Tablet-like TiO2/C nanocomposites for repeated type I sonodynamic therapy of pancreatic cancer

Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.

Download Full-text

A133 DEVELOPMENT OF TYPE 3 ACHALASIA WITH DISTANT PANCREATIC MALIGNANCY

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwz047.132 ◽

2020 ◽

Vol 3 (Supplement_1) ◽

pp. 153-155

Author(s):

K Leung ◽

F Habal ◽

M Alrukaibi ◽

L W Liu

Keyword(s):

Pancreatic Cancer ◽

Bile Duct ◽

Common Bile Duct ◽

Enteric Neurons ◽

Thoracic Esophagus ◽

Residual Pressure ◽

Type I ◽

Duodenal Stent ◽

History Of ◽

Type 3

Abstract Background Pseudoachalasia is often caused by malignant involvement at the gastroesophageal junction (GEJ) leading to dysphagia. Aims We describe a case of type 3 achalasia presenting in a woman with metastatic pancreatic cancer with no direct involvement at the GEJ, fundus or cardia. Methods A case report and literature review were performed. Results A 53-year-old woman presented with a 2-month-history of progressive abdominal pain, nausea and vomiting with a 30-pound weight loss. She had a remote history of breast cancer in remission after surgery and chemoradiation. On presentation, she denied chest pain, reflux, dysphagia or odynophagia. Abdominal exam revealed focal epigastric tenderness and jaundice. Abdominal CT showed a 6.7 x 5.8 cm conglomerate mass involving the hepatic hilum, pancreatic head, duodenum, common bile duct, and portal vein with gastric outlet and biliary obstruction. This mass was confirmed to be a pancreatic adenocarcinoma on pathology. She then underwent nasogastric tube decompression. Initial esophagogastroduodenoscopy (EGD) confirmed a stenotic area at the distal duodenal cap. A duodenal stent and common bile duct stent were placed during a second EGD. The esophagus and GEJ were unremarkable on both endoscopic exams. She was started on chemotherapy with gemcitabine and abraxane. Two weeks after her stent placement, she rapidly developed severe retrosternal squeezing discomfort and choking occurring with swallowing. CT chest and abdomen were negative for any intrathoracic and diaphragmatic involvement with stability of the mass. A barium swallow study demonstrated tertiary contractions in the thoracic esophagus with marshmallow hold-up in the distal esophagus. She then underwent a high-resolution esophageal manometry study that demonstrated an elevation of integrated residual pressure (IRP) of the lower esophageal sphincter (LES) and absence of peristalsis, with the distal 2/3rds of the esophagus showing a simultaneous and prolonged pressure front consistent with type 3 achalasia, Chicago classification v3.0 [Figure 1]. All contractions had a distal contractile integral (DCI) of >8000 mmHg-cm-s. She experienced significant symptom improvement with pinaverium bromide, a gut-specific calcium channel antagonist. A review of the literature revealed that there have been 4 English-language cases published on pseudoachalasia associated with pancreatic cancer, with all cases describing direct infiltration of pancreatic cancer in the GEJ, cardia or fundus with manometric features of type I achalasia. Conclusions We report the first case of type 3 achalasia with no evidence of direct malignant infiltration at the GEJ on radiographic and endoscopic evaluations. Possible mechanisms to explain this phenomenon include paraneoplastic antibody-mediated impairment of enteric neurons that decrease nitric oxide availability, or microscopic disease involvement at the GEJ. Funding Agencies None

Download Full-text

Abstract B28: Dynamic interplay between type I collagen signaling and invasion in pancreatic cancer

10.1158/1538-7445.panca16-b28 ◽

2016 ◽

Author(s):

Mario A. Shields ◽

Pascal Maguin ◽

Sarah L. Dallas ◽

Mikala Egeblad

Keyword(s):

Pancreatic Cancer ◽

Type I Collagen ◽

Type I ◽

Dynamic Interplay

Download Full-text

Type I Interferons in the Treatment of Pancreatic Cancer

Annals of Surgery ◽

10.1097/01.sla.0000261460.07110.f2 ◽

2007 ◽

Vol 246 (2) ◽

pp. 259-268 ◽

Cited By ~ 47

Author(s):

Giovanni Vitale ◽

Casper H. J. van Eijck ◽

Peter M. van Koetsveld Ing ◽

Joris I. Erdmann ◽

Ernst Jan M. Speel ◽

...

Keyword(s):

Pancreatic Cancer ◽

Type I Interferons ◽

Type I

Download Full-text

Gemcitabine loaded microbubbles for targeted chemo-sonodynamic therapy of pancreatic cancer

Journal of Controlled Release ◽

10.1016/j.jconrel.2018.04.018 ◽

2018 ◽

Vol 279 ◽

pp. 8-16 ◽

Cited By ~ 33

Author(s):

Heather Nesbitt ◽

Yingjie Sheng ◽

Sukanta Kamila ◽

Keiran Logan ◽

Keith Thomas ◽

...

Keyword(s):

Pancreatic Cancer ◽

Sonodynamic Therapy

Download Full-text

Pancreatic Cancer Cells Respond to Type I Collagen by Inducing Snail Expression to Promote Membrane Type 1 Matrix Metalloproteinase-dependent Collagen Invasion

Journal of Biological Chemistry ◽

10.1074/jbc.m110.195628 ◽

2011 ◽

Vol 286 (12) ◽

pp. 10495-10504 ◽

Cited By ~ 77

Author(s):

Mario A. Shields ◽

Surabhi Dangi-Garimella ◽

Seth B. Krantz ◽

David J. Bentrem ◽

Hidayatullah G. Munshi

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Type I Collagen ◽

Epithelial Mesenchymal Transition ◽

Three Dimensional ◽

Type I ◽

Collagen Gels ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Membrane Type

Pancreatic ductal adenocarcinoma (PDAC) is characterized by pronounced fibrotic reaction composed primarily of type I collagen. Although type I collagen functions as a barrier to invasion, pancreatic cancer cells have been shown to respond to type I collagen by becoming more motile and invasive. Because epithelial-mesenchymal transition is also associated with cancer invasion, we examined the extent to which collagen modulated the expression of Snail, a well known regulator of epithelial-mesenchymal transition. Relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels induced Snail. Inhibiting the activity or expression of the TGF-β type I receptor abrogated collagen-induced Snail. Downstream of the receptor, we showed that Smad3 and Smad4 were critical for the induction of Snail by collagen. In contrast, Smad2 or ERK1/2 was not involved in collagen-mediated Snail expression. Overexpression of Snail in PDAC cells resulted in a robust membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14)-dependent invasion through collagen-coated transwell chambers. Snail-expressing PDAC cells also demonstrated MT1-MMP-dependent scattering in three-dimensional collagen gels. Mechanistically, Snail increased the expression of MT1-MMP through activation of ERK-MAPK signaling, and inhibiting ERK signaling in Snail-expressing cells blocked two-dimensional collagen invasion and attenuated scattering in three-dimensional collagen. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that pancreatic cancer cells increase Snail on encountering collagen-rich milieu and suggest that the desmoplastic reaction actively contributes to PDAC progression.

Download Full-text

Collagen type I-induced Smad-interacting protein 1 expression downregulates E-cadherin in pancreatic cancer

Oncogene ◽

10.1038/sj.onc.1210012 ◽

2006 ◽

Vol 26 (16) ◽

pp. 2381-2385 ◽

Cited By ~ 76

Author(s):

Y Imamichi ◽

A König ◽

T Gress ◽

A Menke

Keyword(s):

Pancreatic Cancer ◽

Collagen Type ◽

Collagen Type I ◽

Type I ◽

Interacting Protein ◽

E Cadherin

Download Full-text

Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90356.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. G709-G717 ◽

Cited By ~ 139

Author(s):

Atsushi Masamune ◽

Kazuhiro Kikuta ◽

Takashi Watanabe ◽

Kennichi Satoh ◽

Morihisa Hirota ◽

...

Keyword(s):

Pancreatic Cancer ◽

Growth Factor ◽

Type I Collagen ◽

Stellate Cells ◽

Conditioned Media ◽

Pancreatic Stellate Cells ◽

Endothelial Cell Proliferation ◽

Type I ◽

Cell Functions ◽

Pancreatic Cancer Cells

Pancreatic cancer is characterized by excessive desmoplastic reaction and by a hypoxic microenvironment within the solid tumor mass. Chronic pancreatitis is also characterized by fibrosis and hypoxia. Fibroblasts in the area of fibrosis in these pathological settings are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have suggested that a hypoxic environment concomitantly exists not only in pancreatic cancer cells but also in surrounding PSCs. This study aimed to clarify whether hypoxia affected the cell functions in PSCs. Human PSCs were isolated and cultured under normoxia (21% O2) or hypoxia (1% O2). We examined the effects of hypoxia and conditioned media of hypoxia-treated PSCs on cell functions in PSCs and in human umbilical vein endothelial cells. Hypoxia induced migration, type I collagen expression, and vascular endothelial growth factor (VEGF) production in PSCs. Conditioned media of hypoxia-treated PSCs induced migration of PSCs, which was inhibited by anti-VEGF antibody but not by antibody against hepatocyte growth factor. Conditioned media of hypoxia-treated PSCs induced endothelial cell proliferation, migration, and angiogenesis in vitro and in vivo. PSCs expressed several angiogenesis-regulating molecules including VEGF receptors, angiopoietin-1, and Tie-2. In conclusion, hypoxia induced profibrogenic and proangiogenic responses in PSCs. In addition to their established profibrogenic roles, PSCs might play proangiogenic roles during the development of pancreatic fibrosis, where they are subjected to hypoxia.

Download Full-text

Phase II/III clinical trial with VEGFR2-epitope peptide and gemcitabine for patients with locally advanced, metastatic, or unresectable pancreatic cancer: Pegasus-PC study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.223 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 223-223 ◽

Cited By ~ 2

Author(s):

Hiroki Yamaue ◽

Masaji Tani ◽

Motoki Miyazawa ◽

Kenji Yamao ◽

Nobumasa Mizuno ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Phase I ◽

Sample Size ◽

Survival Time ◽

Phase Ii ◽

Locally Advanced ◽

Type I ◽

Unresectable Pancreatic Cancer ◽

Epitope Peptide

223 Background: Gemcitabine is a key drug for treating pancreatic cancer; however, with the limitation in clinical benefits, the development of another potent therapeutic was strongly called for. VEGF-receptor 2 (VEGFR2: Flk-1 and KDR) is an essential target for tumor angiogenesis, and we have executed a phase I clinical trial using gemcitabine and VEGFR2-peptide (Cancer Sci 2010). Based on promising phase I trial results, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been conducted (UMIN000001664). Methods: The eligibility criteria are: locally advanced, metastatic, or unresectable pancreatic cancer. Patients were allocated to either VEGFR2 peptide (OTS102) + gemcitabine group or placebo + gemcitabine in 2:1 ratio by dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test, with the weight proportional to cumulative death probability, was used for the statistical analysis under the time-lagged effect of immunotherapy. Sample size was estimated presuming the effects will be observed from the time point of 50% cumulative survival rate. Assuming a type I error alpha (two-sided) level of 5% and a power of 80% or more for 50%-60% reduction of hazard, sample size necessary was estimated as 100 patients for the active group and 50 patients for the placebo group. Results: No statistically significant survival time prolongation was observed in OTS102 add-on group (p = 0.92). However, the three-month landmark analysis revealed significant interaction between the treatment and reports of indurations or ulcerations (p = 0.005) in add-on group, and if patients survived for over three months, grade 1-2 patients had better survival than grade 0 (1-year survival: 47%(23/49) and 22%(9/44), respectively) in add-on group. Conclusions: Despite the lack of survival time prolongation by OTS102 add-on to gemcitabine therapy, patients experienced injection site indurations or ulcerations may have better survival, suggesting new prognostic factors for VEGFR2-epitope peptide. Our results indicate the possibility of epitope peptide used in cocktail therapies. Clinical trial information: UMIN000001664.

Download Full-text

A phase III trial of tumor-treating fields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC): PANOVA-3.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps448 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS448-TPS448

Author(s):

Vincent J. Picozzi ◽

Teresa Macarulla ◽

Philip Agop Philip ◽

Carlos Roberto Becerra ◽

Tomislav Dragovich

Keyword(s):

Pancreatic Cancer ◽

Overall Survival ◽

Disease Progression ◽

Objective Response ◽

Locally Advanced ◽

Phase Iii ◽

Rank Test ◽

Type I ◽

Tumor Treating Fields ◽

Local Disease

TPS448 Background: Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma. TTFields at specific frequency (150-200 kHz) are delivered via transducer arrays placed on the skin in proximity to the tumor site. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The phase 2 PANOVA study, the first trial testing TTFields in pancreatic cancer patients, demonstrated the safety and preliminary efficacy of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy and safety of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC. Methods: Patients (N = 556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150 kHz) will be delivered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%. Clinical trial information: NCT03377491.

Download Full-text