GammaTile® (GT) as a brachytherapy platform for rapidly proliferating glioblastomas: from case series to clinical trials.

PURPOSE: Radiation plays a central role in glioblastoma treatment. Logistics related to coordinating clinic visits, radiation planning, and surgical recovery necessitate delay in radiation delivery from the time of diagnosis. Unimpeded tumor growth occurs during this period, and is associated with poor clinical outcome. Here we provide a pilot experience of GammaTile ® (GT), a collagen tile-embedded Cesium-131 (131Cs) brachytherapy platform for such aggressive tumors. METHODS: We prospectively followed seven consecutive patients (2019-2023) with newly diagnosed (n = 3) or recurrent (n = 4) isocitrate dehydrogenase wild-type glioblastoma that grew > 100% in volume during the 30 days between the time of initial diagnosis/surgery and the radiation planning MRI. These patients underwent re-resection followed by GT placement. RESULTS: There were no surgical complications. One patient developed right hemiparesis prior to re-resection/GT placement and was discharged to rehabilitation, all others were discharged home-with a median hospital stay of 2 days (range: 1-5 days). There was no 30-day mortality and one 30-day readmission (hydrocephalus, requiring ventriculoperitoneal shunting (14%)). With a median follow-up of 347 days (11.6 months), median progression free survival of ≥ 320 days (10.6 months) was achieved for both newly and recurrent glioblastoma patients. The median overall survival (mOS) was 304 and 347 days (10 and 11.5 mo) for recurrent and newly diagnosed glioblastoma patients, respectively. CONCLUSION: Our pilot experience suggests that GT offers favorable local control and safety profile for patients afflicted with rapidly proliferating glioblastomas and lay the foundation for future clinical trial design.

Comparison of Gamma Knife (GK) and Linear Accelerator (LINAC) radiosurgery of brain metastasis resection cavity: a systematic review and proportional meta-analysis.

PURPOSE: Stereotactic radiosurgery (SRS) to the resection cavity is essential in the treatment of brain metastasis (BM) amenable to surgical resection. The two most common platforms for SRS delivery include Gamma Knife (GK) and LINAC. Here we collated the available peer-reviewed literature and performed a meta-analysis on clinical outcomes after GK or LINAC resection cavity SRS. METHODS: Following PRISMA Guidelines, a search on PUBMED and MEDLINE was performed to include all studies evaluating each post-operative SRS modality. Local control, overall survival, radiation necrosis, and leptomeningeal disease were evaluated from the available data. A proportional meta-analysis was performed via R using the metafor package to pool the outcomes of studies and a moderator effect to assess the significance between groups. RESULTS: We identified 21 GK studies (n = 2009) and 28 LINAC studies (n = 2219). The radiosurgery doses employed were comparable between GK and LINAC studies. The pooled estimate of 1-year local control, 1-year overall survival, and risk of leptomeningeal disease were statistically comparable between GK and LINAC (81.7 v 85.8%; 61.4 v 62.7%; 10.6 v 12.5%, respectively). However, the risk of radiation necrosis (RN) was higher for LINAC resection cavity SRS (5.4% vs. 10%, p = 0.036). The volume of the resection cavity was a significant modifying factor for RN in both modalities (p = 0.007) with a 0.5% and 0.7% increase in RN risk with every 1 cm3 increase in tumor volume for GK and LINAC, respectively. CONCLUSIONS: Our meta-analysis suggests that GK and LINAC SRS of resection cavity achieve comparable 1-year local control and survival. However, resection cavity treated with GK SRS was associated with lowered RN risk relative to those treated with LINAC SRS.

Preoperative Versus Postoperative Radiosurgery of Brain Metastases: A Meta-Analysis.

OBJECTIVE: While postoperative resection cavity radiosurgery (post-SRS) is an accepted treatment paradigm for brain metastasis (BM) patients who undergo surgical resection, there is emerging interest in preoperative radiosurgery (pre-SRS) followed by surgical resection as an alternative treatment paradigm. Here, we performed a meta-analysis of the available literature on this matter. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of all studies evaluating pre-SRS and post-SRS was completed. Local recurrence (LR), overall survival (OS), radiation necrosis (RN), and leptomeningeal disease (LMD) were evaluated from the available data. Moderator analysis and pooled effect sizes were performed using a proportional meta-analysis with R using the metafor package. Statistics are presented as mean [95% confidence interval]. RESULTS: We identified 6 pre-SRS and 33 post-SRS studies with comparable tumor volume (4.5-17.6 cm3). There were significant differences in the pooled estimates of LR and LMD, favoring pre-SRS over post-SRS. Pooled aggregate for LR was 11.0% [4.9-13.7] and 17.5% [15.1-19.9] for pre- and post-SRS studies (P = 0.014). Similarly, pooled estimates of LMD favored pre-SRS, 4.4% [2.6-6.2], relative to post-SRS, 12.3% [8.9-15.7] (P = 0.019). In contrast, no significant differences were found in terms of RN and OS. Pooled estimates for RN were 6.4% [3.1-9.6] and 8.9% [6.3-11.6] for pre- and post-SRS studies (P = 0.393), respectively. Pooled estimates for OS were 60.2% [55.8-64.6] and 60.5% [56.9-64.0] for pre- and post-SRS studies (P = 0.974). CONCLUSIONS: This meta-analysis supports further exploration of pre-SRS as a strategy for the treatment of BM.

Comparison of peripheral leukocyte parameters in patients receiving conventionally and hypofractionated radiotherapy schemes for the treatment of newly diagnosed glioblastoma.

Introduction: Treatment for glioblastomas, aggressive and nearly uniformly fatal brain tumors, provide limited long-term success. Immunosuppression by myeloid cells in both the tumor microenvironment and systemic circulation are believed to contribute to this treatment resistance. Standard multi-modality therapy includes conventionally fractionated radiotherapy over 6 weeks; however, hypofractionated radiotherapy over 3 weeks or less may be appropriate for older patients or populations with poor performance status. Lymphocyte concentration changes have been reported in patients with glioblastoma; however, monocytes are likely a key cell type contributing to immunosuppression in glioblastoma. Peripheral monocyte concentration changes in patients receiving commonly employed radiation fractionation schemes are unknown. Methods: To determine the effect of conventionally fractionated and hypofractionated radiotherapy on complete blood cell leukocyte parameters, retrospective longitudinal concentrations were compared prior to, during, and following standard chemoradiation treatment. Results: This study is the first to report increased monocyte concentrations and decreased lymphocyte concentrations in patients treated with conventionally fractionated radiotherapy compared to hypofractionated radiotherapy. Discussion: Understanding the impact of fractionation on peripheral blood leukocytes is important to inform selection of dose fractionation schemes for patients receiving radiotherapy.

Novel intraocular shielding device for eye plaque brachytherapy using magnetite nanoparticles: A proof-of-concept study using radiochromic film and Monte Carlo simulations.

PURPOSE: Eye plaque brachytherapy is a mainstay treatment for uveal melanomas despite potential toxicities to normal tissues. This work proposes a nanoparticle ferrofluid as a novel intraocular shielding device. With a modified magnetic plaque, the shielding particles are drawn to the tumor surface, attenuating dose beyond the tumor while maintaining prescription dose to the target. METHODS AND MATERIALS: Ferromagnetic nanoparticles suspended in a silicone polymer were synthesized to provide a high-density shielding medium. The ferrofluid's half-value layer (HVL) was quantified for 125I photons using radiochromic film and Monte Carlo methods. A magnetic COMS plaque was created and evaluated in its ability to attract ferrofluid over the tumor. Two ferrofluid shielding mediums were evaluated in their ability to attenuate dose at adjacent structures with in vitro measurements using radiochromic film, in addition to Monte Carlo studies. RESULTS: The shielding medium's HVL measured approximately 1.3 mm for an 125I photon spectrum, using film and Monte Carlo methods. With 0.8 mL of shielding medium added to the vitreous humor, it proved to be effective at reducing dose to normal tissues of the eye. Monte Carlo-calculated dose reductions of 65%, 80%, and 78% at lateral distances 5, 10, and 18 mm from a tumor (5-mm apical height) in a modeled 20-mm COMS plaque. CONCLUSIONS: The magnitude of dose reduction could reduce the likelihood of normal tissue side effects for plaque brachytherapy patients, including patients with normal tissues close to the plaque or tumor. Additional studies, safety considerations, and preclinical work must supplement these findings before use.

So many choices, so little time: Food preference and movement vary with the landscape of fear.

Spatial and temporal variation in perceived predation risk is an important determinant of movement and foraging activity of animals. Foraging in this landscape of fear, individuals need to decide where and when to move, and what resources to choose. Foraging theory predicts the outcome of these decisions based on energetic trade-offs, but complex interactions between perceived predation risk and preferences of foragers for certain functional traits of their resources are rarely considered. Here, we studied the interactive effects of perceived predation risk on food trait preferences and foraging behavior in bank voles (Myodes glareolus) in experimental landscapes. Individuals (n = 19) were subjected for periods of 24 h to two extreme, risk-uniform landscapes (either risky or safe), containing 25 discrete food patches, filled with seeds of four plant species in even amounts. Seeds varied in functional traits: size, nutrients, and shape. We evaluated whether and how risk modifies forager preference for functional traits. We also investigated whether perceived risk and distance from shelter affected giving-up density (GUD), time in patches, and number of patch visits. In safe landscapes, individuals increased time spent in patches, lowered GUD and visited distant patches more often compared to risky landscapes. Individuals preferred bigger seeds independent of risk, but in the safe treatment they preferred fat-rich over carb-rich seeds. Thus, higher densities of resource levels remained in risky landscapes, while in safe landscapes resource density was lower and less diverse due to selective foraging. Our results suggest that the interaction of perceived risk and dietary preference adds an additional layer to the cascading effects of a landscape of fear which affects biodiversity at resource level.

Pediatric Kidney Transplantation-Living or Deceased Donor?

BACKGROUND: Kidney transplantation is ideal for children and adolescents with chronic end-stage renal disease because it offers better growth, development, and quality of life. Donor choice is vitally important in this age group, given the long life expectancy of these patients. METHODS: A retrospective analysis of pediatric patients (<18 years) who underwent kidney transplantation from January 1999 to December/2018 was performed. Short- and long-term outcomes were compared between living and deceased donor transplants. RESULTS: We included 59 pediatric kidney transplant recipients, 12 from a living donor and 47 from a deceased donor. Thirty-six (61.0%) patients were boys, and 5 (8.5%) had a retransplant. There were no differences between groups on sex, race, and weight of the recipient and donor, as well as the age and the etiology of the recipient's primary disease. Most recipients received induction immunosuppression with basiliximab and maintenance with triple therapy, with no differences between groups. Living donor transplants were mostly pre-emptive (58.3% vs 4.3%, P < .001) and had fewer HLA mismatches (≤3: 90.9% vs 13.0%, P < .001), older donors (38.4 vs 24.3 years, P < .001) and shorter hospital stays (8.8 vs 14.1 days, P = .004). There were no statistically significant differences regarding medical-surgical complications and graft or patient survival. However, we found that at 13 years post-transplant 91.7% of the living donor grafts were functioning vs 72.3% of the deceased donor grafts. CONCLUSION: Our experience points out that a living donor graft in pediatric patients is associated with a higher probability of pre-emptive transplant, shorter hospital stay, greater HLA compatibility, and increased graft survival.

GammaTile® (GT) as a brachytherapy platform for rapidly growing brain metastasis.

Background: A subset of brain metastasis (BM) shows rapid recurrence post-initial resection or aggressive tumor growth between interval scans. Here we provide a pilot experience in the treatment of these BM with GammaTile® (GT), a collagen tile-embedded Cesium 131 (131Cs) brachytherapy platform. Methods: We identified ten consecutive patients (2019-2023) with BM that showed either (1) symptomatic recurrence while awaiting post-resection radiosurgery or (2) enlarged by >25% of tumor volume on serial imaging and underwent surgical resection followed by GT placement. Procedural complication, 30-day readmission, local control, and overall survival were assessed. Results: For this cohort of ten BM patients, 3 patients suffered tumor progression while awaiting radiosurgery and 7 showed >25% tumor growth prior to surgery and GT placement. There were no procedural complications or 30-day mortality. All patients were discharged home, with a median hospital stay of 2 days (range: 1-9 days). 4/10 patients experienced symptomatic improvement while the remaining patients showed stable neurologic conditions. With a median follow-up of 186 days (6.2 months, range: 69-452 days), no local recurrence was detected. The median overall survival (mOS) for the newly diagnosed BM was 265 days from the time of GT placement. No patients suffered from adverse radiation effects. Conclusion: Our pilot experience suggests that GT offers favorable local control and safety profile in patients suffering from brain metastases that exhibit aggressive growth patterns and support the future investigation of this treatment paradigm.

The Distant Molecular Effects on the Brain by Cancer Treatment.

Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.

Forager-mediated cascading effects on food resource species diversity.

Perceived predation risk varies in space and time. Foraging in this landscape of fear alters forager-resource interactions via cascading nonconsumptive effects. Estimating these indirect effects is difficult in natural systems. Here, we applied a novel measure to quantify the diversity at giving-up density that allows to test how spatial variation in perceived predation risk modifies the diversity of multispecies resources at local and regional spatial levels. Furthermore, we evaluated whether the nonconsumptive effects on resource species diversity can be explained by the preferences of foragers for specific functional traits and by the forager species richness. We exposed rodents of a natural community to artificial food patches, each containing an initial multispecies resource community of eight species (10 items each) mixed in sand. We sampled 35 landscapes, each containing seven patches in a spatial array, to disentangle effects at local (patch) and landscape levels. We used vegetation height as a proxy for perceived predation risk. After a period of three nights, we counted how many and which resource species were left in each patch to measure giving-up density and resource diversity at the local level (alpha diversity) and the regional level (gamma diversity and beta diversity). Furthermore, we used wildlife cameras to identify foragers and assess their species richness. With increasing vegetation height, i.e., decreasing perceived predation risk, giving-up density, and local alpha and regional gamma diversity decreased, and patches became less similar within a landscape (beta diversity increased). Foragers consumed more of the bigger and most caloric resources. The higher the forager species richness, the lower the giving-up density, and alpha and gamma diversity. Overall, spatial variation of perceived predation risk of foragers had measurable cascading effects on local and regional resource species biodiversity, independent of the forager species. Thus, nonconsumptive predation effects modify forager-resource interactions and might act as an equalizing mechanism for species coexistence.

Enriching captivity conditions with natural elements does not prevent the loss of wild-like gut microbiota but shapes its compositional variation in two small mammals.

As continued growth in gut microbiota studies in captive and model animals elucidates the importance of their role in host biology, further pursuit of how to retain a wild-like microbial community is becoming increasingly important to obtain representative results from captive animals. In this study, we assessed how the gut microbiota of two wild-caught small mammals, namely Crocidura russula (Eulipotyphla, insectivore) and Apodemus sylvaticus (Rodentia, omnivore), changed when bringing them into captivity. We analyzed fecal samples of 15 A. sylvaticus and 21 C. russula, immediately after bringing them into captivity and 5 weeks later, spread over two housing treatments: a "natural" setup enriched with elements freshly collected from nature and a "laboratory" setup with sterile artificial elements. Through sequencing of the V3-V4 region of the 16S recombinant RNA gene, we found that the initial microbial diversity dropped during captivity in both species, regardless of treatment. Community composition underwent a change of similar magnitude in both species and under both treatments. However, we did observe that the temporal development of the gut microbiome took different trajectories (i.e., changed in different directions) under different treatments, particularly in C. russula, suggesting that C. russula may be more susceptible to environmental change. The results of this experiment do not support the use of microbially enriched environments to retain wild-like microbial diversities and compositions, yet show that specific housing conditions can significantly affect the drift of microbial communities under captivity.

Analysis of dose to the macula, optic disc, and lens in relation to vision toxicities - A retrospective study using COMS eye plaques.

PURPOSE: The aim of this study was to relate common toxicity endpoints with dose to the macula, optic disc, and lens for uveal melanoma patients treated with Iodine-125 Collaborative Ocular Melanoma Study (COMS) eye plaque brachytherapy. METHODS: A cohort of 52 patients treated at a single institution between 2005 and 2019 were retrospectively reviewed. Demographics, dosimetry, and clinical outcomes were recorded. Univariate, relative risk, and Kaplan-Meier analyses were performed to relate dose to toxicity endpoints including retinopathy, vision decline, and cataracts. RESULTS: By the end of follow up (Median = 3.6 years, Range = 0.4 - 13.5 years), 65 % of eyes sustained radiation retinopathy, 40 % demonstrated moderate vision decline (>5 Snellen lines lost), and 56 % developed cataracts. Significant (p < 0.05) risk estimates exist for retinopathy and VA decline for doses >52 Gy to the macula and >42 Gy to the optic disc. Moreover, dose to the lens > 16 Gy showed a significant risk for cataract formation. Kaplan-Meier analysis demonstrated significantly different incidence of radiation retinopathy for > 52 Gy to the macula and > 42 Gy to the optic disc. In addition, the Kaplan-Meier analysis showed significantly different incidence of cataract formation for patients with lens dose > 16 Gy. CONCLUSIONS: Dose-effect relationships exist for the macula and optic disc with respect to the loss of visual acuity and the development of retinopathy. To better preserve vision after treatment, further research is needed to reduce macula, optic disc, and lens doses while maintaining tumor control.

Liver Transplantation After Hematopoietic Stem Cell Transplant for the Treatment of Sickle Cell Disease: A Case Report.

Sickle cell anemia is the most common of the hemoglobinopathies, in which the abnormal hemoglobin formed in deoxygenation states undergoes a polymerization process with consequent erythrocyte deformation and vaso-occlusive events. The need for multiple blood transfusions, prolonged ineffective erythropoiesis, hemolysis, and increased iron absorption can cause iron overload in the liver, leading to liver fibrosis. Hematopoietic stem cell transplantation (HSCT) is currently the only treatment with a curative potential for this disease and can establish normal complete or partial donor-derived erythropoiesis and stabilize or restore function in affected organs, preventing further deterioration of function. However, it does not reverse preexisting liver fibrosis and siderosis. One of the possible complications of patients who undergo HSCT is chronic liver disease, which has a multifactorial cause, with iron overload being an important factor. In the long term, the prevalence of chronic liver disease in HSCT patients, including cirrhosis and its complications, can be significant. Solid organ transplantation after allogeneic hematopoietic cell transplantation for end-organ failure remains a very rare event. It may offer a valuable treatment strategy in selected recipients, although it is associated with significant morbidity and mortality. We report the case of a patient with sickle cell anemia who underwent HSCT and developed severe liver dysfunction requiring liver transplantation 13 years after the procedure. We found no previous report in the literature of orthotopic liver transplant after HCT for the treatment of sickle cell disease.

Refractory Hypernatremia and Osmotic Demyelination Syndrome After Liver Transplantation: A Case Report.

Osmotic demyelination syndrome is an uncommon neurologic condition, characterized by noninflammatory demyelination involving the pons and other areas of the central nervous system. As chronic hyponatremia is frequently associated with cirrhosis, patients undergoing liver transplantation are at an increased risk for developing this condition. We report the case of a patient who developed refractory hypernatremia and osmotic demyelination syndrome after liver transplantation. The patient was a 40-year-old man, who underwent liver transplantation for the treatment of cryptogenic cirrhosis, and had a preoperative sodium level of 128 mmol/L. Although there were no intraoperative complications, the patient showed signs of mental confusion and drowsiness in the second postoperative day, and we noticed an increase to 136 mmol/L in his serum sodium. Treatment with 5% dextrose and desmopressin was initiated, but his serum sodium continued to increase steadily, while his neurologic condition gradually worsened. Serum sodium rose to 157 mmol/L, and a magnetic resonance imaging of the brain showed extensive lesions consistent with osmotic demyelination syndrome. The clinical condition of the patient continued to deteriorate until his death 17 days after the transplant. Although the occurrence of this syndrome after liver transplantation is well described, the steady increase in serum sodium despite early treatment, as described in this case, is highly unusual, and highlights the great attention that must be taken with monitoring and control of serum sodium in patients who undergo liver transplant in the context of chronic hyponatremia. This manuscript is compliant with the Helsinki Congress and the Istanbul Declaration.

Incidental Finding of Multiple Synchronous Neoplasms in Explanted Liver After Transplantation: A Case Report.

Liver transplantation is the only potentially curative treatment for patients with end-stage liver disease. After the procedure, histopathologic analysis of the liver explant may reveal neoplasms that were not previously diagnosed in preoperative imaging examinations. This incidental finding of primary liver neoplasms in the explant is not an uncommon situation in liver transplant, and hepatocarcinomas and cholangiocarcinomas are the types of tumors most frequently encountered in this scenario. These are the most common primary neoplasms of the liver, and liver transplantation is often a curative treatment for these types of tumors when they are in their earlier stages. In contrast, liver plasmacytoma is a rare type of plasma cell neoplasm, consisting of a single mass of monoclonal plasma cells, which is treated primarily by radiotherapy and is seldom encountered in the setting of liver transplant. We report the case of a patient who underwent liver transplantation for the treatment of cryptogenic cirrhosis, with no preoperative diagnosis of liver tumors. Analysis of the liver explant revealed the presence of three synchronous neoplasms with different histologic origins: a 27-mm hepatocellular carcinoma, a 17-mm intrahepatic cholangiocarcinoma, and a 25-mm solitary hepatic plasmacytoma. The patient received no further adjuvant treatment and remained well and with no signs of disease recurrence over an observation period of 44 months. We found no previous report in the literature of the synchronous presence of these three types of liver neoplasms.

Hemophagocytic Lymphohistiocytosis Secondary to Tuberculosis After Liver Transplantation: A Case Report.

Hemophagocytic lymphohistiocytosis (HL) is a rare syndrome characterized by a hyperinflammatory state, resulting from an excessive but ineffective immune response. There is a continuous stimulation of TCD8 + lymphocytes, associated with an uncontrolled release of cytokines, causing the infiltration of multiple organs by histiocytes and activated lymphocytes. HL can be a primary condition as a consequence of genetic disorder that most often affects children, or it can be secondary to neoplasms, autoimmune conditions or various infectious diseases in patients of all ages. HL caused by infection by Mycobacterium tuberculosis is highly unusual, with few cases reported in the literature. There is no clinical manifestation or laboratorial finding that is specific to HL, and a high index of clinical suspicion is necessary for the correct diagnosis, which is usually confirmed by biopsy. Treatment consists of controlling the causative event and the use of immunosuppressant drugs such as corticosteroids, etoposide, and cyclosporine to suppress the exacerbated immune response. We report the case of a patient who developed HL 2 months after liver transplantation. The initial presentation was persistent fever, prompting a search for a site of infection and the use of broad-spectrum antibiotics. As the clinical condition of the patient continued to deteriorate, HL was diagnosed through a bone marrow biopsy, and a cerebrospinal fluid culture positive for M. tuberculosis established the diagnosis of disseminated tuberculosis. Despite optimal treatment with immunosuppressors and antituberculosis drugs, there was no significant response and the patient died. This article is compliant with the Helsinki Congress and the Istanbul Declaration.

Early Effects of Extracellular Vesicles Secreted by Adipose Tissue Mesenchymal Cells in Renal Ischemia Followed by Reperfusion: Mechanisms Rely on a Decrease in Mitochondrial Anion Superoxide Production.

Acute kidney injury (AKI) caused by ischemia followed by reperfusion (I/R) is characterized by intense anion superoxide (O2•-) production and oxidative damage. We investigated whether extracellular vesicles secreted by adipose tissue mesenchymal cells (EVs) administered during reperfusion can suppress the exacerbated mitochondrial O2•- formation after I/R. We used Wistar rats subjected to bilateral renal arterial clamping (30 min) followed by 24 h of reperfusion. The animals received EVs (I/R + EVs group) or saline (I/R group) in the kidney subcapsular space. The third group consisted of false-operated rats (SHAM). Mitochondria were isolated from proximal tubule cells and used immediately. Amplex Red™ was used to measure mitochondrial O2•- formation and MitoTracker™ Orange to evaluate inner mitochondrial membrane potential (Δψ). In vitro studies were carried out on human renal proximal tubular cells (HK-2) co-cultured or not with EVs under hypoxic conditions. Administration of EVs restored O2•- formation to SHAM levels in all mitochondrial functional conditions. The gene expression of catalase and superoxide dismutase-1 remained unmodified; transcription of heme oxygenase-1 (HO-1) was upregulated. The co-cultures of HK-2 cells with EVs revealed an intense decrease in apoptosis. We conclude that the mechanisms by which EVs favor long-term recovery of renal structures and functions after I/R rely on a decrease of mitochondrial O2•- formation with the aid of the upregulated antioxidant HO-1/Nuclear factor erythroid 2-related factor 2 system, thus opening new vistas for the treatment of AKI.

Bone Marrow Mononuclear Cells Restore Normal Mitochondrial Ca2+ Handling and Ca2+-Induced Depolarization of the Internal Mitochondrial Membrane by Inhibiting the Permeability Transition Pore After Ischemia/Reperfusion.

Acute kidney injury due to ischemia followed by reperfusion (IR) is a severe clinical condition with high death rates. IR affects the proximal tubule segments due to their predominantly oxidative metabolism and profoundly altered mitochondrial functions. We previously described the impact of IR on oxygen consumption, the generation of membrane potential (ΔΨ), and formation of reactive oxygen species, together with inflammatory and structural alterations. We also demonstrated the benefits of bone marrow mononuclear cells (BMMC) administration in these alterations. The objective of the present study has been to investigate the effect of IR and the influence of BMMC on the mechanisms of Ca2+ handling in mitochondria of the proximal tubule cells. IR inhibited the rapid accumulation of Ca2+ (Ca2+ green fluorescence assays) and induced the opening of the cyclosporine A-sensitive permeability transition pore (PTP), alterations prevented by BMMC. IR accelerated Ca2+-induced decrease of ΔΨ (Safranin O fluorescence assays), as evidenced by decreased requirement for Ca2+ load and t1/2 for complete depolarization. Addition of BMMC and ADP recovered the normal depolarization profile, suggesting that stabilization of the adenine nucleotide translocase (ANT) in a conformation that inhibits PTP opening offers a partial defense mechanism against IR injury. Moreover, as ANT forms a complex with the voltage-dependent anion channel (VDAC) in the outer mitochondrial membrane, it is possible that this complex is also a target for IR injury-thus favoring Ca2+ release, as well as the supramolecular structure that BMMC protects. These beneficial effects are accompanied by a stimulus of the citric acid cycle-which feed the mitochondrial complexes with the electrons removed from different substrates-as the result of accentuated stimulus of citrate synthase activity by BMMC.

GammaTile® brachytherapy in the treatment of recurrent glioblastomas.

BACKGROUND: GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. METHODS: We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. RESULTS: The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure postsurgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. CONCLUSIONS: This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.

Diminazene Aceturate, an angiotensin converting enzyme 2 (ACE2) activator, promotes cardioprotection in ischemia/reperfusion-induced cardiac injury.

This study aimed to investigate whether the Diminazene Aceturate (DIZE), an angiotensin-converting enzyme 2 (ACE2) activator, can revert cardiac dysfunction in ischemia reperfusion-induced (I/R) injury in animals and examine the mechanism underlying this effect. Wistar rats systemically received DIZE (1 mg/kg) for thirty days. Cardiac function in isolated rat hearts was evaluated using the Langendorff technique. After I/R, ventricular non-I/R and I/R samples were used to evaluate ATP levels. Mitochondrial function was assessed using cardiac permeabilized fibers and isolated cardiac mitochondria. Cardiac cellular electrophysiology was evaluated using the patch clamp technique. DIZE protected the heart after I/R from arrhythmia and cardiac dysfunction by preserving ATP levels, independently of any change in coronary flow and heart rate. DIZE improved mitochondrial function, increasing the capacity for generating ATP and reducing proton leak without changing the specific citrate synthase activity. The activation of the ACE2 remodeled cardiac electrical profiles, shortening the cardiac action potential duration at 90 % repolarization. Additionally, cardiomyocytes from DIZE-treated animals exhibited reduced sensibility to diazoxide (KATP agonist) and a higher KATP current compared to the controls. DIZE was able to improve mitochondrial function and modulate cardiac electrical variables with a cardio-protective profile, resulting in direct myocardial cell protection from I/R injury.