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Cureus Aug 2023Radiation necrosis (RN) is caused by vascular damage and brain parenchymal injury resulting in inflammation following radiotherapy (RT) for brain metastases. The impact...
Characterization of Immune Infiltrates Associated With Radiation Necrosis in the Setting of Brain Metastases Following Stereotactic Radiosurgery and Immunotherapy: A Retrospective Cohort Analysis.
INTRODUCTION
Radiation necrosis (RN) is caused by vascular damage and brain parenchymal injury resulting in inflammation following radiotherapy (RT) for brain metastases. The impact of immunotherapy (IO) on the immune cellular microenvironment in patients' brain metastases is unknown. The objective of this study was to characterize the inflammatory microenvironment in the setting of RN compared to recurrent metastasis and determine whether IO treatment affects the cellular infiltrates.
METHODS
Adult patients with brain metastases from solid tumors who received both systemic IO and RT prior to resection of intracranial lesions were retrospectively analyzed. The resection either showed biopsy-proven RN or recurrent tumor. A group of patients who developed RN and were not on IO was reviewed as well. A total of 18 patients were categorized into one of three groups: necrosis, IO+RT; tumor, IO+RT; and necrosis, RT. Surgical specimens were stained for immune and inflammatory components and reviewed by a neuro-pathologist who remained blinded during the analysis. The presence or absence of lymphocytes, perivascular cuffs, plasma cells, macrophages, and fibrinoid vascular changes was characterized in a semiquantitative manner.
RESULTS
The median age was 61.5 years (range 37-82 years). Seventy-seven percent of primary cancers were melanoma. Patients with RN were more likely to exhibit immune infiltrates compared to patients with recurrent metastasis. Limited analysis showed 100% of patients in "necrosis, IO+RT" had quantifiable cell counts; conversely, 83.3% of patients in "tumor, IO+RT" lacked quantifiable cell counts. Additionally, 83.3% of patients in "necrosis, RT" showed immune cells, including lymphocytes, macrophages, plasma cells, and cuffing.
CONCLUSION
The immune microenvironment of brain metastasis following RT and IO showed higher levels of cell infiltrates in the RN setting versus the recurrent tumor setting. Patients who received prior IO compared to those with no IO had similar immune cell infiltrates adjacent to RN. Lower levels of immune cells in tumor recurrence following IO and RT raise the possibility that an environment lacking primed immune cells may decrease the efficacy of IO.
PubMed: 37719517
DOI: 10.7759/cureus.43528 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jul 2023Necroptosis is a cell death type mediated by receptor interacting protein 3 (RIP3)/mixed lineage kinase domain-like protein (MLKL). It has been reported that mammalian...
OBJECTIVES
Necroptosis is a cell death type mediated by receptor interacting protein 3 (RIP3)/mixed lineage kinase domain-like protein (MLKL). It has been reported that mammalian target of rapamycin plays a regulatory role in necroptosis. Eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1)-eukaryotic initiation factor 4E (eIF4E) pathway is a key down streamer of mammalian target of rapamycin. However, whether 4EBP1-eIF4E pathway is involved in necroptosis is still unknown. This study aims to investigate the changes of 4EBP1-eIF4E pathway in necroptosis.
METHODS
TNF-α/SM-164/Z-VAD-FMK (TSZ), a necroptosis inducer, was used to induce necroptosis in murine fibroblastoid cell line L929. Cell necrosis was observed under an optical microscope. Then, TSZ was added to L929 cells with and gene knockout. Propidium iodide (PI) staining was used to observe cell necrosis. Real-time fluorescence quantitative PCR and Western blotting were used to determine the mRNA and protein expression of and , respectively.
RESULTS
After treating L929 cells with TSZ, the number of necrotic cells was increased, the mRNA and protein expression levels of were significantly downregulated, and the ratio of phosphorylated 4EBP1 (p-4EBP1) to 4EBP1 was increased (<0.05 or <0.01); the mRNA expression level of was significantly upregulated, and the ratio of phosphorylated eIF4E (p-eIF4E) to eIF4E was increased (both <0.01). After knocking out and in L929 cells, PI positive necrotic cells were significantly reduced, the mRNA and protein expression levels of were significantly upregulated, and the ratio of p-4EBP1 to 4EBP1 was decreased (<0.05 or <0.01); the mRNA expression level of was significantly downregulated, and the ratio of p-eIF4E to eIF4E was decreased (both <0.01).
CONCLUSIONS
4EBP1-eIF4E pathway is activated in the RIP3/MLKL mediated-necroptosis.
Topics: Animals; Mice; Cell Line; Eukaryotic Initiation Factor-4E; Fluorescence; Necroptosis; Protein Kinases; TOR Serine-Threonine Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37724400
DOI: 10.11817/j.issn.1672-7347.2023.230153 -
International Journal of Molecular... Sep 2023Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of...
Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.
PubMed: 37762522
DOI: 10.3390/ijms241814219 -
Gland Surgery Sep 2023Autologous breast reconstruction has consistently demonstrated excellent patient satisfaction, ideal aesthetic results, and a low risk of complications. With the... (Review)
Review
Autologous breast reconstruction has consistently demonstrated excellent patient satisfaction, ideal aesthetic results, and a low risk of complications. With the increasing incidence of breast cancer diagnoses and higher reconstruction rates, surgeons encounter a broader spectrum of patients. Obese patients undergoing breast reconstruction are more likely to experience a surgical complication. While free tissue transfer carries a higher donor site complication rate, implant-based reconstruction carries a higher loss of reconstruction in this population. Additionally, autologous reconstruction consistently demonstrates better patient-reported outcomes. Oncoplastic reconstruction is an oncologically safe alternative to free tissue transfer and implant reconstruction which reduces the risk of complications and the risk of delaying adjuvant therapy. Particularly in obese patients for whom radiation is indicated based on tumor size or nodal involvement, oncoplastic reconstruction is maximally beneficial. The Goldilocks mastectomy is yet another alternative to free tissue transfer or implant reconstruction which carries an acceptable risk profile, especially when augmentation with tissue expander or implant is delayed and performed at a second stage. In patients with breast ptosis undergoing skin-sparing mastectomy, vertical skin reduction allows an acceptable aesthetic result while minimizing the risk for mastectomy flap necrosis (MFN), especially in comparison to Wise pattern skin reduction. If a nipple-sparing mastectomy (NSM) is to be performed in the setting of breast ptosis, a nipple delay or a pre-mastectomy reduction/mastopexy is the safest and most conservative approach, but can alter the timeline for primary cancer resection and therefore is predominantly performed in patients with a genetic predisposition or those undergoing a prophylactic mastectomy. Patients with obesity, breast ptosis, advanced age, active smoking history, prior radiation therapy, or abdominal procedures can carry an increased risk of complications and present a challenge to plastic surgeons. We review the most recent literature published regarding reconstruction in these patient groups and seek to provide practical information to help inform clinical decision-making and operative execution.
PubMed: 37842527
DOI: 10.21037/gs-22-710 -
International Microbiology : the... Nov 2023Recently, many efforts have been made to treat cancer using recombinant bacterial toxins and this strategy has been used in clinical trials of various cancers....
Recently, many efforts have been made to treat cancer using recombinant bacterial toxins and this strategy has been used in clinical trials of various cancers. Therapeutic DNA cancer vaccines are now considered as a promising strategy to activate the immune system against cancer. Cancer vaccines could induce specific and long-lasting immune responses against tumors. This study aimed to evaluate the antitumor potency of the SEB DNA vaccine as a new antitumor candidate against breast tumors in vivo. To determine the effect of the SEB construct on inhibiting tumor cell growth in vivo, the synthetic SEB gene, subsequent codon optimization, and embedding the cleavage sites were sub-cloned to an expression vector. Then, SEB construct, SEB, and PBS were injected into the mice. After being vaccinated, 4T1 cancer cells were injected subcutaneously into the right flank of mice. Then, the cytokine levels of IL-4 and IFN-γ were estimated by the ELISA method to evaluate the antitumor activity. The spleen lymphocyte proliferation, tumor size, and survival time were assessed. The concentration of IFN-γ in the SEB-Vac group showed a significant increase compared to other groups. The production of IL-4 in the group that received the DNA vaccine did not change significantly compared to the control group. The lymphocyte proliferation increased significantly in the mice group that received SEB construct than PBS control group (p < 0.001). While there was a meaningful decrease in tumor size (p < 0.001), a significant increase in tumor tissue necrosis (p < 0.01) and also in survival time of the animal model receiving the recombinant construct was observed. The designed SEB gene construct can be a new model vaccine for breast cancer because it effectively induces necrosis and produces specific immune responses. This structure does not hurt normal cells and is a safer treatment than chemotherapy and radiation therapy. Its slow and long-term release gently stimulates the immune system and cellular memory. It could be applied as a new model for inducing apoptosis and antitumor immunity to treat cancer.
Topics: Mice; Animals; Vaccines, DNA; Disease Models, Animal; Cancer Vaccines; Interleukin-4; Necrosis; Mice, Inbred BALB C; Neoplasms
PubMed: 36991248
DOI: 10.1007/s10123-023-00348-y -
Journal of Neurosurgery. Case Lessons Oct 2023Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs)...
Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.
BACKGROUND
Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation.
OBSERVATIONS
Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma.
LESSONS
Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.
PubMed: 37870755
DOI: 10.3171/CASE23361 -
Frontiers in Oncology 2023The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel...
The clinical success of immune checkpoint inhibitors (ICIs) has demonstrated the promise and challenges of cancer immunotherapy. There is an unmet need to develop novel cancer therapies that can provide clinical benefit for most patients with solid malignancies, which harbor innate or acquired resistance to ICIs. Interleukin-12 (IL-12) is a promising cytokine for cancer therapy given its direct stimulatory effects on innate and adaptive immunity. However, unfavorable pharmacokinetics and a narrow therapeutic index render recombinant IL-12 (rIL-12) less attractive as a cancer therapy. NHS-IL12 is a fusion protein of IL-12 and NHS76 (human IgG1) antibody engineered to target single and double stranded DNA present in necrotic areas solid tumors. In preclinical tumor models, NHS-IL12 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8 T lymphocytes, with engagement of myeloid immunity. NHS-IL12 is currently being evaluated clinically in combination with various therapeutic modalities, including chemotherapy, radiation therapy, immune checkpoint inhibition, vaccines, and epigenetic modulation. Here we review the preclinical and clinical studies involving NHS-IL12 for the treatment of solid malignancies.
PubMed: 38260854
DOI: 10.3389/fonc.2023.1321318 -
Radiation Oncology (London, England) Sep 2023In patients with nasopharyngeal cancer (NPC), radiation-induced temporal lobe injury (TLI) is the most dreaded late-stage complication following radiation therapy (RT)....
BACKGROUND
In patients with nasopharyngeal cancer (NPC), radiation-induced temporal lobe injury (TLI) is the most dreaded late-stage complication following radiation therapy (RT). We currently lack a definitive algorithmic administration for this entity. In the meantime, the pathogenesis of TLI and the mechanism-based interventions to prevent or treat this adverse effect remain unknown. To better answer the aforementioned questions, it is necessary to comprehend the intellectual foundations and prospective trends of this field through bibliometric analysis.
METHODS
Articles were gathered from the Web of Science Core Collection (WoSCC) database between 2000 and 2022. CiteSpace was utilized to create a country/institutional co-authorship network, perform dual-map analysis, and find keywords with citation bursts. VOSviewer was used to build networks based on author co-authorship, journal citation, co-citation analysis of authors, references, and journals, and keyword co-occurrence.
RESULTS
A total of 140 articles and reviews were included in the final analysis. The number of publications has steadily increased with some fluctuations over the years. The country and institution contributing most to this field are the China and Sun Yat-Sen University. Han Fei was the most prolific author, while Lee Awm was the most frequently cited. The analysis of co-occurrence revealed three clusters, including: "radiation-induced injury or necrosis in NPC," "clinical studies on chemotherapy/radiotherapy complications and survival in recurrent NPC," and "IMRT/chemotherapy outcomes and toxicities in head and neck cancer"). Most recent keyword bursts were "volume," "temporal lobe injury," "toxicities," "model," "survival," "intensity modulated radiotherapy," "induced brain injury," "head and neck cancer," and "temporal lobe."
CONCLUSION
This study provides some insights of the major areas of interest in the field of radiation-induced TLI in patients with NPC by bibliometric analyses. This study assists scholars in locating collaborators and significant literature in this field, provides guidance for publishing journals, and identifies research hotspots. This analysis acknowledges significant contributions to the discipline and encourages the scientific community to conduct additional research.
Topics: Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Prospective Studies; Neoplasm Recurrence, Local; Radiation Injuries; Bibliometrics
PubMed: 37705085
DOI: 10.1186/s13014-023-02345-x -
American Journal of Ophthalmology Case... Sep 2023To describe an atypical case of a choroidal melanoma presenting with eyelid edema, chemosis, pain and diplopia and demonstrating significant extraocular extension on...
PURPOSE
To describe an atypical case of a choroidal melanoma presenting with eyelid edema, chemosis, pain and diplopia and demonstrating significant extraocular extension on ultrasonography and neuroimaging.
OBSERVATIONS
A 69-year-old woman presented with a headache, eyelid edema, chemosis and pain in the right eye. Upon subsequent onset of diplopia, MRI of the orbits was performed and demonstrated a predominantly extraocular, intraconal mass with a small intraocular component. She was started on corticosteroids and referred to the ocular oncology service for evaluation. On fundus examination, she was noted to have a pigmented choroidal lesion consistent with melanoma, and ultrasound showed a large area of extraocular extension. Enucleation, enucleation with subsequent radiation and exenteration were discussed, and the patient requested an opinion from radiation oncology. A repeat MRI obtained by radiation oncology demonstrated a decrease in the extraocular component after corticosteroid treatment. The improvement was interpreted as suggestive of lymphoma by the radiation oncologist who recommended external beam radiation (EBRT). Fine needle aspiration biopsy was insufficient for cytopathologic diagnosis, and the patient elected to proceed with EBRT in the absence of a definitive diagnosis. Next generation sequencing revealed GNA11 and SF3B1 mutations, which supported the diagnosis of uveal melanoma and led to enucleation.
CONCLUSION AND IMPORTANCE
Choroidal melanoma may present with pain and orbital inflammation secondary to tumor necrosis, which may delay diagnosis and decrease the diagnostic yield of fine-needle aspiration biopsy. Next generation sequencing may aid the diagnosis of choroidal melanoma when there is clinical uncertainty and cytopathology is unavailable.
PubMed: 37273243
DOI: 10.1016/j.ajoc.2023.101862 -
Cancers Dec 2023Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal...
BACKGROUND
Breast cancer is the second most common cause of brain metastases (BM). Despite increasing incidence of BM in older women, there are limited data on the optimal management of BM in this age group. In this study, we assessed the survival outcomes and treatment patterns of older breast cancer patients ≥65 years old with BM compared to younger patients at our institution.
METHODS
An IRB-approved single-institutional retrospective review of biopsy-proven breast cancer patients with BM treated with 1- to 5-fraction stereotactic radiation therapy (SRS) from 2015 to 2020 was performed. Primary endpoint was intracranial progression-free survival (PFS) defined as the time interval between the end of SRS to the date of the first CNS progression. Secondary endpoints were overall survival (OS) from the end of SRS and radiation treatment patterns. Kaplan-Meier estimates and Cox proportional hazard regression method were used for survival analyses.
RESULTS
A total of 112 metastatic breast cancer patients with BMs were included of which 24 were ≥65 years old and 88 were <65 years old. Median age at RT was 72 years (range 65-84) compared to 52 years (31-64) in younger patients. There were significantly higher number of older women with ER/PR positive disease (75% vs. 49%, = 0.036), while younger patients were more frequently triple negative (32% vs. 12%, = 0.074) and HER2 positive (42% vs. 29%, = 0.3). Treatment-related adverse events were similar in both groups. Overall, 14.3% patients had any grade radiation necrosis (RN) (older vs. young: 8.3% vs. 16%, = 0.5) while 5.4% had grade 3 or higher RN (0% vs. 6.8%, = 0.7). Median OS after RT was poorer in older patients compared to younger patients (9.5 months vs. 14.5 months, = 0.037), while intracranial PFS from RT was similar between the two groups (9.7 months vs. 7.1 months, = 0.580). On univariate analysis, significant predictors of OS were age ≥65 years old (hazard risk, HR = 1.70, = 0.048), KPS ≤ 80 (HR = 2.24, < 0.001), HER2 positive disease (HR = 0.46, < 0.001), isolated CNS metastatic disease (HR = 0.29, < 0.001), number of brain metastases treated with RT (HR = 1.06, = 0.028), and fractionated SRS (HR = 0.53, = 0.013). On multivariable analysis, KPS ≤ 80, HER2 negativity and higher number of brain metastases predicted for poorer survival, while age was not a significant factor for OS after adjusting for other variables. Patients who received systemic therapy after SRS had a significantly improved OS on univariate and multivariable analysis (HR = 0.32, < 0.001). Number of brain metastases treated was the only factor predictive of worse PFS (HR = 1.06, = 0.041), which implies a 6% additive risk of progression for every additional metastasis treated.
CONCLUSIONS
Although older women had poorer OS than younger women, OS was similar after adjusting for KPS, extracranial progression, and systemic therapy; and there was no difference in rates of intracranial PFS, neurological deaths, and LMD in the different age groups. This study suggests that age alone may not play an independent role in treatment-selection and that outcomes for breast cancer patients with BMs and personalized decision-making including other clinical factors should be considered. Future studies are warranted to assess neurocognitive outcomes and other radiation treatment toxicities in older patients.
PubMed: 38201564
DOI: 10.3390/cancers16010137