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Radiology Case Reports Aug 2024We report a case of a 44-year-old male patient, who presented to the University Hospital of Salzburg, Austria with abdominal pain, persistent jaundice, and lack of...
We report a case of a 44-year-old male patient, who presented to the University Hospital of Salzburg, Austria with abdominal pain, persistent jaundice, and lack of appetite. Radiological work-up (CT, MRI, PET/CT) indicated a suspicious mass of the uncinate process of the pancreatic head with adjacent infiltration and regional lymphadenopathy. The differential diagnosis was between primary pancreatic cancer and focal autoimmune pancreatitis. Further laparoscopic biopsies from multiple areas, showed only fibrous scarring processes, with no malignancy. Treatment with steroids didn't give any benefits. After multiple follow-up CTs and MRs within 6 months-additional biopsies were done, which eventually demonstrated adenocarcinoma. Evidently the cancer diagnosis was much delayed and the patient started receiving chemotherapy, but radical surgery was not possible. Multiple articles and case reports can be found in the literature, that are reviewing the fact that pancreatic inflammatory processes are mimicking pancreatic tumor, but not many articles or case reports are available in the literature, where neoplastic processes are misinterpreted as inflammatory and incorrectly proven with histological examination. One of the main reasons for improper diagnosis is the desmoplastic reaction around the pancreatic malignancy. Another important aspect is the acceptance of histological diagnosis as conclusive, where no opposing arguments are specified, based on radiological criteria.
PubMed: 38881618
DOI: 10.1016/j.radcr.2024.05.025 -
Turkish Neurosurgery Jan 2024Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and...
AIM
Medulloblastomas (MBs) are the most commonly observed malignant brain tumors affecting children; they can be classified into molecular subgroups based on the 2016 and 2021 WHO classifications, as WNT-activated, SHH-activated and TP53-wild type, SHH-activated and TP53-mutant, and non-WNT/non-SHH. However, the molecular methods to determine these subgroups are not easily accessible for routine testing as they are expensive. Here, we investigated the efficacy of immunohistochemical methods to determine molecular subgroups and prognostic predictions of MB.
MATERIAL AND METHODS
β-catenin, GAB1, YAP1, filamin A and p53 were immunohistochemically stained, and MYC and MYCN fluorescent in situ hybridization (FISH) procedures were applied to 218 cases in our series.
RESULTS
Based on the histomorphological characteristics of the cases, 67.9% were deemed classic MB; 15.6% as desmoplastic/nodular medulloblastoma (DNMB); 12.8% as large cell/anaplastic (LC/A) MB; 3.7% as medulloblastoma with extensive nodularity (MBEN). Molecular characteristics revealed that 50.5% had non-WNT/non-SHH; 33.9% had SHH-activated and TP53-wildtype; 8.7% had WNT-activated; 6.9% had SHH-activated and TP53-mutant. According to the survival curves, LC/A MBs or non-WNT/non-SHH tumors showed the worst prognosis, whereas DNMBs and WNT-activated tumors showed the best prognosis. Classic MBs or SHH-activated tumors showed a moderate course. MYCN amplification was found to act as an independent poor prognostic factor in the study.
CONCLUSION
The distribution of histological subtypes and molecular subgroups, amplification rates, and prognostic data obtained through immunohistochemical methods in our study were consistent with those reported in the literature. It was therefore hypothesized that the determination of molecular subgroups by immunohistochemical methods can be useful in daily diagnostic practice, especially in centers with limited access to molecular techniques.
PubMed: 38874255
DOI: 10.5137/1019-5149.JTN.45863-23.2 -
BioRxiv : the Preprint Server For... May 2024Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC's poor prognosis and resistance to immunotherapy are attributed in part to its...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC's poor prognosis and resistance to immunotherapy are attributed in part to its dense, fibrotic tumor microenvironment (TME), which is known to inhibit immune cell infiltration. We recently demonstrated that PDAC patients with higher natural killer (NK) cell content and activation have better survival rates. However, NK cell interactions in the PDAC TME have yet to be deeply studied. We show here that NK cells are present and active in the human PDAC TME.
METHODS
We used imaging mass cytometry (IMC) to assess NK cell content, function, and spatial localization in human PDAC samples. Then, we used CellChat, a tool to infer ligand-receptor interactions, on a human PDAC scRNAseq dataset to further define NK cell interactions in PDAC.
RESULTS
Spatial analyses showed for the first time that active NK cells are present in the PDAC TME, and both associate and interact with malignant epithelial cell ducts. We also found that fibroblast-rich, desmoplastic regions limit NK cell infiltration in the PDAC TME. CellChat analysis identified that the CD44 receptor on NK cells interacts with PDAC extracellular matrix (ECM) components such as collagen, fibronectin and laminin expressed by fibroblasts and malignant epithelial cells. This led us to hypothesize that these interactions play roles in regulating NK cell motility in desmoplastic PDAC TMEs. Using 2D and 3D assays, we found that CD44 neutralization significantly increased NK cell invasion through matrix.
CONCLUSIONS
Targeting ECM-immune cell interactions may increase NK cell invasion into the PDAC TME.
PubMed: 38853982
DOI: 10.1101/2024.05.23.593868 -
BioRxiv : the Preprint Server For... May 2024Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are...
Genes encoding the RNA-binding proteins FUS, EWSR1, and TAF15 (FET proteins) are involved in chromosomal translocations in rare sarcomas. FET-rearranged sarcomas are often aggressive malignancies affecting patients of all ages. New therapies are needed. These translocations fuse the 5' portion of the FET gene with a 3' partner gene encoding a transcription factor (TF). The resulting fusion proteins are oncogenic TFs with a FET protein low complexity domain (LCD) and a DNA binding domain. FET fusion proteins have proven stubbornly difficult to target directly and promising strategies target critical co-regulators. One candidate is lysine specific demethylase 1 (LSD1). LSD1 is recruited by multiple FET fusions, including EWSR1::FLI1. LSD1 promotes EWSR1::FLI1 activity and treatment with the noncompetitive inhibitor SP-2509 blocks EWSR1::FLI1 transcriptional function. A similar molecule, seclidemstat (SP-2577), is currently in clinical trials for FET-rearranged sarcomas (NCT03600649). However, whether seclidemstat has pharmacological activity against FET fusions has not been demonstrated. Here, we evaluate the potency of seclidemstat against multiple FET-rearranged sarcoma cell lines, including Ewing sarcoma, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid liposarcoma. We also define the transcriptomic effects of seclidemstat treatment and evaluated the activity of seclidemstat against FET fusion transcriptional regulation. Seclidemstat showed potent activity in cell viability assays across FET-rearranged sarcomas and disrupted the transcriptional function of all tested fusions. Though epigenetic and targeted inhibitors are unlikely to be effective as a single agents in the clinic, these data suggest seclidemstat remains a promising new treatment strategy for patients with FET-rearranged sarcomas.
PubMed: 38826330
DOI: 10.1101/2024.05.19.594897 -
Yonsei Medical Journal Jun 2024The microenvironment of pancreatic ductal adenocarcinoma (PDAC) with extensive desmoplastic stroma contributes to aggressive cancer behavior. Angiotensin system...
PURPOSE
The microenvironment of pancreatic ductal adenocarcinoma (PDAC) with extensive desmoplastic stroma contributes to aggressive cancer behavior. Angiotensin system inhibitors (ASIs) reduce stromal fibrosis and are a promising therapeutic strategy. The purpose of this study was to examine how ASIs affected the oncological results of patients who had their PDAC removed.
MATERIALS AND METHODS
A retrospective assessment was conducted on the clinicopathological and survival data of patients who received curative resection for PDAC at Severance Hospital between January 2012 and December 2019.
RESULTS
A total of 410 participants (228 male and 182 female), with a median follow-up period of 12.8 months, were included in this study. Patients were divided into three groups, based on ASI use and history of hypertension: group 1, normotensive and never used ASI (n=210, 51.2%); group 2, ASI non-users with hypertension (n=50, 12.2%); and group 3, ASI users with hypertension (n=150, 36.6%). The three groups did not differ significantly in terms of age, sex, kind of operation, T and N stages, or adjuvant and neoadjuvant therapy. Moreover, there was no discernible difference in disease-free survival between those who used ASI and those who did not (=0.636). The 5-year overall survival (OS) rates in groups 1, 2, and 3 were 52.6%, 32.3%, and 38.0%, respectively. However, the OS rate of ASI users was remarkably higher than that of non-users (=0.016).
CONCLUSION
In patients with resected PDAC, ASI is linked to longer survival rates. Furthermore, for individuals with hypertension, ASI in conjunction with conventional chemotherapy may be an easy and successful treatment option.
Topics: Humans; Male; Female; Pancreatic Neoplasms; Middle Aged; Retrospective Studies; Aged; Carcinoma, Pancreatic Ductal; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Disease-Free Survival; Adult
PubMed: 38804026
DOI: 10.3349/ymj.2023.0399 -
Turk Patoloji Dergisi May 2024The tumor microenvironment is a heterogeneous and constantly changing territory that plays an active role in tumor formation and progression. It constantly interacts...
OBJECTIVE
The tumor microenvironment is a heterogeneous and constantly changing territory that plays an active role in tumor formation and progression. It constantly interacts with tumor cells, plays an active role in tumor development, and even appears as a parameter of prognostic importance, and the importance of the tumor microenvironment in breast cancer has been emphasized by recent studies. In this study, we aimed to retrospectively evaluate the relationship between the tumor microenvironment and prognostic parameters in invasive breast carcinomas of no special type.
MATERIAL AND METHODS
A total of 271 cases diagnosed as invasive breast carcinoma of no special type from resection materials in our center between 2007 and 2015 were included in the study. Hematoxylin-eosin stained slides with a thickness of 4-5 micrometers were evaluated in terms of tumor infiltrating lymphocytes, peritumoral and intratumoral desmoplastic reaction, intratumoral and peritumoral tumor budding, stromal features, and tumor growth pattern.
RESULTS
When parameters related to the tumor microenvironment were compared with other prognostic parameters, there was a significant relationship between TILs and tumor grade, size, stage, immunohistochemical subgroup and Ki-67 proliferation index. A significant relationship was detected between intratumoral stromal reaction and tumor grade, size, molecular subgroup and the Ki-67 proliferation index (p < 0.05). When stroma and other prognostic parameters were compared, tumors with desmoplastic stroma had higher grades and higher Ki-67 proliferation indexes, and they were observed more frequently in the triple negative molecular subgroup.
CONCLUSION
We believe that including parameters related to tumor microenvironment in breast cancer reports, which hold a prognostic and predictive importance, will contribute to patient management. Considering the fact that these can be easily evaluated from routinely used hematoxylin-eosin stained slides, this does not cause additional costs or excessive time loss.
PubMed: 38801127
DOI: 10.5146/tjpath.2024.12805 -
Frontiers in Immunology 2024Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors...
BACKGROUND
Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.
CASE PRESENTATION
We report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.
CONCLUSION
Efficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.
Topics: Humans; Male; Melanoma; Middle Aged; Immune Checkpoint Inhibitors; Immunotherapy; Skin Neoplasms; CTLA-4 Antigen; Treatment Outcome; Programmed Cell Death 1 Receptor
PubMed: 38799429
DOI: 10.3389/fimmu.2024.1369531 -
Life (Basel, Switzerland) Apr 2024Desmoplastic melanoma accounts for 5% of all cases of melanoma, but its diagnosis can be difficult due to its frequent clinical presentation with amelanotic lesions....
Desmoplastic melanoma accounts for 5% of all cases of melanoma, but its diagnosis can be difficult due to its frequent clinical presentation with amelanotic lesions. Histologically, spindled melanocytes surrounded by a collagenous stroma are observed. Compared with other types of melanoma, the desmoplastic types presents greater local aggression, and is more prone to local recurrence, but has a lower risk of lymph node metastasis. Early detection, accurate staging, and proper surgical management are the main factors associated with higher survival rates in melanoma patients. Reflectance confocal microscopy (RCM) has proven to be a valuable imaging tool in the diagnosis of skin neoplasms, being useful for orientating practitioners towards the diagnosis of melanoma and indicating the necessity of performing a diagnostic biopsy. We present the case of 52-year-old woman, who presented to the dermatology department with an irregular, dark-colored plaque in the right deltoid region. Dermoscopy showed asymmetry with an atypical network and some areas of regression. RCM revealed pagetoid cells in the upper epidermis, cell atypia, non-edged papillae, dermal inflammation, and nucleated cells in the dermis, which are highly suggestive of melanoma. A biopsy was also performed. A histopathology exam confirmed the diagnosis of superficially spreading melanoma with a desmoplastic component, and revealed a Breslow index of 0.9 mm, Clark level IV, an absence of mitoses, angiolymphatic invasion and regression, and complete excision. The CT and PET-CT scans were negative. A biopsy of the axillary sentinel lymph node was conducted, with a negative result obtained, establishing the IB stage of the disease. The patient will remain under follow-up to look for a recurrence or a new primary melanoma.
PubMed: 38792595
DOI: 10.3390/life14050574 -
Biomedicines May 2024The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics,...
The poor prognosis for pancreatic ductal adenocarcinoma (PDAC) patients is due in part to the highly fibrotic nature of the tumors that impedes delivery of therapeutics, including nanoparticles (NPs). Our prior studies demonstrated that proglumide, a cholecystokinin receptor (CCKR) antagonist, reduced fibrosis pervading PanIN lesions in mice. Here, we further detail how the reduced fibrosis elicited by proglumide achieves the normalization of the desmoplastic tumor microenvironment (TME) and improves nanoparticle uptake. One week following the orthotopic injection of PDAC cells, mice were randomized to normal or proglumide-treated water for 3-6 weeks. Tumors were analyzed ex vivo for fibrosis, vascularity, stellate cell activation, vascular patency, and nanoparticle distribution. The histological staining and three-dimensional imaging of tumors each indicated a reduction in stromal collagen in proglumide-treated mice. Proglumide treatment increased tumor vascularity and decreased the activation of cancer-associated fibroblasts (CAFs). Additionally, PANC-1 cells with the shRNA-mediated knockdown of the CCK2 receptor showed an even greater reduction in collagen, indicating the CCK2 receptors on tumor cells contribute to the desmoplastic TME. Proglumide-mediated reduction in fibrosis also led to functional changes in the TME as evidenced by the enhanced intra-tumoral distribution of small (<12 nm) Rhodamine-loaded nanoparticles. The documented in vivo, tumor cell-intrinsic anti-fibrotic effects of CCK2R blockade in both an immunocompetent syngeneic murine PDAC model as well as a human PDAC xenograft model demonstrates that CCK2R antagonists, such as proglumide, can improve the delivery of nano-encapsulated therapeutics or imaging agents to pancreatic tumors.
PubMed: 38790986
DOI: 10.3390/biomedicines12051024 -
Cells May 2024A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where... (Review)
Review
A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Identifying the molecular underpinnings for such multidirectional crosstalk among the various normal and neoplastic cell types in the TME may provide new targets and novel opportunities for therapeutic intervention. This review highlights recent concepts regarding the complexity of CAF biology in cholangiocarcinoma, a highly desmoplastic cancer. The discussion focuses on CAF heterogeneity, functionality in drug resistance, contributions to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.
Topics: Humans; Tumor Microenvironment; Cholangiocarcinoma; Cancer-Associated Fibroblasts; Disease Progression; Bile Duct Neoplasms; Animals; Signal Transduction; Drug Resistance, Neoplasm
PubMed: 38786020
DOI: 10.3390/cells13100796