Search Results (39)

Src homology 2-domain containing protein tyrosine phosphatase 2 (SHP2), encoded by the Ptpn11 gene (Tyrosine-protein phosphatase non-receptor type 11), is a key downstream effector of PD-1/PD-L1 signaling and is likely important, in addition to immune modulation, in tumor development and vascular homeostasis. SHP2 conveys PD-1 mediated inhibitory signaling in T cells, and is emerging as a therapeutic target. Importantly, there is an association between immune checkpoint inhibitors (ICIs), immune-related adverse events (irAEs), and cardiovascular complications, underscoring the need to understand SHP2’s role in these processes. This review aims to summarize current knowledge on SHP2/PTPN11 biology, its role in immune regulation, cancer progression, and vascular homeostasis, and to discuss emerging therapeutic strategies targeting this pathway. The concept of using SHP2 inhibitors with immune checkpoint inhibitors (ICIs) is being investigated to address ICI resistance and to improve anti-tumor efficacy substantially. SHP2 is also being studied in non-cancer cell contexts, and signaling responses can differ by large magnitudes depending on the biological context and stimuli. Under normal circumstances, SHP2 promotes vascular homeostasis in endothelial cells (ECs) and myeloid cells and inhibits inflammation, and the reduction in SHP2 activity by oxidative stress, such as in atherosclerosis or diabetes, upregulates inflammation. In contrast, in response to radiation, the fibrotic response and subsequent lung injury were increased by endothelial SHP2 induction via Notch-Jag1 signaling. Vascular smooth muscle cells SHP2 act as a pro-atherogenic effector by enhancing ERK/MAPK signaling, and the upregulation of mitochondria localized SHP2 can also induce cellular senescence-associated inflammation by upregulating mitochondrial reactive oxygen species. Taken together, the two opposite signaling effects of SHP2 suggest that both the immune and vascular system responses appear to be more modulated by the redox, cell, and compartment-specific signaling of SHP2. More studies are needed for mitigating cardiovascular toxicity to patients, particularly with ICI-based treatment regimens. Full article

Heterotopic ossification (HO) refers to the pathological formation of bone in soft tissues, typically following trauma, surgical procedures, or as a result of genetic disorders. Notably, injuries to the central nervous system significantly increase the risk of HO, a condition referred to as neurogenic HO (NHO). This review outlines the cellular and molecular mechanisms driving HO, focusing on the inflammatory response, progenitor cell reprogramming, and current treatment strategies. HO is primarily fuelled by a prolonged and dysregulated inflammatory response, characterized by sustained expression of osteoinductive cytokines secreted by M1 macrophages. These cytokines promote the aberrant differentiation of fibro-adipogenic progenitor cells (FAPs) into osteoblasts, leading to ectopic mineralization. Additional factors such as hypoxia, BMP signalling, and mechanotransduction pathways further contribute to extracellular matrix (ECM) remodelling and osteogenic reprogramming of FAPs. In the context of NHO, neuroendocrine mediators enhance ectopic bone formation by influencing both local inflammation and progenitor cell fate decisions. Current treatment options such as nonsteroidal anti-inflammatory drugs (NSAIDs), radiation therapy, and surgical excision offer limited efficacy and are associated with significant risks. Novel therapeutic strategies targeting inflammation, neuropeptide signalling, and calcium metabolism may offer more effective approaches to preventing or mitigating HO progression. Full article

Background: Desmoid tumors (DTs) are rare, non-metastatic but locally aggressive connective tissue neoplasms. While standard treatments include surgery, radiation, and ablation, current guidelines advocate active surveillance unless tumors progress or symptoms worsen. Cryotherapy has shown promise in treating DTs; however, its application in rectus abdominis DTs has been limited due to proximity to critical intra-abdominal structures. Methods: This case series describes a novel approach involving laparoscopic-assisted cryoablation in three patients with rectus abdominis DTs. Laparoscopic visualization was employed to improve tumor localization and procedural safety during percutaneous cryoablation. Results: The average tumor size was 7.4 cm, and a mean of 14 cryoprobes were used per case. All patients experienced complete symptom resolution. One patient developed a complication—injury to the inferior epigastric artery—requiring embolization. Follow-up imaging at three months showed significant tumor shrinkage and necrosis in two patients. The third patient had increased lesion volume due to post-procedural hematoma, although radiological markers of cryoablation efficacy were present. Conclusions: Laparoscopic-assisted cryoablation appears to be a feasible and effective technique for treating rectus abdominis DTs, providing symptom relief and favorable early tumor response. Further studies are warranted to evaluate long-term outcomes and validate this approach in broader clinical settings. Full article

The clinicopathological and molecular features of synchronous parathyroid carcinoma (PC) and thyroid carcinoma in a male patient are presented. At 11, he received mantle field radiotherapy for Hodgkin lymphoma. He had a 26-year adulthood history of recurrent nephrolithiasis treated five times with lithotripsy. At 52, he was referred to our clinic for hypercalcemia. Primary hyperparathyroidism was diagnosed (calcium: 3.46 mmol/L, parathormone: 150 pmol/L, preserved renal function, nephrolithiasis, and osteoporosis). Neck ultrasound revealed a 41 × 31 × 37 mm nodule in the left thyroid and smaller nodules in the right thyroid. Enlarged cervical lymph nodes were not observed. The large nodule was interpreted as parathyroid adenoma on 99Tc-pertechnetate scintigraphy/99Tc-MIBI scintigraphy with SPECT/CT. Total left-sided and subtotal right-sided thyroidectomy were performed. Histopathology confirmed locally invasive, low-grade PC (pT2; positive for parafibromin and E-cadherin, negative for galectin-3 and PGP9.5; wild-type expression for p53 and retinoblastoma protein; Ki-67 index 10%) and incidental papillary thyroid carcinoma (pT1b). Genetic profiling revealed no loss in CDC73, MEN1, CCND1, PIK3CA, CDH1, RB1, and TP53 genes. Deletions in CDKN2A, LATS1, ARID1A, ARID1B, RAD54L, and MUTYH genes and monosomies in nine chromosomes were identified. The tumor mutational burden and genomic instability score were low, and the tumor was microsatellite-stable. The thyroid carcinoma exhibited a TRIM24::BRAF fusion. Following surgery, the parathormone and calcium levels had normalized, and the patient underwent radioiodine treatment for thyroid cancer. The follow-up of 14 months was eventless. In summary, the clinical, laboratory, and imaging features of hyperparathyroidism taken together could have suggested malignancy, then confirmed histologically. The synchronous carcinomas were most likely caused by irradiation treatment diagnosed 41 years after exposure. It seems that the radiation injury initially induced parathyroid adenoma in young adulthood, which underwent a malignant transformation around age fifty. Full article

Background/Objectives: Pre-operative radiation (Pre-RT) decreases local recurrence following soft tissue sarcoma (STS) resection but carries the risk of wound healing complications (WHCs). This study evaluated skin specimens and clinical characteristics of STS patients to (1) compare patients with and without Pre-RT, (2) compare Pre-RT patients with and without WHCs, and (3) explore associations between clinical characteristics and WHCs. Methods: This retrospective study included 54 adults who underwent STS resection with primary closure (Pre-RT n = 30). A pathologist who was blinded to the clinical outcomes evaluated the skin specimens microscopically. Results: Irradiated skin had lower vessel density and was more likely to lack hair follicles and sebaceous glands, consistent with the effects of radiation. Irradiated skin was also more likely to include plasma cells. Irradiated skin demonstrated higher mean TAZ H-scores; however, within the Pre-RT subset, those patients who developed WHCs demonstrated comparatively lower TAZ. Conclusions: This novel finding may suggest that higher TAZ in irradiated skin reflects a response to injury but that comparatively lower TAZ in irradiated skin might contribute to WHCs. Future studies should consider more focused evaluation of TAZ in STS resections with Pre-RT as they may help to predict WHCs when used in combination with other histologic factors and could suggest a therapeutic target. Full article

Currently, there are no U.S. Food and Drug Administration (FDA)-approved medical countermeasures (MCMs) for radiation combined injury (RCI), partially due to limited understanding of its mechanisms. Our previous research suggests that endothelial dysfunction may contribute to a poor prognosis of RCI. In this study, we demonstrated an increased risk of mortality, body weight loss, and delayed skin wound healing in RCI mice compared to mice with skin wounds alone or radiation injury (RI) 30 days post-insult. Furthermore, we evaluated biomarkers of endothelial dysfunction, inflammation, and impaired wound healing in mice at early time points after RCI. Mice were exposed to 9.0 Gy total-body irradiation (TBI) followed by skin wound. Samples were collected on days 3, 7, and 14 post-TBI. Endothelial dysfunction markers were measured by ELISA, and skin wound healing was assessed histologically. Our results show that endothelial damage and inflammation are more severe and persistent in the RCI compared to the wound-alone group. Additionally, RCI impairs granulation tissue formation, reduces myofibroblast presence, and delays collagen deposition, correlating with more severe endothelial damage. TGF signaling may play a key role in this impaired healing. These findings suggest that targeting the endothelial dysfunction and TGF-β pathways may provide potential therapeutic strategies for improving delayed wound healing in RCI, which could subsequently influence outcomes such as survival after RCI. Full article

Radiation injuries, particularly those resulting from therapeutic or accidental exposure, present complex challenges for medical management. These injuries can manifest localized skin damage or extend to deeper tissues, presenting as various clinical entities that require treatment strategies, ranging from conservative management to complex surgical interventions. Radiation treatment constitutes a fundamental component of neoplastic management, with nearly two out of three oncological instances undergoing it as an element of their therapeutic strategy. The therapeutic approach to radiation injury consists of expanding prophylactic measures while maintaining the efficacy of treatment, such as conservative treatment or local debridement followed by reconstruction. The armamentarium of reconstructive methods available for plastic surgeons, from secondary healing to free tissue transfer, can be successfully applied to radiation injuries. However, the unique pathophysiological changes induced by radiation necessitate a careful and specialized approach for their application, considering the altered tissue characteristics and healing dynamics. The therapeutic strategy is guided by both the severity and progression of the injury, with the primary aim of restoring functionality and aesthetic aspects while simultaneously minimizing the risk of complications. This paper explores the various conditions encompassed by the term “radiation injury,” reviews both non-surgical and surgical therapeutic strategies for managing these injuries, and highlights the unique challenges associated with treating irradiated tissues within specific oncological contexts. Full article

Brain radiation is a crucial tool in neuro-oncology for enhancing local tumor control, but it can lead to mild-to-profound and progressive impairments in cognitive function. Radiation-induced brain injury is a significant adverse effect of radiotherapy for cranioencephalic tumors, primarily caused by indirect cellular damage through the formation of free radicals. This results in late neurotoxicity manifesting as cognitive impairment due to free radical production. The aim of this review is to highlight the role of different substances, such as drugs used in the clinical setting and antioxidants such as ascorbate, in reducing the neurotoxicity associated with radiation-induced brain injury. Currently, there is mainly preclinical and clinical evidence supporting the benefit of these interventions, representing a cost-effective and straightforward neuroprotective strategy. Full article

Background: Radiation-induced liver disease (RILD) is a severe complication arising from radiotherapy, particularly when treating abdominal malignancies such as hepatocellular carcinoma. The liver’s critical role in systemic metabolism and its proximity to other abdominal organs make it highly susceptible to radiation-induced damage. This vulnerability significantly limits the maximum safe therapeutic dose of radiation, thereby constraining the overall efficacy of radiotherapy. Among the various modalities, electron beam therapy has gained attention due to its ability to precisely target tumors while minimizing exposure to surrounding healthy tissues. However, despite its advantages, the long-term impacts of electron beam exposure on liver tissue remain inadequately understood, particularly concerning chronic injury and fibrosis driven by sustained oxidative stress. Objectives: to investigate the molecular and cellular mechanisms underlying the radioprotective effects of vitamin C in a model of radiation-induced liver disease. Methods: Male Wistar rats (n = 120) were randomly assigned to four groups: control, fractionated local electron irradiation (30 Gy), pre-treatment with vitamin C before irradiation, and vitamin C alone. The study evaluated the effects of electron beam radiation and vitamin C on liver tissue through a comprehensive approach, including biochemical analysis of serum enzymes (ALT, AST, ALP, and bilirubin), cytokine levels (IL-1β, IL-6, IL-10, and TNF-α), and oxidative stress markers (MDA and SOD). Histological and morphometric analyses were conducted on liver tissue samples collected at 7, 30, 60, and 90 days, which involved standard staining techniques and advanced imaging, including light and electron microscopy. Gene expression of Bax, Bcl-2, and caspase-3 was analyzed using real-time PCR. Results: The present study demonstrated that fractional local electron irradiation led to significant reductions in body weight and liver mass, as well as marked increases in biochemical markers of liver damage (ALT, AST, ALP, and bilirubin), inflammatory cytokines (IL-1β, IL-6, and TNF-α), and oxidative stress markers (MDA) in the irradiated group. These changes were accompanied by substantial histopathological alterations, including hepatocyte degeneration, fibrosis, and disrupted microvascular circulation. Pre-treatment with vitamin C partially mitigated these effects, reducing the severity of the liver damage, oxidative stress, and inflammation, and preserving a more favorable balance between hepatocyte proliferation and apoptosis. Overall, the results highlight the potential protective role of vitamin C in reducing radiation-induced liver injury, although the long-term benefits require further investigation. Conclusions: The present study highlights vitamin C’s potential as a radioprotective agent against electron beam-induced liver damage. It effectively reduced oxidative stress, apoptosis, and inflammation, particularly in preventing the progression of radiation-induced liver fibrosis. These findings suggest that vitamin C could enhance radiotherapy outcomes by minimizing liver damage, warranting further exploration into its broader clinical applications. Full article

Early changes in lung tissue following ionizing radiation (IR) initiate processes that may lead to either regeneration or fibrosis. Intercellular junction proteins play a crucial role in the organization and function of epithelial tissues, both under normal conditions and after injuries. Alterations in the expression and localization of these proteins can influence the fate of epithelial cells. This study aims to investigate the effects of IR on lung tissue structure, as well as on the levels and distribution of intercellular junction proteins. Wistar rats were subjected to total X-ray irradiation at doses of 2 and 10 Gy. Lung tissue samples were collected for Western blot and histological analysis 72 h post-IR. IR at doses of 2 and 10 Gy led to structural changes in lung tissue and elevated levels of E-cadherin. The 10 Gy IR resulted in increased claudin-4 and occludin in lung parenchyma, decreased claudin-8 and claudin-12 in bronchial epithelium and endothelium, and suppression of apoptosis. Data evaluation indicated that alterations in the protein composition of intercellular junctions are essential processes in lung tissue at early stages after IR, and at least some of these alterations are associated with adaptation. Full article

Skin is the largest organ and a multifunctional interface between the body and its environment. It acts as a barrier against cold, heat, injuries, infections, chemicals, radiations or other exogeneous factors, and it is also known as the mirror of the soul. The skin is involved in body temperature regulation by the storage of fat and water. It is an interesting tissue in regard to the local and transdermal application of active ingredients for prevention or treatment of pathological conditions. Topical and transdermal delivery is an emerging route of drug and cosmetic administration. It is beneficial for avoiding side effects and rapid metabolism. Many pharmaceutical, technological and cosmetic innovations have been described and patented recently in the field. In this review, the main features of skin morphology and physiology are presented and are being followed by the description of classical and novel nanoparticulate dermal and transdermal drug formulations. The biophysical aspects of the penetration of drugs and cosmetics into or across the dermal barrier and their investigation in diffusion chambers, skin-on-a-chip devices, high-throughput measuring systems or with advanced analytical techniques are also shown. The current knowledge about mathematical modeling of skin penetration and the future perspectives are briefly discussed in the end, all also involving nanoparticulated systems. Full article

Background: Moderate hypofractionated radiotherapy (MHRT) has emerged as the preferred treatment modality for localized prostate cancer based on randomized controlled studies regarding efficacy and toxicity using contemporary radiotherapy techniques. In the setting of MHRT, available data on dosimetric parameters and late rectal toxicity are limited. Aim: To present the effects of MHRT on late rectal toxicity while conducting an extensive dosimetric analysis in conjunction with rectoscopy results. Methods: This is a prospective study including patients with intermediate-risk prostate adenocarcinoma. All patients were treated with MHRT 44 Gy in 16 fractions to the seminal vesicles and to the prostate, followed by a sequential boost to the prostate alone of 16.5 Gy in 6 fractions delivered with three-dimensional conformal radiation therapy (3DCRT). Acute and late toxicity were assessed. Endoscopy was performed at baseline, every 3 months post-therapy for the first year, and every 6 months for the year after. The Vienna Rectoscopy Score (VRS) was used to assess rectal mucosal injury related to radiotherapy. Dosimetric analysis for the rectum, rectal wall, and its subsegments (upper, mid, and low 1/3) was performed. Results: Between September 2015 and December 2019, 20 patients enrolled. Grade 1 late gastrointestinal toxicity occurred in 10% of the patients, whereas 5% had a grade ≥2. Twelve months post radiotherapy: 4 (20%) patients had VRS 1; 2 (10%) patients had VRS 2; 1(5%) patient had VRS 3. 24 months post radiotherapy, VRS 1 was observed in 4 patients (20%) and VRS 2 in 3 (15%) patients. The dosimetric analysis demonstrated noticeable variations between the rectum, rectal wall, and rectal wall subsegments. The dosimetric analysis of the rectum, rectal wall, and its mid and low segments with respect to rectoscopy findings showed that the higher dose endpoints V52.17_Gy and V56.52_Gy are associated with rectal mucosal injury. Conclusions: A thorough delineation of the rectal wall and its subsegments, together with the dosimetric analysis of these structures, may reduce late rectal toxicity. Dosimetric parameters such as V52.17_Gy and V56.52_Gy were identified to have a significant impact on rectal mucosal injury; additional dose endpoint validation and its relation to late GI toxicity is needed. Full article

Extra-abdominal desmoid-type fibromatosis (EADTF) is a rare neoplastic condition of monoclonal fibroblastic proliferation characterized by local aggressiveness with a distinct tendency to recur. Although EADTF is a benign disease entity, these tumors have a tendency to infiltrate surrounding normal tissues, making it difficult to completely eliminate them without adjacent healthy tissue injury. Surgical excision of these locally aggressive tumors without clear resection margins often leads to local recurrence. The aim of this thorough review was to assess the current treatment concepts for these rare tumors. A comprehensive search of articles published in the Cochrane Library, MEDLINE (PubMed), and EMBASE databases between January 2008 and February 2023 was conducted. Surgical intervention is no longer the first-line approach for most cases; instead, strategies like active surveillance or systemic therapies are used as initial treatment options. With the exception of EADTFs situated near vital structures, a minimum of 6–12 months of active surveillance is currently advocated for, during which some disease progression may be considered acceptable. Non-surgical interventions such as radiation or cryoablation may be employed in certain patients to achieve local control. The currently preferred systemic treatment options include tyrosine kinase inhibitors, low-dose chemotherapy, and gamma-secretase inhibitors, while hormone therapy is not advised. Nonsteroidal anti-inflammatory drugs are utilized primarily for pain management. Full article

Background: Tracking the migration pathways of living cells after their introduction into a patient’s body is a topical issue in the field of cell therapy. Questions related to studying the possibility of long-term intravital biodistribution of mesenchymal stromal cells in the body currently remain open. Methods: Forty-nine laboratory animals were used in the study. Modeling of local radiation injuries was carried out, and the dynamics of the distribution of mesenchymal stromal cells labeled with [⁸⁹Zr]Zr-oxine in the rat body were studied. Results: the obtained results of the labelled cell distribution allow us to assume that this procedure could be useful for visualization of local radiation injury using positron emission tomography. However, further research is needed to confirm this assumption. Conclusions: intravenous injection leads to the initial accumulation of cells in the lungs and their subsequent redistribution to the liver, spleen, and kidneys. When locally injected into tissues, mesenchymal stromal cells are not distributed systemically in significant quantities. Full article

Metastasis to bone is a common occurrence among epithelial tumors, with a high incidence rate in the Western world. As a result, bone lesions are a significant burden on the healthcare system, with a high morbidity index. These injuries are often symptomatic and can lead to functional limitations, which in turn cause reduced mobility in patients. Additionally, they can lead to secondary complications such as pathological fractures, spinal cord compression, hypercalcemia, or bone marrow suppression. The treatment of bone metastases requires collaboration between multiple healthcare professionals, including oncologists, orthopedists, neurosurgeons, physiatrists, and radiotherapists. The primary objective of this study is to evaluate the correlation between two methods used to assess local control. Specifically, the study aims to determine if a reduction in the volume of bone lesions corresponds to better symptomatic control in the clinical management of patients, and vice versa. To achieve this objective, the study evaluates morphological criteria by comparing pre- and post-radiotherapy treatment imaging using MRI and RECIST 1.1 criteria. MRI without contrast is the preferred diagnostic imaging method, due to its excellent tolerance by patients, the absence of exposure to ionizing radiation, and the avoidance of paramagnetic contrast media side effects. This imaging modality allows for accurate assessment of bone lesions. One of the secondary objectives of this study is to identify potentially useful parameters that can distinguish patients into two classes: “good” and “poor” responders to treatment, as reported by previous studies in the literature. These parameters can be evaluated from the imaging examinations by analyzing morphological changes and radiomic features on different sequences, such as T1, STIR (short tau inversion recovery), and DWI-MRI (diffusion-weighted). Full article