Intussusception in adults is a rare surgical emergency. Unlike in children, most adult intussusceptions arise from a pathological lead point. Ileal intussusception caused by a submucosal liposarcoma is a particularly rare phenomenon. This report describes the diagnosis and management of adult ileal intussusception secondary to submucosal liposarcoma in adult to provide a reference for future clinical work. A 64-year-old female presented to the emergency department with worsening abdominal pain associated with an 8 h history of intermittent vomiting. Based on physical examination, laboratory investigations, and computed tomography, the most likely diagnosis was ileal intussusception secondary to liposarcoma. Thus, emergency laparotomy was performed. During exploration, an ileal invagination was visualised approximately 30 cm from the ileocecal valve, and a flexible polypoid mass was palpable at the lead point of the intussusception. Subsequently, the patient underwent radical resection of pathological tissues with a primary end-to-end ileal anastomosis. Histopathological examination revealed a well-differentiated submucosal liposarcoma. Postoperatively, the patient recovered uneventfully and was doing well at the 6-month follow-up in the outpatient clinic. Thus, clinicians should consider the origin of submucosal liposarcomas in adult with intussusception. Once ileal intussusception secondary to submucosal liposarcoma is diagnosed, timely radical resection is recommended.
Abstract The sialoglycoprotein podocalyxin is absent in normal pancreas but is overexpressed in pancreatic cancer and is associated with poor clinical outcome. Here, we investigate the role of podocalyxin in migration and metastasis of pancreatic adenocarcinomas using SW1990 and Pa03c as cell models. Although ezrin is regarded as a cytoplasmic binding partner of podocalyxin that regulates actin polymerization via Rac1 or RhoA, we did not detect podocalyxin–ezrin association in pancreatic cancer cells. Moreover, depletion of podocalyxin did not alter actin dynamics or modulate Rac1 and RhoA activities in pancreatic cancer cells. Using mass spectrometry, bioinformatics analysis, coimmunoprecipitation, and pull-down assays, we discovered a novel, direct binding interaction between the cytoplasmic tail of podocalyxin and the large GTPase dynamin-2 at its GTPase, middle, and pleckstrin homology domains. This podocalyxin–dynamin-2 interaction regulated microtubule growth rate, which in turn modulated focal adhesion dynamics and ultimately promoted efficient pancreatic cancer cell migration via microtubule- and Src-dependent pathways. Depletion of podocalyxin in a hemispleen mouse model of pancreatic cancer diminished liver metastasis without altering primary tumor size. Collectively, these findings reveal a novel mechanism by which podocalyxin facilitates pancreatic cancer cell migration and metastasis. Significance: These findings reveal that a novel interaction between podocalyxin and dynamin-2 promotes migration and metastasis of pancreatic cancer cells by regulating microtubule and focal adhesion dynamics.
Race disparities in the healthcare system and the resulting inequality in clinical data among different races hinder the ability to generate equitable prediction results. This study aims to reduce healthcare disparities arising from data imbalance by leveraging advanced transfer learning (TL) methods.
Abstract Anti-cancer therapies usually focus on tumor cells, but non-tumor stromal components in the tumor microenvironment also play vital roles in tumor initiation and progression, which may be the prognostic factors and potential therapeutic targets. Cancer-associated fibroblasts (CAFs) are the essential component in the tumor environment, exhibiting high heterogeneity in their cell origin and phenotype with diverse functions that influence tumor angiogenesis, immune systems, and metabolism. Single-cell RNA sequencing and genetically engineered mouse models have increased our understanding of CAF diversity, and many subtypes have been defined. However, the precise functions of these subtypes need to be studied and validated. Studies of signaling pathways and epigenetic changes in CAFs facilitate understanding of the phenotypes of CAFs and the crosstalk between tumor cells and CAFs to provide potential therapeutic targets. Some clinical trials, including phase III trials targeting CAFs, have been performed recently. However, few of these trials have generated promising results, which indicates that the complexity of CAFs in the tumor microenvironment remains largely unknown, and in-depth investigations of CAFs should be performed. This review summarizes the research on CAFs, focusing on the heterogeneity of their phenotypes and functions, specific signaling pathways, and the therapeutic strategies involving CAFs. Additionally, we briefly discuss the current technologies commonly used in CAF studies and describe the challenges and future perspectives of CAF research.
Supplementary Table from Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
Abstract Introduction: Our phase I/II human clinical trials utilizing a GM-CSF secreting allogeneic pancreas tumor vaccine (GVAX) have been shown to be safe and effective in inducing anti-tumor immune response in pancreatic adenocarcinoma patients. GVAX treated patients have demonstrated infiltration of PD-1+ T cells which is a major immunosuppressive mechanism in the tumor microenvironment. We hypothesized that the use of a PD-1 blocking antibody and GVAX will improve vaccine therapy and pancreatic cancer survival. Methods: Mice were orthotopically transplanted with 2 x 106 Panc02 pancreatic tumor cells to form liver metastases by a hemisplenectomy technique on day 0. Following tumor transplantation, wild-type or PD-1 knockout mice were treated subcutaneously with a mouse GM-CSF secreting pancreatic tumor vaccine (mouse GVAX) in combination with anti-PD-1 antibodies or IgG isotype control. GVAX was given subcutaneously to mice on days 4, 7, 14, and 21 following tumor transplantation, together with a single low-dose of Cytoxan on day 3. Anti-PD-1 antibodies or IgG were administered twice weekly starting post-operative day 3. Results: PD-1 knockout mice challenged with pancreatic liver metastases had a significant survival advantage over wild-type mice (p=0.0002). Wild-type mice showed improved survival both with anti-PD-1 antibody alone (p=0.008) or in combination with vaccine (p<0.0001) versus IgG controls. GVAX in combination with anti-PD-1 antibodies versus anti-PD-1 antibodies alone shows a statistically significant improved survival (p<0.05). Memory T cell analysis demonstrated a strong trend toward increased tumor infiltration of CD8+ effector memory T cells in the combinatorial treatment group versus vaccine alone (66.67% vs 26.47%, p= 0.1). Tumor antigen (mesothelin)-specific cytotoxic CD8+ tumor infiltrating lymphocytes were increased in the combination treatment group (GVAX and anti-PD1 therapy) versus GVAX alone (13.4% vs 5.29%). Conclusions: PD-1 blockade through monoclonal antibodies or genetic knockout in combination with vaccine result in a synergistic anti-tumor effect in a preclinical model of pancreatic cancer versus treatment with anti-PD1 alone. Additionally, anti-PD1 treatment facilitates tumor infiltration of functionally activated mesothelin specific CD8+ T cells. Anti-PD-1 blockade antibody is currently being tested in phase II clinical trials for treating chemotherapy-refractory solid tumor patients. Our study provides a strong rationale for combining PD-1 antibody with GVAX therapy for pancreatic cancer treatment. This abstract is also presented as Poster B28. Citation Format: Kevin C. Soares, Kelly Olino, Barish Edil, Donger Zhou, Anthony Wamwea, Ashley Leubner, Richard Schulick, Drew Pardoll, Elizabeth Jaffee, Lei Zheng. Granulocyte macrophage colony stimulating factor (GM-CSF) pancreas tumor vaccine in combination with blockade of PD-1 in a preclinical model of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr PR9.
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