-47), respectively, while 9 (31%) patients survived beyond 5 years from diagnosis; a rate that compares very favorably with contemporaneous series. CONCLUSION: Compared to historical data, neoadjuvant autophagy inhibition with HCQ plus gemcitabine is associated with encouraging long-term survival for patients with PDAC.

5.
Am J Physiol Gastrointest Liver Physiol ; 321(5): G449-G460, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34523348

RESUMO

Chronic pancreatitis (CP) is a complex inflammatory disorder with numerous associated genetic and environmental risk factors. The most distressing characteristic of CP is recalcitrant pain, often requiring surgical resection including total pancreatectomy with islet autotransplantation (TPIAT). We studied five consented subjects undergoing pancreatic resection and processed isolated cells for single-cell RNA sequencing (scRNA-Seq). Using high-dimensional transcriptomic cluster analysis, we identified 11 unique cell clusters in the pancreas tissue. These cell clusters include a cluster of undifferentiated/dedifferentiated cells and two unique clusters of acinar cells, one of which appears to be in a transitional stage. To determine the cellular response to protease inhibitor and stimulation, we treated aliquots of cells from one subject with a protease inhibitor cocktail with and without bethanechol (a muscarinic receptor agonist) at 100 and 400 µM and compared gene expression profiles. The protease inhibitors appeared to reduce cell stress. Pancreatic digestive enzymes and islet hormones were upregulated in both doses of bethanechol-treated cells compared with naïve cells. High-dose bethanechol appeared to be toxic and consistent with hyperstimulation. These studies demonstrate the feasibility of investigating human acinar cell physiology at the single-cell level and initial evidence that these cells retain responsiveness to agonist stimulation with predicted second messenger and transcriptomic responses.NEW & NOTEWORTHY We conducted single cell RNA sequencing on pancreas tissue from five individuals. We identified eleven unique cell clusters including a large population of dedifferentiated cells as well as two unique clusters of acinar cells, one of which appears to exist in a transitional state. We also examined the cellular response of pancreas tissue to stimulation and identified affected genes and pathways, including pancreatic digestive enzymes.


Assuntos
Células Acinares/metabolismo , Perfilação da Expressão Gênica , Pâncreas/metabolismo , Pancreatite Crônica/genética , RNA-Seq , Análise de Célula Única , Transcriptoma , Células Acinares/efeitos dos fármacos , Células Acinares/patologia , Desdiferenciação Celular , Análise por Conglomerados , Estudos de Viabilidade , Humanos , Agonistas Muscarínicos/farmacologia , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Pancreaticoduodenectomia , Pancreatite Crônica/metabolismo , Pancreatite Crônica/patologia , Pancreatite Crônica/cirurgia , Inibidores de Proteases/farmacologia
6.
Am J Surg Pathol ; 45(8): 1098-1107, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232602

RESUMO

Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59±12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS-mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS, CDKN1B (encodes p27), and RNF123. In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.


Assuntos
Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
7.
Nat Rev Gastroenterol Hepatol ; 18(7): 457-468, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099908

RESUMO

Due to its poor prognosis and the late stage at which it is typically diagnosed, early detection of pancreatic cancer is a pressing clinical problem. Advances in genomic analysis of human pancreatic tissue and other biospecimens such as pancreatic cyst fluid, pancreatic juice and blood have opened the possibility of DNA-based molecular approaches for early detection of pancreatic cancer. In this Review, we discuss and focus on the pathological and molecular features of precancerous lesions of the pancreas, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm, which are target lesions of early detection approaches. We also discuss the most prevalent genetic alterations in these precancerous lesions, including somatic mutations in the oncogenes KRAS and GNAS as well as tumour suppressor genes CDKN2A, TP53 and SMAD4. We highlight the latest discoveries related to genetic heterogeneity and multifocal neoplasia in precancerous lesions. In addition, we review specific approaches, challenges and clinically available assays for early detection of pancreatic cancer using DNA-based molecular techniques. Although detection and risk stratification of precancerous pancreatic neoplasms are difficult problems, progress in this field highlights the promise of molecular approaches for improving survival of patients with this disease.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Análise de Sequência de DNA/métodos , Biomarcadores Tumorais/análise , DNA de Neoplasias/análise , Heterogeneidade Genética , Humanos , Mutação , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia
8.
Clin Transl Sci ; 14(5): 1822-1829, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34002944

RESUMO

SMAD4, a tumor suppressor gene, is lost in up to 60%-90% of pancreatic adenocarcinomas (PDAs). Loss of SMAD4 allows tumor progression by upregulating autophagy, a cell survival mechanism that counteracts apoptosis and allows intracellular recycling of macromolecules. Hydroxychloroquine (HCQ) is an autophagy inhibitor. We studied whether HCQ treatment in SMAD4 deficient PDA may prevent therapeutic resistance induced by autophagy upregulation. We retrospectively analyzed the SMAD4 status of patients with PDA enrolled in two prospective clinical trials evaluating pre-operative HCQ. The first dose escalation trial demonstrated the safety of preoperative gemcitabine with HCQ (NCT01128296). More recently, a randomized trial of gemcitabine/nab-paclitaxel +/- HCQ evaluated Evans Grade histopathologic response (NCT01978184). The effect of SMAD4 loss on response to HCQ and chemotherapy was studied for association with clinical outcome. Fisher's exact test and log-rank test were used to assess response and survival. Fifty-two patients receiving HCQ with neoadjuvant chemotherapy were studied. Twenty-five patients had SMAD4 loss (48%). 76% of HCQ-treated patients with SMAD4 loss obtained a histopathologic response greater than or equal to 2A, compared with only 37% with SMAD4 intact (p = 0.006). Although loss of SMAD4 has been associated with worse outcomes, in the current study, loss of SMAD4 was not associated with a detriment in median overall survival in HCQ-treated patients (34.43 months in SMAD4 loss vs. 27.27 months in SMAD4 intact, p = 0.18). The addition of HCQ to neoadjuvant chemotherapy in patients with PDA may improve treatment response in those with SMAD4 loss. Further study of the relationship among SMAD4, autophagy, and treatment outcomes in PDA is warranted.

9.
Cancers (Basel) ; 13(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921282

RESUMO

Hepatocellular cancer (HCC), the most common primary liver tumor, has been gradually growing in incidence globally. The whole-genome and whole-exome sequencing of HCC has led to an improved understanding of the molecular drivers of this tumor type. Activation of the Wnt signaling pathway, mostly due to stabilizing missense mutations in its downstream effector ß-catenin (encoded by CTNNB1) or loss-of-function mutations in AXIN1 (the gene which encodes for Axin-1, an essential protein for ß-catenin degradation), are seen in a major subset of HCC. Because of the important role of ß-catenin in liver pathobiology, its role in HCC has been extensively investigated. In fact, CTNNB1 mutations have been shown to have a trunk role. ß-Catenin has been shown to play an important role in regulating tumor cell proliferation and survival and in tumor angiogenesis, due to a host of target genes regulated by the ß-catenin transactivation of its transcriptional factor TCF. Proof-of-concept preclinical studies have shown ß-catenin to be a highly relevant therapeutic target in CTNNB1-mutated HCCs. More recently, studies have revealed a unique role of ß-catenin activation in regulating both tumor metabolism as well as the tumor immune microenvironment. Both these roles have notable implications for the development of novel therapies for HCC. Thus, ß-catenin has a pertinent role in driving HCC development and maintenance of this tumor-type, and could be a highly relevant therapeutic target in a subset of HCC cases.

10.
Head Neck Pathol ; 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33929681

RESUMO

Somatostatin receptor 2 (SSTR2) expression has previously been documented in olfactory neuroblastoma (ONB). Here, we fully characterize SSTR2 expression in ONB and correlate staining results with clinicopathologic parameters including Hyams grade. We also assess SSTR2 immunohistochemistry expression in various histologic mimics of ONB to assess its diagnostic functionality. 78 ONBs (51 primary biopsies/excisions and 27 recurrences/metastases) from 58 patients were stained for SSTR2. H-scores based on intensity (0-3 +) and percentage of tumor cells staining were assigned to all cases. 51 histologic mimics were stained and scored in an identical fashion. 77/78 (99%) ONB cases demonstrated SSTR2 staining (mean H-score: 189, range: 0-290). There were no significant differences in staining between primary tumors and recurrences/metastases (mean H-score: 185 vs 198). Primary low-grade ONB had somewhat stronger staining than high-grade tumors (mean H-score: 200 vs 174). SSTR2 expression had no prognostic value when considering disease-free or disease-specific survival. SSTR2 staining is significantly higher in ONB than its histologic mimics (mean H-score: 189 vs 12.9, p < 0.001) suggesting a potential use of the marker in diagnosis of ONB. In conclusion, SSTR2 is consistently expressed in ONB suggesting a role for somatostatin-analog based imaging and therapy in this disease. More generally, SSTR2 may be another marker of neuroendocrine differentiation in ONB.

11.
Hum Pathol ; 112: 9-19, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33727167

RESUMO

Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , Mucosa Intestinal/patologia , Lesões Pré-Cancerosas/patologia , Adenocarcinoma/etiologia , Adenocarcinoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Lesões Pré-Cancerosas/genética , Análise de Sequência de DNA
13.
Hepatology ; 74(2): 741-759, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33529367

RESUMO

BACKGROUND AND AIMS: HCC remains a major unmet clinical need. Although activating catenin beta-1 (CTNNB1) mutations are observed in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Coexpression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between ß-catenin and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in HCC. APPROACH AND RESULTS: Public HCC data sets were assessed for concomitant presence of CTNNB1 mutations and either mutations in nuclear factor erythroid-2-related factor-2 (NFE2L2) or Kelch like-ECH-associated protein 1 (KEAP1), or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following coexpression of T41A-CTNNB1 with either wild-type (WT)-, G31A-, or T80K-NFE2L2. Based on mammalian target of rapamycin complex 1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mammalian target of rapamycin (mTOR) inhibitor was investigated. Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were attributable to mutations in NFE2L2/KEAP1. Coexpression of mutated CTNNB1 with mutant NFE2L2, but not WT-NFE2L2, led to HCC development and mortality by 12-14 weeks. These HCCs were positive for ß-catenin targets, like glutamine synthetase and cyclin-D1, and Nrf2 targets, like NAD(P)H quinone dehydrogenase 1 and peroxiredoxin 1. RNA-sequencing and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (iron homeostasis and glioblastoma multiforme signaling) and expected (glutamine metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5-mg/kg diet ad libitum), which led to >50% decrease in tumor burden. CONCLUSIONS: Coactivation of ß-catenin and Nrf2 is evident in 9% of all human HCCs. Coexpression of mutant NFE2L2 and mutant CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

14.
Ann Surg Oncol ; 28(5): 2438-2446, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33523364

RESUMO

AIMS: National studies have demonstrated disparities in the treatment and survival of pancreatic cancer patients based on socioeconomic status (SES). This study aimed to identify specific differences in perioperative management and outcomes based on patient SES and to study the role of a multidisciplinary clinic (MDC) in mitigating any variations. METHODS: The study analyzed patients undergoing pancreaticoduodenectomy for pancreatic ductal adenocarcinoma in a large hospital system. The patients were categorized into groups of high and low SES and whether they were managed by the authors' pancreatic cancer MDC or not. The study compared differences in disease characteristics, receipt of multimodality therapy, perioperative outcomes, and recurrence-free and overall survival. RESULTS: Of the 162 low-SES patients and 119 high-SES patients, 54% were managed in the MDC. Outside the MDC, low-SES patients were less likely to receive neoadjuvant chemotherapy and had less minimally invasive surgery, a longer OR time, less enhanced recovery participation, and more major complications (p < 0.05). No SES disparities were observed among the MDC patients. Despite similar tumor characteristics, the low-SES patients had inferior median overall survival (21 vs 32 months; p = 0.005), but the MDC appeared to eliminate this disparity. Low SES correlated with inferior survival for the non-MDC patients (17 vs 32 months; p < 0.001), but not for the MDC patients (24 vs 25 months; p = 0.33). These findings persisted in the multivariable analysis. CONCLUSION: A pancreatic cancer MDC standardizes treatment decisions, eliminates disparities in surgical outcomes, and improves survival for low-SES patients.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/cirurgia , Disparidades em Assistência à Saúde , Humanos , Recidiva Local de Neoplasia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia , Classe Social
15.
J Surg Oncol ; 123(1): 245-251, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33103242

RESUMO

BACKGROUND: There are limited data on the efficacy of neoadjuvant therapy (NAT) for early-stage distal pancreas adenocarcinoma (PDAC). Previous studies focused on adenocarcinoma of the head of the pancreas or dealt with borderline and locally advanced tumors of the body and tail. METHODS: This is a retrospective study of the National Cancer Database between 2006 and 2015. A propensity-matched analysis was performed to compare overall survival estimates between NAT and upfront resection (UR) groups. RESULTS: A total of 5003 distal pancreatectomies for PDAC were identified, of whom 408 (9%) received NAT. After 1:1 matching, 353 NAT patients were compared with 353 UR patients. NAT was associated with lower 90-day mortality. There were no differences in the number of lymph nodes retrieved, or length of stay. With matching, the NAT group had higher median overall survival compared with UR (33.0 vs. 27.0 months; p = 0.009) and adjusted overall survival (hazard ratio = 0.63, 95% confidence interval = 0.51-0.77; p < 0.001). CONCLUSION: The receipt of NAT followed by distal pancreatectomy for early-stage distal PDAC is associated with improved overall survival compared with UR. This study supports the use of NAT in the multimodal therapy paradigm of early-stage adenocarcinoma of the body and tail of the pancreas.


Assuntos
Adenocarcinoma/mortalidade , Quimioterapia Adjuvante/mortalidade , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/mortalidade , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Idoso , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Pontuação de Propensão , Estudos Retrospectivos , Taxa de Sobrevida
16.
Ann Surg Oncol ; 28(7): 3873-3881, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33231767

RESUMO

BACKGROUND: Goblet cell carcinoids (GCC) are an aggressive, albeit rare, subtype of appendiceal tumors that exhibit distinct histologic features and lack clear treatment guidelines. We aimed to ascertain the impact of adjuvant chemotherapy (AC) for GCC in a national cohort of patients. METHODS: Patients who underwent a right hemicolectomy for stage I-III GCC of the appendix between 2006 and 2016 were selected from the National Cancer Database (NCDB). Stratification based on AC receipt was performed. Kaplan-Meier survival estimates and Cox proportional hazard regression were used to identify predictors of overall survival (OS). RESULTS: A total of 867 patients were identified, of whom 124 (14%) received AC. Patients in the AC group were significantly younger (54 vs. 57 years; p = 0.006) and were predominantly of male sex (60 vs. 48%; p = 0.012). On histopathology, patients in the AC group had a higher proportion of poorly/undifferentiated grade (27 vs. 5%; p < 0.001), T4 disease (35 vs. 11%; p < 0.001), and lymph node-positive disease (45 vs. 7%; p < 0.001) than patients who did not receive AC. After excluding patients diagnosed in 2016 due to a lack of follow-up data (n = 162), a survival advantage for the AC group was detected only after stratification for lymph node-positive disease (p = 0.007). On Cox proportional hazard regression, AC demonstrated an independent association with improved OS (hazard ratio 0.24, 95% confidence interval 0.084-0.683; p = 0.007). CONCLUSION: The current analysis from the NCDB supports the role of AC for GCC of the appendix, chiefly for patients with lymph node metastatic disease.


Assuntos
Neoplasias do Apêndice , Apêndice , Tumor Carcinoide , Neoplasias do Apêndice/tratamento farmacológico , Tumor Carcinoide/tratamento farmacológico , Quimioterapia Adjuvante , Humanos , Estimativa de Kaplan-Meier , Masculino
17.
Ann Surg Oncol ; 28(7): 3779-3788, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33231769

RESUMO

BACKGROUND: Neoadjuvant therapy is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). It is unknown whether neoadjuvant chemoradiotherapy is more effective than chemotherapy (NCRT vs. NAC). We aim to compare pathological and survival outcomes of NCRT and NAC in patients with PDAC. PATIENTS AND METHODS: Single-center analysis of PDAC patients treated with NCRT or NAC followed by resection between December 2008 and December 2018 was performed. Average treatment effect (ATE) was estimated after case-control matching using Mahalanobis distance nearest-neighbor matching. Inverse probability weighted estimates (IPWE)-based ATE was estimated for disease-free survival (DFS) and overall survival (OS). RESULTS: Among the 418 patients (mean age 66.8 years, 51% female) included in the study, 327 received NAC and 91 received NCRT. NCRT patients had higher rates of locally advanced disease, number of neoadjuvant chemotherapy cycles, more chemotherapy regimen crossover (gemcitabine and 5-FU based), and were more likely to undergo open surgical procedures and/or vascular resection (all p < 0.05). After matched analysis, NCRT was associated with a significant reduction in lymph node positive disease [ATE = (-)0.24, p = 0.007] and lymphovascular invasion [ATE = (-)0.20, p = 0.02]. While NCRT was associated with significantly improved DFS by 9.5 months (p = 0.006), it did not affect OS by IPWE-based ATE after adjusting for adjuvant therapy (ATE = 5.5 months; p = 0.32). CONCLUSION: Compared with NAC alone, NCRT is associated with improved pathologic surrogates and disease-free survival, but not overall survival in patients with PDAC.


Assuntos
Terapia Neoadjuvante , Neoplasias Pancreáticas , Idoso , Quimiorradioterapia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Pancreáticas/terapia , Estudos Retrospectivos
18.
Hum Pathol ; 112: 70-83, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33383041

RESUMO

With major advancements and frequent use of abdominal imaging techniques, hepatic cysts are increasingly encountered in clinical practice. Although the majority of cysts are benign, a small subset represents neoplastic precursors to cholangiocarcinoma. These cystic precursors include intraductal papillary neoplasms of the bile duct (IPNB) and mucinous cystic neoplasms of the liver (MCN-L), and bear striking pathologic resemblance to corresponding cystic neoplastic precursors within the pancreas. This review examines the salient clinical, gross, microscopic and molecular features of IPNBs and MCN-Ls, and, in particular, provides histopathologic comparison to their pancreatic counterparts. Considering these neoplasms may be diagnostically challenging, we also discuss other hepatic lesions within the differential diagnosis, and the potential for molecular methods to improve their preoperative evaluation and the early detection of cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Cistadenocarcinoma Mucinoso/patologia , Neoplasias Hepáticas/patologia , Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico , Cistadenocarcinoma Mucinoso/diagnóstico , Diagnóstico Diferencial , Humanos , Neoplasias Hepáticas/diagnóstico
19.
Artigo em Inglês | MEDLINE | ID: mdl-33278573

RESUMO

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

20.
Am J Surg Pathol ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33284191

RESUMO

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

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