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1.
Ann Surg Oncol ; 2022 Apr 30.
Article in English | MEDLINE | ID: mdl-35501583

ABSTRACT

BACKGROUND: Lymph node metastases (LNMs) are rare in patients with soft tissue sarcoma (STS), and there is limited evidence to guide clinical management. We describe our experience with sentinel lymph node biopsy (SLNB) and lymphadenectomy in STS patients. METHODS: A single-center, retrospective review was performed for patients with STS treated with SLNB and/or lymphadenectomy from 1994 to 2018. Clinicopathologic characteristics, multimodality treatment, regional/distant recurrence-free survival (RFS), and overall survival (OS) were examined. RESULTS: Eighty-six patients underwent SLNB (n = 34) and/or lymphadenectomy (n = 60) for STS. The most frequent histologic subtypes were epithelioid, clear cell, and undifferentiated pleomorphic sarcoma. Eight of 34 (23.5%) patients had a positive SLNB with 5-year OS of 71.4% compared with 71.9% for those with a negative SLNB. Eight of the 26 SLN-negative patients (30.8%) eventually developed nodal recurrence (n = 2) and/or (n = 6) distant metastasis with an estimated 5-year OS of 50%. Of patients undergoing lymphadenectomy, estimated 5-year OS was 44.6% and median RFS was 12 months. Eight (13.3%) had distant disease at time of lymphadenectomy, 20 (33.3%) developed distant recurrence after lymphadenectomy, and 6 (10%) developed regional-only recurrence. Patients with regional-only recurrence after lymphadenectomy had an estimated 5-year OS of 66.7% compared with 29.1% for those who recurred distantly. CONCLUSIONS: Patients with positive SLNB had similar survival to those with negative SLNB. Lymphadenectomy for isolated nodal disease is associated with poor RFS but reasonable 5-year OS when recurrence is regional-only. In STS, regional disease appears clinically distinct from distant metastatic disease and has better outcomes.

2.
Front Oncol ; 12: 913736, 2022.
Article in English | MEDLINE | ID: mdl-35912209

ABSTRACT

Background: Sorafenib, a kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC) but provides only a limited survival benefit. Disulfiram (DSF), a drug for treating alcoholism and a chelator of copper (Cu), forms a complex with Cu (DSF/Cu). DSF/Cu is a potent inducer of autophagic apoptosis of cancer stem cells, which can demonstrate drug resistance. Thus, we hypothesized that DSF/Cu could increase the sensitivity of HCC cells to sorafenib by targeting hepatic cancer stem cells. Methods: The synergistic effect of DSF/Cu and sorafenib on human HCC cell lines was assessed by cell viability MTT assay. Changes in stemness gene expression in HCC cells were investigated by assessing the presence of hepatic cancer stem cells (HCSCs) (defined as ALDH+ cells) using flow cytometry, sphere formation ability as an index of in vitro tumorigenicity, and expression of stemness gene-encoded proteins by western blot. Autophagic apoptosis and the ERK signaling pathway were also assessed by western blot. Most importantly, the in vivo anti-tumor efficacy of DSF/Cu and sorafenib was tested using orthotopic HCC xenografts in mice. Results: Compared with sorafenib alone, DSF/Cu + sorafenib synergistically inhibited proliferation of all HCC cell lines, decreased the stemness of HCC cells, and increased the autophagy and apoptosis of HCC cells. The mechanism by which DSF/Cu mediated these phenomena with sorafenib was sustained activation of the ERK pathway. The combination of DSF/Cu (formed with endogenous Cu2+) and sorafenib was significantly more effective than sorafenib alone in inhibiting the growth of orthotopic HCC xenografts in mice. This in vivo anti-tumor efficacy was associated with decreased stemness in treated HCC tumors. Conclusions: DSF/Cu and sorafenib can synergistically and effectively treat HCC by targeting HCSCs in vitro and in vivo. Our data provide a foundation for clinical translation.

3.
Ther Adv Med Oncol ; 14: 17588359221083052, 2022.
Article in English | MEDLINE | ID: mdl-35251322

ABSTRACT

The treatment of malignant melanoma has drastically changed over the past decade with the advent of immune checkpoint blockade, targeted therapy with BRAF/MEK inhibition, and other novel therapies such as oncolytic virus intralesional therapy. Despite improvements in patient response rates and survival with these new treatments, there exists a large portion of patients with surgically resectable disease that are high risk for relapse. Patients with high-risk resectable melanoma account for up to 20% of newly diagnosed cases. For this high-risk group of patients, neoadjuvant therapy has many purposed advantages over adjuvant therapy, including a more robust immune response due to abundant tumor antigens at treatment initiation, the ability to assess pathologic response to therapy, tumor downstaging leading to increased disease resectability, and a potential decreased need for extensive lymphadenectomies. These findings have been backed by preclinical models and multiple neoadjuvant trials are underway. In this review, we will discuss the trials that have set the foundation for the current treatment standards and discuss the role and rationale for neoadjuvant therapy for high-risk malignant melanomas.

4.
Int J Cancer ; 150(12): 2012-2024, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35128664

ABSTRACT

Palbociclib has been evaluated in early phase trials for well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) patients, with reported median progression-free survival (PFS) of 18 weeks. Here, we report on real-world use and surgical outcomes associated with palbociclib treatment. We retrospectively reviewed 61 consecutive patients with retroperitoneal WDLPS (n = 14) or DDLPS (n = 47) treated with palbociclib monotherapy between 1 March 2016 and 28 February 2021 at The University of Texas MD Anderson Cancer Center. At palbociclib initiation, median age was 64 (interquartile range [IQR] 56-72). In WDLPS and DDLPS cohorts, the median number of prior systemic treatments was 0 (IQR 0-0) and 2 (IQR 0-4), respectively. Median number of prior surgeries was 2 (WDLPS IQR 1-2.75) and 2 (DDLPS IQR 1-3). Median PFS was 9.2 (WDLPS IQR 3.9-21.9) and 2.6 months (DDLPS IQR 2.0-6.1), with median time on treatment of 7.4 months (WDLPS IQR 3.5-14.2) and 2.7 months (DDLPS IQR 2.0-5.7). Twelve patients ultimately underwent surgical resection. Resections were macroscopically complete (R0/R1) in half (n = 6/12), among whom only one patient experienced relapse after resection (median follow-up 7.5 months). All patients who underwent macroscopically incomplete resections progressed after surgery with median time to progression of 3.3 months (IQR 2.3-4.4). Surgery after palbociclib treatment was not associated with improved overall survival. Efficacy of palbociclib monotherapy for patients with advanced WDLPS and DDLPS is disappointing. While palbociclib may have been used to delay surgery, there was no clear benefit from treatment and few patients achieved prolonged tumor control.


Subject(s)
Liposarcoma , Soft Tissue Neoplasms , Humans , Liposarcoma/drug therapy , Liposarcoma/pathology , Middle Aged , Neoplasm Recurrence, Local , Piperazines , Pyridines , Retroperitoneal Neoplasms , Retrospective Studies , Soft Tissue Neoplasms/pathology
5.
Cell Mol Gastroenterol Hepatol ; 13(5): 1483-1509, 2022.
Article in English | MEDLINE | ID: mdl-35093588

ABSTRACT

BACKGROUND & AIMS: During liver fibrosis, tissue repair mechanisms replace necrotic tissue with highly stabilized extracellular matrix proteins. Extracellular matrix stabilization influences the speed of tissue recovery. Here, we studied the expression and function of peroxidasin (PXDN), a peroxidase that uses hydrogen peroxide to cross-link collagen IV during liver fibrosis progression and regression. METHODS: Mouse models of liver fibrosis and cirrhosis patients were analyzed for the expression of PXDN in liver and serum. Pxdn-/- and Pxdn+/+ mice were either treated with carbon tetrachloride for 6 weeks to generate toxin-induced fibrosis or fed with a choline-deficient L-amino acid-defined high-fat diet for 16 weeks to create nonalcoholic fatty liver disease fibrosis. Liver histology, quantitative real-time polymerase chain reaction, collagen content, flowcytometry and immunostaining of immune cells, RNA-sequencing, and liver function tests were analyzed. In vivo imaging of liver reactive oxygen species (ROS) was performed using a redox-active iron complex, Fe-PyC3A. RESULTS: In human and mouse cirrhotic tissue, PXDN is expressed by stellate cells and is secreted into fibrotic areas. In patients with nonalcoholic fatty liver disease, serum levels of PXDN increased significantly. In both mouse models of liver fibrosis, PXDN deficiency resulted in elevated monocyte and pro-fibrolysis macrophage recruitment into fibrotic bands and caused decreased accumulation of cross-linked collagens. In Pxdn-/- mice, collagen fibers were loosely organized, an atypical phenotype that is reversible upon macrophage depletion. Elevated ROS in Pxdn-/- livers was observed, which can result in activation of hypoxic signaling cascades and may affect signaling pathways involved in macrophage polarization such as TNF-a via NF-kB. Fibrosis resolution in Pxdn-/- mice was associated with significant decrease in collagen content and improved liver function. CONCLUSION: PXDN deficiency is associated with increased ROS levels and a hypoxic liver microenvironment that can regulate recruitment and programming of pro-resolution macrophages. Our data implicate the importance of the liver microenvironment in macrophage programming during liver fibrosis and suggest a novel pathway that is involved in the resolution of scar tissue.


Subject(s)
Non-alcoholic Fatty Liver Disease , Peroxidases , Animals , Collagen/metabolism , Extracellular Matrix Proteins/metabolism , Fibrosis , Humans , Liver Cirrhosis/pathology , Macrophages/metabolism , Mice , Non-alcoholic Fatty Liver Disease/pathology , Peroxidases/genetics , Reactive Oxygen Species/metabolism
6.
Clin Adv Hematol Oncol ; 20(1): 47-55, 2022 Jan.
Article in English | MEDLINE | ID: mdl-35060962

ABSTRACT

Effective systemic therapies, including targeted BRAF/MEK inhibition and immune checkpoint blockade, have significantly changed the treatment landscape for malignant melanoma. Specifically, there have been promising clinical trial findings associated with the use of neoadjuvant therapy for clinically node-positive and oligometastatic disease, conditions that have historically been managed with up-front surgical resection when possible. This review focuses on the burgeoning field of neoadjuvant therapy for melanoma. We review the rationale for this treatment approach, summarize completed and ongoing neoadjuvant clinical trials, and contextualize these findings within the growing body of knowledge about targeted and immune checkpoint therapy. Finally, we discuss future directions for neoadjuvant trials in melanoma, with particular focus on biomarker development, treatment effect modification, novel therapeutic regimens, and evolving surgical indications for regional and oligometastatic disease.


Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Neoadjuvant Therapy , Skin Neoplasms/drug therapy
7.
Ann Surg Oncol ; 29(4): 2539-2548, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34787737

ABSTRACT

INTRODUCTION: Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. METHODS: Patients captured in the National Cancer Database (NCDB; 2004-2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. RESULTS: The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1 year, 41%; 3 years, 13%; 5 years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60 years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. CONCLUSIONS: Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.


Subject(s)
Carcinoma, Neuroendocrine , Rectal Neoplasms , Carcinoma, Neuroendocrine/surgery , Humans , Lymph Node Excision , Lymph Nodes/pathology , Male , Middle Aged , Neoplasm Staging , Prognosis , Rectal Neoplasms/pathology , Retrospective Studies
8.
J Natl Compr Canc Netw ; : 1-12, 2021 Oct 22.
Article in English | MEDLINE | ID: mdl-34678759

ABSTRACT

BACKGROUND: The optimal number of examined lymph nodes (ELNs) and the positive lymph node ratio (LNR) for potentially curable gastric cancer are not established. We sought to determine clinical benchmarks for these values using a large national database. METHODS: Demographic, clinicopathologic, and treatment-related data from patients treated using an R0, curative-intent gastrectomy registered in the National Cancer Database during 2004 to 2016 were evaluated. Patients with node-positive (pTxN+M0) disease were considered for analysis. RESULTS: A total of 22,018 patients met the inclusion criteria, with a median follow-up of 2.2 years. Mean age at diagnosis was 65.6 years, 66% were male, 68% were White, 33% of tumors were located near the gastroesophageal junction, and 29% of patients had undergone preoperative therapy. Most primary tumors (62%) were category pT3-4, 67% had a poor or anaplastic grade, and 19% had signet features. Clinical nodal staging was inaccurate compared with staging at final pathology. The mean [SD] number of nodes examined was 19 [11]. On multivariable analysis, the pN category, ELNs, and LNR were independently associated with survival (all P<.0001). Using receiver operating characteristic (ROC) analysis, an optimal ELN threshold of ≥30 was established for patients with pN3b disease and was applied to the entire cohort. Node positivity and LNR had minimal change beyond 30 examined nodes. Stage-specific LNR thresholds calculated by ROC analysis were 11% for pN1, 28% for pN2, 58% for pN3a, 64% for pN3b, 30% for total combined. By using an ELN threshold of ≥30, prognostically advantageous stage-specific LNR values could be determined for 96% of evaluated patients. CONCLUSIONS: Using a large national cancer registry, we determined that an ELN threshold of ≥30 allowed for prognostically advantageous LNRs to be achieved in 96% of patients. Therefore, ≥30 examined nodes should be considered a clinical benchmark for practice in the United States.

10.
Clin Infect Dis ; 74(6): 1081-1084, 2022 03 23.
Article in English | MEDLINE | ID: mdl-34245255

ABSTRACT

The clinical significance of severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) RNA in stool remains uncertain. We found that extrapulmonary dissemination of infection to the gastrointestinal tract, assessed by the presence of SARS-CoV-2 RNA in stool, is associated with decreased coronavirus disease 2019 (COVID-19) survival. Measurement of SARS-CoV-2 RNA in stool may have utility for clinical risk assessment.


Subject(s)
COVID-19 , SARS-CoV-2 , Feces , Gastrointestinal Tract , Humans , RNA, Viral , SARS-CoV-2/genetics
11.
Surgery ; 170(4): 1231-1239, 2021 10.
Article in English | MEDLINE | ID: mdl-34059344

ABSTRACT

BACKGROUND: We aimed to elucidate prognostic markers of node-positive gastric cancers with a focus on examined lymph nodes and lymph node ratio. METHODS: Patients treated with curative-intent gastrectomy at The University of Texas MD Anderson Cancer Center from 1995-2019 were evaluated. Patients with non-metastatic, node-positive gastric cancers were considered for analysis. RESULTS: Of 775 patients, 281 met the inclusion criteria. The mean age was 58 years, 61% were male, 51% were White, 65% received preoperative therapy, and 71% of tumors were located in the gastric body. The median overall survival was 3.6 years, and 1-, 5-, and 10-year overall survival rates were 91%, 41%, and 29%, respectively. pN3 category was associated with worse overall survival (hazard ratio 1.79, P = .001) and recurrence-free survival (hazard ratio 1.92, P = .004). Nodal burden was associated with aggressive biologic traits in primary tumors, including higher rates of lymphovascular and perineural invasion and lower preoperative therapy response rates. By receiver-operative characteristic analysis, threshold values of ≥30 examined lymph nodes and <30% lymph node ratio were most discriminant for overall survival. On adjusted analysis, positive margins, additional organ resection, <30 examined lymph nodes, and ≥30% lymph node ratio were associated with worse recurrence-free survival and overall survival. Among patients with high node burden (pN3), <30 examined lymph nodes remained significant on adjusted survival analysis. CONCLUSION: Greater than or equal to 30 examined lymph nodes and <30% lymph node ratio were significantly associated with longer recurrence-free survival and overall survival, independent of lymphadenectomy type. These prognostic benchmarks should be considered in the surgical management of gastric cancer in the United States.


Subject(s)
Benchmarking , Gastrectomy/methods , Lymph Node Excision/methods , Lymph Nodes/pathology , Neoplasm Staging , Stomach Neoplasms/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Lymph Nodes/surgery , Lymphatic Metastasis , Male , Middle Aged , Retrospective Studies , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate/trends , Texas/epidemiology
12.
Ann Surg Oncol ; 28(11): 6638-6648, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33754224

ABSTRACT

BACKGROUND: This study sought to determine prognostic markers for disease recurrence and survival in a cohort of neoadjuvant-treated, node-negative gastric cancer patients (ypT0-4N0M0). METHODS: Clinicopathologic data from patients treated with neoadjuvant therapy followed by curative-intent gastrectomy at the University of Texas MD Anderson Cancer Center from 1995 to 2017 were evaluated. Patients with AJCC TNM stage ypT0-4N0M0 were considered for analysis. RESULTS: The inclusion criteria were met by 212 patients with a mean age of 58.3 years. Of these patients, 60 % were male, 53 % were Caucasian, 87 % received chemoradiation, and 13 % received chemotherapy. The findings showed a median overall survival (OS) rate of 11.3 years, a 5-year survival rate of 72 %, and a 10-year survival rate of 57 %. During a median follow-up period of 5.5 years, 38.2 % of the patients died. In the multivariable analysis, ypT4-stage and nodal yield fewer than 16 were significantly associated with reduced OS. Cancer classified as ypT4 had more aggressive biologic traits, including lymphovascular and perineural invasion, and was treated more aggressively with total gastrectomy and additional organ resection despite frequent positive margins. Depth of invasion remained significantly associated with worse outcome after the analysis controlled for nodal yield and possible stage migration. Compared with ypT0-3 tumors, ypT4 cancers were associated with significantly more recurrences (13 % vs. 45 %; p < 0.05), and the primary modes of failure for ypT4 lesions were local recurrence and peritoneal metastases (88 % of recurrences). CONCLUSIONS: Depth of primary tumor invasion and nodal yield were significantly associated with OS among the patients with ypT0-4N0M0 gastric cancer. Serosal invasion (ypT4) was associated with a high rate of peritoneal recurrence, and trials of intraperitoneal therapy targeting these patients should be considered.


Subject(s)
Neoadjuvant Therapy , Stomach Neoplasms , Gastrectomy , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Retrospective Studies , Stomach Neoplasms/pathology , Stomach Neoplasms/therapy
13.
Sci Rep ; 11(1): 6105, 2021 03 17.
Article in English | MEDLINE | ID: mdl-33731798

ABSTRACT

Non-alcoholic steatohepatitis (NASH) is an increasing cause of chronic liver disease characterized by steatosis, inflammation, and fibrosis which can lead to cirrhosis, hepatocellular carcinoma, and mortality. Quantitative, noninvasive methods for characterizing the pathophysiology of NASH at both the preclinical and clinical level are sorely needed. We report here a multiparametric magnetic resonance imaging (MRI) protocol with the fibrogenesis probe Gd-Hyd to characterize fibrotic disease activity and steatosis in a common mouse model of NASH. Mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with advanced fibrosis. Mice fed normal chow and CDAHFD underwent MRI after 2, 6, 10 and 14 weeks to measure liver T1, T2*, fat fraction, and dynamic T1-weighted Gd-Hyd enhanced imaging of the liver. Steatosis, inflammation, and fibrosis were then quantified by histology. NASH and fibrosis developed quickly in CDAHFD fed mice with strong correlation between morphometric steatosis quantification and liver fat estimated by MRI (r = 0.90). Sirius red histology and collagen quantification confirmed increasing fibrosis over time (r = 0.82). Though baseline T1 and T2* measurements did not correlate with fibrosis, Gd-Hyd signal enhancement provided a measure of the extent of active fibrotic disease progression and correlated strongly with lysyl oxidase expression. Gd-Hyd MRI accurately detects fibrogenesis in a mouse model of NASH with advanced fibrosis and can be combined with other MR measures, like fat imaging, to more accurately assess disease burden.


Subject(s)
Contrast Media/pharmacology , Coordination Complexes/pharmacology , Gadolinium/pharmacology , Liver/diagnostic imaging , Magnetic Resonance Imaging , Non-alcoholic Fatty Liver Disease/diagnostic imaging , Animals , Diet, High-Fat/adverse effects , Disease Models, Animal , Male , Mice , Non-alcoholic Fatty Liver Disease/chemically induced
14.
J Clin Med ; 9(12)2020 Nov 25.
Article in English | MEDLINE | ID: mdl-33255794

ABSTRACT

Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality globally. Given the limited therapeutic efficacy in advanced HCC, prevention of HCC carcinogenesis could serve as an effective strategy. Patients with chronic fibrosis due to viral or metabolic etiologies are at a high risk of developing HCC. Primary prevention seeks to eliminate cancer predisposing risk factors while tertiary prevention aims to prevent HCC recurrence. Secondary prevention targets patients with baseline chronic liver disease. Various epidemiological and experimental studies have identified candidates for secondary prevention-both etiology-specific and generic prevention strategies-including statins, aspirin, and anti-diabetic drugs. The introduction of multi-cell based omics analysis along with better characterization of the hepatic microenvironment will further facilitate the identification of targets for prevention. In this review, we will summarize HCC risk factors, pathogenesis, and discuss strategies of HCC prevention. We will focus on secondary prevention and also discuss current challenges in translating experimental work into clinical practice.

15.
Clin Cancer Res ; 26(18): 5007-5018, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32611647

ABSTRACT

PURPOSE: To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC. EXPERIMENTAL DESIGN: Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101. RESULTS: In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS P = 0.028, DFS P = 0.047). CPA increased the prognostic accuracy of a multivariable logistic regression model comprised of previously established PDAC risk factors [AUC CPA (-) = 0.76, AUC CPA (+) = 0.82]. In multiple murine orthotopic PDAC models, FOLFIRINOX therapy reduced tumor weight (P < 0.05) and increased tumor fibrosis by collagen staining (P < 0.05). CM-101 MR signal was significantly increased in fibrotic tumor regions. CM-101 signal retention was also increased in the more fibrotic FOLFIRINOX-treated tumors compared with untreated controls (P = 0.027), consistent with selective probe binding to collagen. No treatment-related differences were observed with Gd-DOTA imaging. CONCLUSIONS: In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.


Subject(s)
Carcinoma, Pancreatic Ductal/therapy , Chemoradiotherapy, Adjuvant , Neoadjuvant Therapy/methods , Neoplasm Recurrence, Local/epidemiology , Pancreas/pathology , Pancreatic Neoplasms/therapy , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/mortality , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , Collagen/analysis , Collagen/metabolism , Disease-Free Survival , Female , Fibrosis , Fluorouracil/administration & dosage , Follow-Up Studies , Heterocyclic Compounds/administration & dosage , Humans , Irinotecan/administration & dosage , Leucovorin/administration & dosage , Magnetic Resonance Imaging/methods , Male , Mice , Middle Aged , Molecular Imaging/methods , Molecular Probes/administration & dosage , Neoplasm Recurrence, Local/prevention & control , Organometallic Compounds/administration & dosage , Oxaliplatin/administration & dosage , Pancreas/diagnostic imaging , Pancreas/surgery , Pancreatectomy , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Prognosis , Retrospective Studies , Survival Analysis , Xenograft Model Antitumor Assays
16.
Am J Surg ; 220(6): 1579-1585, 2020 12.
Article in English | MEDLINE | ID: mdl-32580870

ABSTRACT

BACKGROUND: The prognostic significance of the platelet (PLR) and neutrophil (NLR) to lymphocyte ratios for patients with resectable colorectal cancer liver metastases (CLM) was evaluated. METHODS: Clinicopathologic data from patients who underwent hepatectomy for CLM at two tertiary care hospitals between 1995 and 2017 were collected. Blood counts were evaluated for prognostic significance. RESULTS: 151 patients met inclusion criteria. The median age was 58 years, 44% were female, and 58% had synchronous metastases. Median number of liver metastases was 2, and 59% of patients underwent lobectomy or extended lobectomy. On multivariable analysis, NLR ≥5 (HR 2.46 [1.08-5.60 CI], p = 0.032), PLR ≥ 220 (HR 2.10 [1.04-4.23 CI], p = 0.037), and greater than 2 liver metastases (HR 2.41 [1.06-5.45 CI], p = 0.035) were associated with reduced overall survival. CONCLUSIONS: PLR ≥ 220 and NLR ≥ 5 may have utility as preoperative prognostic markers for overall survival in patients with resectable CLM.


Subject(s)
Colorectal Neoplasms/blood , Colorectal Neoplasms/mortality , Liver Neoplasms/blood , Liver Neoplasms/mortality , Lymphocytes , Neutrophils , Adult , Aged , Colorectal Neoplasms/pathology , Female , Hepatectomy , Humans , Leukocyte Count , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Male , Middle Aged , Platelet Count , Predictive Value of Tests , Prognosis , Retrospective Studies
17.
Cancer Prev Res (Phila) ; 13(6): 497-508, 2020 06.
Article in English | MEDLINE | ID: mdl-32253266

ABSTRACT

Hepatocellular carcinoma (HCC) is a highly morbid condition with lack of effective treatment options. HCC arises from chronically inflamed and damaged liver tissue; therefore, chemoprevention may be a useful strategy to reduce HCC incidence. Several reports suggest that epigallocatechin gallate (EGCG), extracted from green tea, can suppress liver inflammation and fibrosis in animal models, but its role in HCC chemoprevention is not well established. In this study, male Wistar rats were injected with diethylnitrosamine at 50 mg/kg for 18 weeks to induce cirrhosis and HCC, and EGCG was given in drinking water at a concentration of 0.02%. Clinically achievable dosing of EGCG was well-tolerated in diethylnitrosamine-injured rats and was associated with improved serum liver markers including alanine transaminase, aspartate transaminase, and total bilirubin, and reduced HCC tumor formation. Transcriptomic analysis of diethylnitrosamine-injured hepatic tissue was notable for increased expression of genes associated with the Hoshida high risk HCC gene signature, which was prevented with EGCG treatment. EGCG treatment also inhibited fibrosis progression, which was associated with inactivation of hepatic stellate cells and induction of the senescence-associated secretory phenotype. In conclusion, EGCG administered at clinically safe doses exhibited both chemopreventive and antifibrotic effects in a rat diethylnitrosamine liver injury model.


Subject(s)
Anticarcinogenic Agents/therapeutic use , Carcinoma, Hepatocellular/prevention & control , Catechin/analogs & derivatives , Cellular Senescence/drug effects , Hepatic Stellate Cells/drug effects , Liver Neoplasms, Experimental/prevention & control , Animals , Anticarcinogenic Agents/pharmacology , Biomarkers , Carcinoma, Hepatocellular/chemically induced , Catechin/pharmacology , Catechin/therapeutic use , Diethylnitrosamine , Hepatic Stellate Cells/metabolism , Liver Cirrhosis/chemically induced , Male , Phenotype , Precancerous Conditions/chemically induced , Rats , Tea/chemistry , Transcriptome
18.
Invest Radiol ; 54(11): 697-703, 2019 11.
Article in English | MEDLINE | ID: mdl-31356382

ABSTRACT

OBJECTIVES: The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats. METHODS: T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional excretion, 1-day biodistribution, and 7-day biodistribution in rats after injection of 2.0 mmol/kg [Mn]Mn-PyC3A or Gd-DOTA were quantified by Mn gamma counting or Gd elemental analysis. Imaging data were compared with a paired t test; biodistribution data were compared with an unpaired t test. RESULTS: The postinjection-preinjection increases in tumor-to-muscle contrast-to-noise ratio (ΔCNR) 3 minutes after injection of Mn-PyC3A and Gd-DOTA (mean ± standard deviation) were 17 ± 3.8 and 20 ± 4.4, respectively (P = 0.34). Liver-to-tumor ΔCNR values at 8 minutes postinjection of Mn-PyC3A and Gd-EOB-DTPA were 28 ± 9.0 and 48 ± 23, respectively (P = 0.11). Mn-PyC3A is eliminated with 85% into the urine and 15% into the feces after administration to rats. The percentage of the injected doses (%ID) of Mn and Gd recovered in tissues after 1 day were 0.32 ± 0.12 and 0.57 ± 0.12, respectively (P = 0.0030), and after 7 days were 0.058 ± 0.051 and 0.19 ± 0.052, respectively (P < 0.0001). CONCLUSIONS: Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases.


Subject(s)
Breast Neoplasms/diagnostic imaging , Contrast Media/pharmacokinetics , Diamines/pharmacokinetics , Image Enhancement/methods , Liver Neoplasms/diagnostic imaging , Magnetic Resonance Imaging/methods , Manganese Compounds/pharmacokinetics , Manganese/pharmacokinetics , Picolinic Acids/pharmacokinetics , Animals , Disease Models, Animal , Female , Gadolinium/administration & dosage , Gadolinium DTPA/pharmacokinetics , Heterocyclic Compounds/pharmacokinetics , Mice , Mice, Inbred BALB C , Organometallic Compounds/pharmacokinetics , Tissue Distribution
20.
FASEB J ; 33(6): 7103-7112, 2019 06.
Article in English | MEDLINE | ID: mdl-30884252

ABSTRACT

Farnesoid X receptor (FXR) is a nuclear receptor that has emerged as a key regulator in the maintenance of hepatic steatosis, inflammation, and fibrosis. However, the role of FXR in renal fibrosis remains to be established. Here, we investigate the effects of the FXR agonist EDP-305 in a mouse model of tubulointerstitial fibrosis via unilateral ureteral obstruction (UUO). Male C57Bl/6 mice received a UUO on their left kidney. On postoperative d 4, mice received daily treatment by oral gavage with either vehicle control (0.5% methylcellulose) or 10 or 30 mg/kg EDP-305. All animals were euthanized on postoperative d 12. EDP-305 dose-dependently decreased macrophage infiltration as measured by the F4/80 staining area and proinflammatory cytokine gene expression. EDP-305 also dose-dependently reduced interstitial fibrosis as assessed by morphometric quantification of the collagen proportional area and kidney hydroxyproline levels. Finally, yes-associated protein (YAP) activation, a major driver of fibrosis, increased after UUO injury and was diminished by EDP-305 treatment. Consistently, EDP-305 decreased TGF-ß1-induced YAP nuclear localization in human kidney 2 cells by increasing inhibitory YAP phosphorylation. YAP inhibition may be a novel antifibrotic mechanism of FXR agonism, and EDP-305 could be used to treat renal fibrosis.-Li, S., Ghoshal, S., Sojoodi, M., Arora, G., Masia, R., Erstad, D. J., Ferriera, D. S., Li, Y., Wang, G., Lanuti, M., Caravan, P., Or, Y. S., Jiang, L.-J., Tanabe, K. K., Fuchs, B. C. The farnesoid X receptor agonist EDP-305 reduces interstitial renal fibrosis in a mouse model of unilateral ureteral obstruction.


Subject(s)
Fibrosis/etiology , Fibrosis/prevention & control , Kidney Diseases/etiology , Kidney Diseases/prevention & control , Receptors, Cytoplasmic and Nuclear/agonists , Steroids/pharmacology , Ureteral Obstruction/complications , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line , Gene Expression Regulation/drug effects , Humans , Inflammation/drug therapy , Mice , Mice, Inbred C57BL , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Steroids/therapeutic use
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