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The Journal of Pathology. Clinical... Jul 2024Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells...
Evidence for the tumour-supporting capacities of the tumour stroma has accumulated rapidly in colorectal cancer (CRC). Tumour stroma is composed of heterogeneous cells and components including cancer-associated fibroblasts (CAFs), small vessels, immune cells, and extracellular matrix proteins. The present study examined the characteristics of CAFs and collagen, major components of cancer stroma, by immunohistochemistry and Sirius red staining. The expression status of five independent CAF-related or stromal markers, decorin (DCN), fibroblast activation protein (FAP), podoplanin (PDPN), alpha-smooth muscle actin (ACTA2), and collagen, and their association with clinicopathological features and clinical outcomes were analysed. Patients with DCN-high tumours had a significantly worse 5-year survival rate (57.3% versus 79.0%; p = 0.044). Furthermore, hierarchical clustering analyses for these five markers identified three groups that showed specific characteristics: a solid group (cancer cell-rich, DCNPDPN); a PDPN-dominant group (DCNPDPN); and a DCN-dominant group (DCNPDPN), with a significant association with patient survival (p = 0.0085). Cox proportional hazards model identified the PDPN-dominant group (hazard ratio = 0.50, 95% CI = 0.26-0.96, p = 0.037) as a potential favourable factor compared with the DCN-dominant group. Of note, DCN-dominant tumours showed the most advanced pT stage and contained the lowest number of CD8+ and FOXP3+ immune cells. This study has revealed that immunohistochemistry and special staining of five stromal factors with hierarchical clustering analyses could be used for the prognostication of patients with CRC. Cancer stroma-targeting therapies may be candidate treatments for patients with CRC.
Topics: Humans; Colorectal Neoplasms; Male; Female; Biomarkers, Tumor; Cancer-Associated Fibroblasts; Aged; Middle Aged; Cluster Analysis; Immunohistochemistry; Tumor Microenvironment; Prognosis; Membrane Glycoproteins; Stromal Cells; Decorin; Adult; Aged, 80 and over; Kaplan-Meier Estimate
PubMed: 38890810
DOI: 10.1002/2056-4538.12386 -
Nature Communications Jun 2024Siglec-6 is a lectin receptor with restricted expression in the placenta, mast cells and memory B-cells. Although Siglec-6 is expressed in patients with chronic...
Siglec-6 is a lectin receptor with restricted expression in the placenta, mast cells and memory B-cells. Although Siglec-6 is expressed in patients with chronic lymphocytic leukemia (CLL), its pathophysiological role has not been elucidated. We describe here a role for Siglec-6 in migration and adhesion of CLL B cells to CLL- bone marrow stromal cells (BMSCs) in vitro and compromised migration to bone marrow and spleen in vivo. Mass spectrometry analysis revealed interaction of Siglec-6 with DOCK8, a guanine nucleotide exchange factor. Stimulation of MEC1-002 CLL cells with a Siglec-6 ligand, sTn, results in Cdc42 activation, WASP protein recruitment and F-actin polymerization, which are all associated with cell migration. Therapeutically, a Siglec-6/CD3-bispecific T-cell-recruiting antibody (T-biAb) improves overall survival in an immunocompetent mouse model and eliminates CLL cells in a patient derived xenograft model. Our findings thus reveal a migratory role for Siglec-6 in CLL, which can be therapeutically targeted using a Siglec-6 specific T-biAb.
Topics: Leukemia, Lymphocytic, Chronic, B-Cell; Humans; Animals; Cell Movement; Cell Adhesion; Lectins; Mice; Antigens, CD; Female; B-Lymphocytes; Antigens, Differentiation, Myelomonocytic; Cell Line, Tumor; Mesenchymal Stem Cells; Male; Xenograft Model Antitumor Assays
PubMed: 38890323
DOI: 10.1038/s41467-024-48678-3 -
Cancer Medicine Jun 2024Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for...
INTRODUCTION
Therapy-induced senescent cancer and stromal cells secrete cytokines and growth factors to promote tumor progression. Therefore, senescent cells may be novel targets for tumor treatment. Near-infrared photoimmunotherapy (NIR-PIT) is a highly tumor-selective therapy that employs conjugates of a molecular-targeting antibody and photoabsorber. Thus, NIR-PIT has the potential to be applied as a novel senolytic therapy. This study aims to investigate the efficacy of NIR-PIT treatment on senescent cancer and stromal cells.
METHODS
Two cancer cell lines (human lung adenocarcinoma A549 cells and human pancreatic cancer MIA PaCa-2 cells) and two normal cell lines (mouse fibroblast transfected with human epidermal growth factor receptor 2 [HER2] cells and human fibroblast WI38 cells) were used. The cytotoxicity of NIR-PIT was evaluated using anti-epidermal growth factor receptor (EGFR) antibody panitumumab and anti-HER2 antibody transtuzumab.
RESULTS
Cellular senescence was induced in A549 and MIA PaCa-2 cells by 10 Gy γ-irradiation. The up-regulation of cellular senescence markers and characteristic morphological changes in senescent cells, including enlargement, flattening, and multinucleation, were observed in cancer cells after 5 days of γ-irradiation. Then, NIR-PIT targeting EGFR was performed on these senescent cancer cells. The NIR-PIT induced morphological changes, including bleb formation, swelling, and the inflow of extracellular fluid, and induced a significant decrease in cellular viability. These results suggested that NIR-PIT may induce cytotoxicity using the same mechanism in senescent cancer cells. In addition, similar morphological changes were also induced in radiation-induced senescent 3T3-HER2 fibroblasts by NIR-PIT targeting human epidermal growth factor receptor 2.
CONCLUSION
NIR-PIT eliminates both senescent cancer and stromal cells in vitro suggesting it may be a novel strategy for tumor treatment.
Topics: Humans; Cellular Senescence; Animals; Mice; Immunotherapy; Stromal Cells; Phototherapy; ErbB Receptors; Cell Line, Tumor; Infrared Rays; Receptor, ErbB-2; Lung Neoplasms; Trastuzumab; Panitumumab; A549 Cells; Gamma Rays
PubMed: 38888415
DOI: 10.1002/cam4.7381 -
BMJ Case Reports Jun 2024Drug-induced pleural effusion is one of the rare causes of exudative pleural effusion and a high index of suspicion is necessary to lead to early diagnosis. We hereby...
Drug-induced pleural effusion is one of the rare causes of exudative pleural effusion and a high index of suspicion is necessary to lead to early diagnosis. We hereby present the case of a young male in his late 30s, known case of metastatic gastrointestinal stromal tumour on sunitinib therapy, who presented with right-sided mild pleural effusion. Diagnostic thoracentesis showed the effusion to be a monomorphic exudate with low adenosine deaminase, which was negative for malignant cells on cytopathology. A contrast-enhanced CT chest revealed an enlarged lymph node (LN) at the 4R station, cytological analysis of which was suggestive of reactive lymphoid hyperplasia. Infective workup of the LN aspirate and bronchoalveolar lavage taken from the right middle lobe was negative. After systematically excluding the usual causes of exudative pleural effusion, sunitinib was considered to be a possible cause and was, therefore, withheld. A repeat chest X-ray after 3 weeks of stopping the drug showed resolution of the pleural effusion.
Topics: Humans; Male; Sunitinib; Pleural Effusion; Adult; Antineoplastic Agents; Gastrointestinal Stromal Tumors; Tomography, X-Ray Computed; Thoracentesis; Indoles
PubMed: 38885996
DOI: 10.1136/bcr-2023-257191 -
Gan To Kagaku Ryoho. Cancer &... May 2024An 80-year-old male patient presented with a 2.5 cm-sized submucosal tumor on the greater curvature side of the upper gastric body during an endoscopic examination in...
An 80-year-old male patient presented with a 2.5 cm-sized submucosal tumor on the greater curvature side of the upper gastric body during an endoscopic examination in 200X. We diagnosed gastric GIST by biopsy and performed laparoscopic- assisted partial gastrectomy. Imatinib was started as postoperative adjuvant therapy, but was discontinued after 1 month due to eyelid edema. The patient was followed up with a contrast-enhanced CT scan and a PET-CT scan. A 7 cm-sized mass in the gastrosplenic region was discovered on a 200X+7 years CT scan; this mass was thought to be possible recurrence of peritoneal dissemination. The patient did not want to undergo surgery or drug treatment, and was followed up. Five months later he complained of abdominal pain. The CT scan showed that the mass had shrunk slightly, but a small amount of ascites was observed, and tumor rupture was suspected. Therefore, we performed resection of the tumor in the office. Numerous disseminated nodules were found in the intra-abdominal cavity. Pathological examination revealed recurrence of GIST, and the patient was started on imatinib 200 mg/day. The dose was temporarily increased to 300 mg/day, but was reduced again to 200 mg/day 1 month later due to eyelid edema. Thereafter, the dose was temporarily discontinued due to stomatitis, and from 200X+8 years, 200 mg/day was administered for 2 weeks and then discontinued for 2 weeks. At present, 14 years after the first surgery and 6 years after recurrence, he remains alive thanks to imatinib continuation.
Topics: Humans; Male; Gastrointestinal Stromal Tumors; Stomach Neoplasms; Aged, 80 and over; Imatinib Mesylate; Recurrence; Gastrectomy; Antineoplastic Agents; Time Factors; Combined Modality Therapy
PubMed: 38881066
DOI: No ID Found -
Arkhiv Patologii 2024Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved...
BACKGROUND
Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC).
OBJECTIVE
To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results.
MATERIAL AND METHODS
The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications.
RESULTS
The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; =0.027) and estrogen receptor expression level (R=0.211; =0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (=0.037).
CONCLUSION
Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.
Topics: Humans; Lymphocytes, Tumor-Infiltrating; Triple Negative Breast Neoplasms; Female; Middle Aged; Adult; Aged; Prognosis; Receptors, Estrogen; Biomarkers, Tumor; Receptor, ErbB-2; Disease-Free Survival
PubMed: 38881000
DOI: 10.17116/patol2024860315 -
Biochemistry. Biokhimiia May 2024Immune system and bone marrow stromal cells play an important role in maintaining normal hematopoiesis. Lymphoid neoplasia disturbs not only development of immune cells,...
Immune system and bone marrow stromal cells play an important role in maintaining normal hematopoiesis. Lymphoid neoplasia disturbs not only development of immune cells, but other immune response mechanisms as well. Multipotent mesenchymal stromal cells (MSCs) of the bone marrow are involved in immune response regulation through both intercellular interactions and secretion of various cytokines. In hematological malignancies, the bone marrow stromal microenvironment, including MSCs, is altered. Aim of this study was to describe the differences of MSCs' immunological function in the patients with acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). In ALL, malignant cells arise from the early precursor cells localized in bone marrow, while in DLBCL they arise from more differentiated B-cells. In this study, only the DLBCL patients without bone marrow involvement were included. Growth parameters, surface marker expression, genes of interest expression, and secretion pattern of bone marrow MSCs from the patients with ALL and DLBCL at the onset of the disease and in remission were studied. MSCs from the healthy donors of corresponding ages were used as controls. It has been shown that concentration of MSCs in the bone marrow of the patients with ALL is reduced at the onset of the disease and is restored upon reaching remission; in the patients with DLBCL this parameter does not change. Proliferative capacity of MSCs did not change in the patients with ALL; however, the cells of the DLBCL patients both at the onset and in remission proliferated significantly faster than those from the donors. Expression of the membrane surface markers and expression of the genes important for differentiation, immunological status maintenance, and cytokine secretion differed significantly in the MSCs of the patients from those of the healthy donors and depended on nosology of the disease. Secretomes of the MSCs varied greatly; a number of proteins associated with immune response regulation, differentiation, and maintenance of hematopoietic stem cells were depleted in the secretomes of the cells from the patients. Lymphoid neoplasia leads to dramatic changes in the functional immunological status of MSCs.
Topics: Humans; Mesenchymal Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Adult; Female; Middle Aged; Bone Marrow Cells; Cell Proliferation; Young Adult
PubMed: 38880649
DOI: 10.1134/S0006297924050092 -
Seminars in Radiation Oncology Jul 2024Treating radioresistant and bulky tumors is challenging due to their inherent resistance to standard therapies and their large size. GRID and lattice spatially... (Review)
Review
Treating radioresistant and bulky tumors is challenging due to their inherent resistance to standard therapies and their large size. GRID and lattice spatially fractionated radiation therapy (simply referred to GRID RT and LRT) offer promising techniques to tackle these issues. Both approaches deliver radiation in a grid-like or lattice pattern, creating high-dose peaks surrounded by low-dose valleys. This pattern enables the destruction of significant portions of the tumor while sparing healthy tissue. GRID RT uses a 2-dimensional pattern of high-dose peaks (15-20 Gy), while LRT delivers a three-dimensional array of high-dose vertices (10-20 Gy) spaced 2-5 cm apart. These techniques are beneficial for treating a variety of cancers, including soft tissue sarcomas, osteosarcomas, renal cell carcinoma, melanoma, gastrointestinal stromal tumors (GISTs), pancreatic cancer, glioblastoma, and hepatocellular carcinoma. The specific grid and lattice patterns must be carefully tailored for each cancer type to maximize the peak-to-valley dose ratio while protecting critical organs and minimizing collateral damage. For gynecologic cancers, the treatment plan should align with the international consensus guidelines, incorporating concurrent chemotherapy for optimal outcomes. Despite the challenges of precise dosimetry and patient selection, GRID RT and LRT can be cost-effective using existing radiation equipment, including particle therapy systems, to deliver targeted high-dose radiation peaks. This phased approach of partial high-dose induction radiation therapy with standard fractionated radiation therapy maximizes immune modulation and tumor control while reducing toxicity. Comprehensive treatment plans using these advanced techniques offer a valuable framework for radiation oncologists, ensuring safe and effective delivery of therapy for radioresistant and bulky tumors. Further clinical trials data and standardized guidelines will refine these strategies, helping expand access to innovative cancer treatments.
Topics: Humans; Neoplasms; Dose Fractionation, Radiation; Radiation Tolerance; Radiotherapy Planning, Computer-Assisted
PubMed: 38880540
DOI: 10.1016/j.semradonc.2024.05.002 -
Molecular Biology Reports Jun 2024Background The incidence of various types of cancers, including leukemia, is on the rise and many challenges in both drug resistance and complications related to...
Background The incidence of various types of cancers, including leukemia, is on the rise and many challenges in both drug resistance and complications related to chemotherapy appeared. Recently, the development and application of extracellular vesicles (EV) such as exosomes in the management of cancers, especially leukemia, holds great significance. In this article, we extracted exosomes from NALM6 cells and assessed their regulatory effects on proliferation and apoptosis in mesenchymal stem cells (MSCs). Method and result We first verified the exosomes using various techniques, including flow cytometry, transient electron microscopy, dynamic light scattering (DLS), and BCA protein assay. Then MTT analysis and flowcytometry (apoptosis and cell cycle assay) besides gene expressions were employed to determine the state of MSC proliferations. The results indicated that exosome-specific pan markers like CD9, CD63, and CD81 were present. Through DLS, we found out that the mean size of the exosomes was 89.68 nm. The protein content was determined to be 956.292 µg/ml. Analysis of MTT, flow cytometry (cell cycle and apoptosis assay), and RT-qPCR showed that in the dose of 50 µg/ml the proliferation of MSCs was increased significantly (p-value < 0.05). Conclusion All these data showed that exosomes use several signaling pathways to increase the MSCs' proliferation and drug resistance, ultimately leading to high mortalities and morbidities of acute lymphoblastic leukemia.
Topics: Exosomes; Mesenchymal Stem Cells; Humans; Cell Proliferation; Apoptosis; Cell Line, Tumor; Tetraspanin 29; Cell Cycle; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tetraspanin 30; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 38874800
DOI: 10.1007/s11033-024-09674-4 -
Radiology. Imaging Cancer Jul 2024Purpose To determine whether metrics from mean apparent propagator (MAP) MRI perform better than apparent diffusion coefficient (ADC) value in assessing the tumor-stroma...
Purpose To determine whether metrics from mean apparent propagator (MAP) MRI perform better than apparent diffusion coefficient (ADC) value in assessing the tumor-stroma ratio (TSR) status in breast carcinoma. Materials and Methods From August 2021 to October 2022, 271 participants were prospectively enrolled (ClinicalTrials.gov identifier: NCT05159323) and underwent breast diffusion spectral imaging and diffusion-weighted imaging. MAP MRI metrics and ADC were derived from the diffusion MRI data. All participants were divided into high-TSR (stromal component < 50%) and low-TSR (stromal component ≥ 50%) groups based on pathologic examination. Clinicopathologic characteristics were collected, and MRI findings were assessed. Logistic regression was used to determine the independent variables for distinguishing TSR status. The area under the receiver operating characteristic curve (AUC) and sensitivity, specificity, and accuracy were compared between the MAP MRI metrics, either alone or combined with clinicopathologic characteristics, and ADC, using the DeLong and McNemar test. Results A total of 181 female participants (mean age, 49 years ± 10 [SD]) were included. All diffusion MRI metrics differed between the high-TSR and low-TSR groups ( < .001 to = .01). Radial non-Gaussianity from MAP MRI and lymphovascular invasion were significant independent variables for discriminating the two groups, with a higher AUC (0.81 [95% CI: 0.74, 0.87] vs 0.61 [95% CI: 0.53, 0.68], < .001) and accuracy (138 of 181 [76%] vs 106 of 181 [59%], < .001) than that of the ADC. Conclusion MAP MRI may serve as a better approach than conventional diffusion-weighted imaging in evaluating the TSR of breast carcinoma. MR Diffusion-weighted Imaging, MR Imaging, Breast, Oncology ClinicalTrials.gov Identifier: NCT05159323 © RSNA, 2024.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Prospective Studies; Carcinoma, Ductal, Breast; Diffusion Magnetic Resonance Imaging; Sensitivity and Specificity; Adult; Breast; Aged; Magnetic Resonance Imaging
PubMed: 38874529
DOI: 10.1148/rycan.230165