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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 -
Revue Medicale Suisse Jun 2024Gastrointestinal Stromal Tumors (GISTs) account for 1 to 2% of gastrointestinal malignant tumors. They are characterized by overexpression of the tyrosine kinase (KIT)....
Gastrointestinal Stromal Tumors (GISTs) account for 1 to 2% of gastrointestinal malignant tumors. They are characterized by overexpression of the tyrosine kinase (KIT). 60% of GISTs originate in the stomach. Managing them remains complex and varies depending on several factors such as location, size, molecular biology, type of clinical presentation, and the risks/benefits of surgical treatment. Surgery remains the only curative treatment, while tyrosine kinase inhibitors have demonstrated their efficacy as systemic treatment in the perioperative context. Risk stratification for recurrence guides the choice of adjuvant treatment, with a recommended duration of 3 years for high-risk patients.
Topics: Gastrointestinal Stromal Tumors; Humans; Stomach Neoplasms; Neoplasm Recurrence, Local
PubMed: 38867560
DOI: 10.53738/REVMED.2024.20.878.1158 -
BMC Urology Jun 2024To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search...
BACKGROUND
To predict outcomes and identify potential therapeutic targets for cancers, it is critical to find novel specific biomarkers. The objective of this study was to search for and explore novel bladder cancer-associated protein biomarkers.
METHODS
A library of monoclonal antibodies (mAbs) against the JAM-ICR cell line was first generated, and clones with high affinity were selected. Hybridomas were screened using bladder cancer (BLCA) cell lines and normal cells. The target of the selected mAb was then characterized through immunoaffinity purification, western blotting, and mass spectrometry analysis. Expression of the target antigen was assessed by flow cytometry and IHC methods. Several databases were also used to evaluate the target antigen in BLCA and other types of cancers.
RESULTS
Based on screenings, a 6D6 clone was selected that recognized an isoform of beta-actin (ACTB). Our data showed that ACTB expression on different cell lines was heterogeneous and varied significantly from low to high intensity. 6D6 bound strongly to epithelial cells while showing weak to no reactivity to stromal, endothelial, and smooth muscle cells. There was no association between ACTB intensity and related prognostic factors in BLCA. In silico evaluations revealed a significant correlation between ACTB and overexpressed genes and biomarkers in BLCA. Additionally, the differential expression of ACTB in tumor and healthy tissue as well as its correlation with survival time in a number of cancers were shown.
CONCLUSIONS
The heterogeneous expression of ACTB may suggest the potential value of this marker in the diagnosis or prognosis of cancer.
Topics: Urinary Bladder Neoplasms; Humans; Antibodies, Monoclonal; Actins; Biomarkers, Tumor; Cell Line, Tumor
PubMed: 38867273
DOI: 10.1186/s12894-024-01489-6 -
Cell Reports. Medicine Jun 2024Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and...
Leptomeningeal disease (LMD) remains a rapidly lethal complication for late-stage melanoma patients. Here, we characterize the tumor microenvironment of LMD and patient-matched extra-cranial metastases using spatial transcriptomics in a small number of clinical specimens (nine tissues from two patients) with extensive in vitro and in vivo validation. The spatial landscape of melanoma LMD is characterized by a lack of immune infiltration and instead exhibits a higher level of stromal involvement. The tumor-stroma interactions at the leptomeninges activate tumor-promoting signaling, mediated through upregulation of SERPINA3. The meningeal stroma is required for melanoma cells to survive in the cerebrospinal fluid (CSF) and promotes MAPK inhibitor resistance. Knocking down SERPINA3 or inhibiting the downstream IGR1R/PI3K/AKT axis results in tumor cell death and re-sensitization to MAPK-targeting therapy. Our data provide a spatial atlas of melanoma LMD, identify the tumor-promoting role of meningeal stroma, and demonstrate a mechanism for overcoming microenvironment-mediated drug resistance in LMD.
Topics: Melanoma; Humans; Tumor Microenvironment; Meningeal Neoplasms; Stromal Cells; Animals; Cell Line, Tumor; Mice; Gene Expression Regulation, Neoplastic; Transcriptome; Gene Expression Profiling; Meninges; Drug Resistance, Neoplasm; Signal Transduction; Female
PubMed: 38866016
DOI: 10.1016/j.xcrm.2024.101606 -
Drug Development Research Jun 2024Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor...
Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription-quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high- and low-HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain- and loss-of-function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria-mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC.
Topics: Humans; Stomach Neoplasms; Apoptosis; Proto-Oncogene Proteins c-akt; Mitochondria; Cell Line, Tumor; MAP Kinase Signaling System; Down-Regulation; Cell Proliferation; Male; Female; Gene Expression Regulation, Neoplastic
PubMed: 38863387
DOI: 10.1002/ddr.22221 -
Techniques in Coloproctology Jun 2024Retrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for...
BACKGROUND
Retrorectal tumors are uncommon lesions developed in the retrorectal space. Data on their minimally invasive resection are scarce and the optimal surgical approach for tumors below S3 remains debated.
METHODS
We performed a retrospective review of consecutive patients who underwent minimally invasive resection of retrorectal tumors between 2005 and 2022 at two tertiary university hospital centers, by comparing the results obtained for lesions located above or below S3.
RESULTS
Of over 41 patients identified with retrorectal tumors, surgical approach was minimally invasive for 23 patients, with laparoscopy alone in 19, with transanal excision in 2, and with combined approach in 2. Retrorectal tumor was above S3 in 11 patients (> S3 group) and below S3 in 12 patients (< S3 group). Patient characteristics and median tumor size were not significantly different between the two groups (60 vs 67 mm; p = 0.975). Overall median operative time was 131.5 min and conversion rate was 13% without significant difference between the two groups (126 vs 197 min and 18% vs 8%, respectively; p > 0.05). Final pathology was tailgut cyst (48%), schwannoma (22%), neural origin tumor (17%), gastrointestinal stromal tumor (4%), and other (19%). The 90-day complication rates were 27% and 58% in the > S3 and < S3 groups, respectively, without severe morbidity or mortality. After a median follow-up of 3.3 years, no recurrence was observed in both groups. Three patients presented chronic pain, three anal dysfunction, and three urinary dysfunction. All were successfully managed without reintervention.
CONCLUSIONS
Minimally invasive surgery for retrorectal tumors can be performed safely and effectively with low morbidity and no mortality. Laparoscopic and transanal techniques alone or in combination may be recommended as the treatment of choice of benign retrorectal tumors, even for lesions below S3, in centers experienced with minimally invasive surgery.
Topics: Humans; Retrospective Studies; Male; Female; Middle Aged; Laparoscopy; Aged; Rectal Neoplasms; Tertiary Care Centers; Adult; Operative Time; Treatment Outcome; Transanal Endoscopic Surgery; Aged, 80 and over; Rectum
PubMed: 38860990
DOI: 10.1007/s10151-024-02938-y