Does the addition of radiation improve survival compared to chemotherapy alone in women with stage IV endometrial carcinoma? Analysis of the NCDB and SEER databases.

OBJECTIVE: To evaluate whether the addition of radiation to adjuvant chemotherapy is associated with improved survival in women with stage IV endometrial cancer following surgery. METHODS: The National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results Program (SEER) registries were queried for patients with stage IV endometrial cancer from 2004 to 2017. Treatment was categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariable Cox regression models assessed associations between treatment modality and overall survival (OS). RESULTS: This analysis included 17,890 (NCDB: 12,812, SEER: 5078) women with stage IV endometrial cancer, including 1757 (9.8%) with IVA disease and 16,133 (90.2%) with IVB. The majority of stage IV patients received chemotherapy alone (NCDB 78.8%, SEER 77.0%). When radiation was utilized in addition to chemotherapy, EBRT was most common (NCDB 15.8%, SEER: 15.4%). In both databases, use of any radiation in addition to chemotherapy was associated with improved OS. Stage IV patients treated with chemotherapy plus EBRT had better survival than those receiving chemotherapy alone [NCDB: HR 0.75 (95% CI 0.70, 0.79), SEER: HR 0.85 (95% CI 0.77, 0.94)]. This benefit was more pronounced in patients with IVA disease [NCDB: HR 0.66 (95% CI 0.55, 0.79), SEER: HR 0.63 (95% CI 0.46, 0.85)]. In histology-stratified analyses, the addition of radiation to chemotherapy was associated with improved OS in all histologies, except clear cell. CONCLUSIONS: In this analysis of the NCDB and SEER registries, the use of multimodality treatment with radiation and chemotherapy was associated with improved OS compared to chemotherapy alone in women with stage IVA and IVB endometrial cancer.

SUMOylation in Glioblastoma: A Novel Therapeutic Target.

Protein SUMOylation is a dynamic post-translational modification which is involved in a diverse set of physiologic processes throughout the cell. Of note, SUMOylation also plays a role in the pathobiology of a myriad of cancers, one of which is glioblastoma (GBM). Accordingly, herein, we review core aspects of SUMOylation as it relates to GBM and in so doing highlight putative methods/modalities capable of therapeutically engaging the pathway for treatment of this deadly neoplasm.

High dietary sodium causes dyssynchrony of the renal molecular clock in rats.

Speed JS, Hyndman KA, Roth K, Heimlich JB, Kasztan M, Fox BM, Johnston JG, Becker BK, Jin C, Gamble KL, Young ME, Pollock JS, Pollock DM. High dietary sodium causes dyssynchrony of the renal molecular clock in rats. Am J Physiol Renal Physiol 314: F89-F98, 2018. First published September 27, 2017; doi:10.1152/ajprenal.00028.2017.-Dyssynchrony of circadian rhythms is associated with various disorders, including cardiovascular and metabolic diseases. The cell autonomous molecular clock maintains circadian control; however, environmental factors that may cause circadian dyssynchrony either within or between organ systems are poorly understood. Our laboratory recently reported that the endothelin (ET-1) B (ETB) receptor functions to facilitate Na+ excretion in a time of day-dependent manner. Therefore, the present study was designed to determine whether high salt (HS) intake leads to circadian dyssynchrony within the kidney and whether the renal endothelin system contributes to control of the renal molecular clock. We observed that HS feeding led to region-specific alterations in circadian clock components within the kidney. For instance, HS caused a significant 5.5-h phase delay in the peak expression of Bmal1 and suppressed Cry1 and Per2 expression in the renal inner medulla, but not the renal cortex, of control rats. The phase delay in Bmal1 expression appears to be mediated by ET-1 because this phenomenon was not observed in the ETB-deficient rat. In cultured inner medullary collecting duct cells, ET-1 suppressed Bmal1 mRNA expression. Furthermore, Bmal1 knockdown in these cells reduced epithelial Na+ channel expression. These data reveal that HS feeding leads to intrarenal circadian dyssynchrony mediated, in part, through activation of ETB receptors within the renal inner medulla.

Endothelin type A receptors mediate pain in a mouse model of sickle cell disease.

Sickle cell disease is associated with acute painful episodes and chronic intractable pain. Endothelin-1, a known pain inducer, is elevated in the blood plasma of both sickle cell patients and mouse models of sickle cell disease. We show here that the levels of endothelin-1 and its endothelin type A receptor are increased in the dorsal root ganglia of a mouse model of sickle cell disease. Pharmacologic inhibition or neuron-specific knockdown of endothelin type A receptors in primary sensory neurons of dorsal root ganglia alleviated basal and post-hypoxia evoked pain hypersensitivities in sickle cell mice. Mechanistically, endothelin type A receptors contribute to sickle cell disease-associated pain likely through the activation of NF-κB-induced Nav1.8 channel upregulation in primary sensory neurons of sickle cell mice. Our findings suggest that endothelin type A receptor is a potential target for the management of sickle cell disease-associated pain, although this expectation needs to be further verified in clinical settings.

Long-Term Endothelin-A Receptor Antagonism Provides Robust Renal Protection in Humanized Sickle Cell Disease Mice.

Sickle cell disease (SCD)-associated nephropathy is a major source of morbidity and mortality in patients because of the lack of efficacious treatments targeting renal manifestations of the disease. Here, we describe a long-term treatment strategy with the selective endothelin-A receptor (ETA) antagonist, ambrisentan, designed to interfere with the development of nephropathy in a humanized mouse model of SCD. Ambrisentan preserved GFR at the level of nondisease controls and prevented the development of proteinuria, albuminuria, and nephrinuria. Microscopy studies demonstrated prevention of podocyte loss and structural alterations, the absence of vascular congestion, and attenuation of glomerulosclerosis in treated mice. Studies in isolated glomeruli showed that treatment reduced inflammation and oxidative stress. At the level of renal tubules, ambrisentan treatment prevented the increased excretion of urinary tubular injury biomarkers. Additionally, the treatment strategy prevented tubular brush border loss, diminished tubular iron deposition, blocked the development of interstitial fibrosis, and prevented immune cell infiltration. Furthermore, the prevention of albuminuria in treated mice was associated with preservation of cortical megalin expression. In a separate series of identical experiments, combined ETA and ETB receptor antagonism provided only some of the protection observed with ambrisentan, highlighting the importance of exclusively targeting the ETA receptor in SCD. Our results demonstrate that ambrisentan treatment provides robust protection from diverse renal pathologies in SCD mice, and suggest that long-term ETA receptor antagonism may provide a strategy for the prevention of renal complications of SCD.

Endothelin-1 as a master regulator of whole-body Na+ homeostasis.

The current study was designed to determine whether vascular endothelial-derived endothelin-1 (ET-1) is important for skin Na(+) buffering. In control mice (C57BL/6J), plasma Na(+) and osmolarity were significantly elevated in animals on high- vs. low-salt (HS and LS, respectively) intake. The increased plasma Na(+) and osmolarity were associated with increased ET-1 mRNA in vascular tissue. There was no detectable difference in skin Na(+):H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na(+):H2O was significantly increased by blockade of the endothelin type A receptor with ABT-627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half-maximal inhibitory concentration, 0.055 nM). ET-1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9 pg/mg vs. 106.4 ± 6.8 pg/mg; P < 0.05), but not in vascular endothelial cell endothelin-1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na(+):H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET-1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET-1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na(+).

Association beween resting heart rate, shear and flow-mediated dilation in healthy adults.

Preclinical data have demonstrated that heart rate (HR) can directly impact vascular endothelial function, in part, through a shear-stress mechanism. This study sought to explore, in humans, the associations between resting heart rate and both shear and endothelial function assessed by flow-mediated dilation (FMD). The brachial artery FMD test was performed in 31 apparently healthy volunteers. Basal (B) and hyperaemic (H) shear were quantified in the following two ways using data from the FMD test: the traditional cumulative shear area under the curve up to peak dilation (Shearcum) method; and our novel method of shear summation (Shearsum), which accounts for HR by summing each individual cardiac cycle shear up to peak dilation. Data were grouped by tertiles based on resting HR as follows: low (LHR = 43-56 beats min(-1); n = 10); middle (MHR = 58-68 beats min(-1); n = 11); and high (HHR = 69-77 beats min(-1); n = 10). Within the LHR group, both B-Shearcum and H-Shearcum were significantly higher (P < 0.001) than B-Shearsum and H-Shearsum, respectively, whereas in the HHR group B-Shearcum and H-Shearcum were significantly lower (P < 0.001) than B-Shearsum and H-Shearsum, respectively. The FMD in the LHR group (8.8 ± 0.8%) was significantly greater than that in both the MHR group (5.5 ± 0.8%; P = 0.009) and the HHR group (5.9 ± 0.8%; P = 0.024). These findings demonstrate the existence of a relationship between heart rate and both shear and endothelial function in humans. Moreover, these findings have implications for considering heart rate as an important physiological variable when quantifying shear and performing the FMD test.

Assessing the Relationship between Surgical Timing and Postoperative Seizure Outcomes in Cavernoma-Related Epilepsy: A Single-Institution Retrospective Analysis of 63 Patients with a Review of the Literature.

Background: Patients with supratentorial cavernous malformations (SCMs) commonly present with seizures. First-line treatments for cavernoma-related epilepsy (CRE) include conservative management (antiepileptic drugs (AEDs)) and surgery. We compared seizure outcomes of CRE patients after early (≤6 months) vs. delayed (>6 months) surgery. Methods: We compared outcomes of CRE patients with SCMs surgically treated at our large-volume cerebrovascular center (1 January 2010-31 July 2020). Patients with 1 sporadic SCM and ≥1-year follow-up were included. Primary outcomes were International League Against Epilepsy (ILAE) class 1 seizure freedom and AED independence. Results: Of 63 CRE patients (26 women, 37 men; mean ± SD age, 36.1 ± 14.6 years), 48 (76%) vs. 15 (24%) underwent early (mean ± SD, 2.1 ± 1.7 months) vs. delayed (mean ± SD, 6.2 ± 7.1 years) surgery. Most (32 (67%)) with early surgery presented after 1 seizure; all with delayed surgery had ≥2 seizures. Seven (47%) with delayed surgery had drug-resistant epilepsy. At follow-up (mean ± SD, 5.4 ± 3.3 years), CRE patients with early surgery were more likely to have ILAE class 1 seizure freedom and AED independence than those with delayed surgery (92% (44/48) vs. 53% (8/15), p = 0.002; and 65% (31/48) vs. 33% (5/15), p = 0.03, respectively). Conclusions: Early CRE surgery demonstrated better seizure outcomes than delayed surgery. Multicenter prospective studies are needed to validate these findings.

Varying presentations of immune checkpoint inhibitor-associated myocarditis: A case report of the clinical characteristics and outcomes of three patients.

•ICI-associated myocarditis is a rare clinical entity, but one with an exceedingly high mortality rate.•The condition can present with a wide variety of manifestations. Thus, clinical suspicion for the diagnosis should remain elevated in at-risk patients receiving immunotherapy.•Early diagnosis and prompt initiation of high-dose steroids are key to optimizing patient outcomes.

A comprehensive assessment of self-reported symptoms among patients harboring an unruptured intracranial aneurysm.

Background: Approximately 3.2%-6% of the general population harbor an unruptured intracranial aneurysm (UIA). Ruptured aneurysms represent a significant healthcare burden, and preventing rupture relies on early detection and treatment. Most patients with UIAs are asymptomatic, and many of the symptoms associated with UIAs are nonspecific, which makes diagnosis challenging. This study explored symptoms associated with UIAs, the rate of resolution of such symptoms after microsurgical treatment, and the likely pathophysiology. Methods: A retrospective review of patients with UIAs who underwent microsurgical treatment from January 1, 2014, to December 31, 2020, at a single quaternary center were identified. Analyses included the prevalence of nonspecific symptoms upon clinical presentation and postoperative follow-up; comparisons of symptomatology by aneurysmal location; and comparisons of patient demographics, aneurysmal characteristics, and poor neurologic outcome at postoperative follow-up stratified by symptomatic versus asymptomatic presentation. Results: The analysis included 454 patients; 350 (77%) were symptomatic. The most common presenting symptom among all 454 patients was headache (n = 211 [46%]), followed by vertigo (n = 94 [21%]), cognitive disturbance (n = 68[15%]), and visual disturbance (n = 64 [14%]). Among 328 patients assessed for postoperative symptoms, 258 (79%) experienced symptom resolution or improvement. Conclusion: This cohort demonstrates that the clinical presentation of patients with UIAs can be associated with vague and nonspecific symptoms. Early detection is crucial to prevent aneurysmal subarachnoid hemorrhage. It is imperative that physicians not rule out aneurysms in the setting of nonspecific neurologic symptoms.

Association between community-level political affiliation and peripartum vaccination.

BACKGROUND: Political affiliation has been associated with vaccine uptake, but whether this association holds in pregnancy, when individuals are recommended to receive multiple vaccinations, remains to be studied. OBJECTIVE: This study aimed to examine the association between community-level political affiliation and vaccinations for tetanus, diphtheria, and pertussis; influenza; and COVID-19 in pregnant and postpartum individuals. STUDY DESIGN: A survey was conducted about tetanus, diphtheria, and pertussis and influenza vaccinations in early 2021, with a follow-up survey of COVID-19 vaccination among the same individuals at a tertiary care academic medical center in the Midwest. Geocoded residential addresses were linked at the census tract to the Environmental Systems Research Institute 2021 Market Potential Index, which ranks a community in comparison to the US national average. The exposure for this analysis was community-level political affiliation, defined by the Market Potential Index as very conservative, somewhat conservative, centrist, somewhat liberal, and very liberal (reference). The outcomes were self-reported vaccinations for tetanus, diphtheria, and pertussis; influenza; and COVID-19 in the peripartum period. Modified Poisson regression was used and adjusted for age, employment, trimester at assessment, and medical comorbidities. RESULTS: Of 438 assessed individuals, 37% lived in a community characterized by very liberal political affiliation, 11% as somewhat liberal, 18% as centrist, 12% as somewhat conservative, and 21% as very conservative. Overall, 72% and 58% of individuals reported receiving tetanus, diphtheria, and pertussis and influenza vaccinations, respectively. Of the 279 individuals who responded to the follow-up survey, 53% reported receiving COVID-19 vaccination. Individuals living in a community characterized by very conservative political affiliation were less likely to report vaccinations for tetanus, diphtheria, and pertussis (64% vs 72%; adjusted risk ratio, 0.83; 95% confidence interval, 0.69-0.99); influenza (49% vs 58%; adjusted risk ratio, 0.79; 95% confidence interval, 0.62-1.00); and COVID-19 (35% vs 53%; adjusted risk ratio, 0.65; 95% confidence interval, 0.44-0.96) than those in a community characterized by very liberal political affiliation. Individuals living in a community characterized by centrist political affiliation were less likely to report vaccinations for tetanus, diphtheria, and pertussis (63% vs 72%; adjusted risk ratio, 0.82; 95% confidence interval, 0.68-0.99) and influenza (44% vs 58%; adjusted risk ratio, 0.70; 95% confidence interval, 0.54-0.92) than those in a community characterized by very liberal political affiliation. CONCLUSION: Compared with pregnant and postpartum individuals living in communities characterized by very liberal political beliefs, those living in communities characterized by very conservative political beliefs were less likely to report vaccinations for tetanus, diphtheria, and pertussis; influenza; and COVID-19, and those in communities characterized by centrist political beliefs were less likely to report vaccinations for tetanus, diphtheria, and pertussis and influenza. Increasing vaccine uptake in the peripartum period may need to consider engaging an individual's broader sociopolitical milieu.

Corrigendum: Pathophysiology of Vascular Stenosis and Remodeling in Moyamoya Disease.

[This corrects the article DOI: 10.3389/fneur.2021.661578.].

Pathophysiology of Vascular Stenosis and Remodeling in Moyamoya Disease.

Moyamoya disease (MMD) and moyamoya syndrome (MMS) are progressive vascular pathologies unique to the cerebrovasculature that are important causes of stroke in both children and adults. The natural history of MMD is characterized by primary progressive stenosis of the supraclinoid internal carotid artery, followed by the formation of fragile collateral vascular networks. In MMS, stenosis and collateralization occur in patients with an associated disease or condition. The pathological features of the stenosis associated with MMD include neointimal hyperplasia, disruption of the internal elastic lamina, and medial attenuation, which ultimately lead to progressive decreases in both luminal and external arterial diameter. Several molecular pathways have been implicated in the pathophysiology of stenosis in MMD with functions in cellular proliferation and migration, extracellular matrix remodeling, apoptosis, and vascular inflammation. Importantly, several of these molecular pathways overlap with those known to contribute to diseases of systemic arterial stenosis, such as atherosclerosis and fibromuscular dysplasia (FMD). Despite these possible shared mechanisms of stenosis, the contrast of MMD with other stenotic pathologies highlights the central questions underlying its pathogenesis. These questions include why the stenosis that is associated with MMD occurs in such a specific and limited anatomic location and what process initiates this stenosis. Further investigation of these questions is critical to developing an understanding of MMD that may lead to disease-modifying medical therapies. This review may be of interest to scientists, neurosurgeons, and neurologists involved in both moyamoya research and treatment and provides a review of pathophysiologic processes relevant to diseases of arterial stenosis on a broader scale.

Rapid Evolution and Rupture of an Incidental Aneurysm During Hyperdynamic Therapy for Cerebral Vasospasm.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Among the most common sequelae of aSAH is delayed cerebral ischemia. Hyperdynamic therapy (fluid supplementation and hypertension) is used to increase cerebral perfusion. However, the safety of hyperdynamic therapy in patients with separate unruptured, unsecured intracranial aneurysms is not well-established. Herein, a rare case demonstrating the rapid evolution and rupture of an incidental unsecured aneurysm in the setting of hyperdynamic therapy is presented. CASE DESCRIPTION: A 56-year-old woman without significant medical history presented with aSAH secondary to rupture of a 3-mm left posterior inferior cerebellar artery aneurysm. After endovascular treatment of this aneurysm, she developed symptomatic vasospasm prompting initiation of hyperdynamic therapy. Seven days after initiation of hyperdynamic therapy, she experienced rupture of an incidental pericallosal artery aneurysm that was found to have increased in size during the hyperdynamic therapy. She ultimately survived and was functionally independent approximately 1 year after her initial ictus. CONCLUSIONS: This case demonstrates that enlargement and rupture of an incidental, previously unruptured aneurysm may occur during hyperdynamic therapy.

Early life stress induces dysregulation of the heme pathway in adult mice.

Early life stress (ELS) is associated with cardiovascular disease (CVD) risk in adulthood, but the underlying vascular mechanisms are poorly understood. Increased hemoglobin and heme have recently been implicated to mediate endothelial dysfunction in several vascular diseases. Chronic physiological stress is associated with alterations in the heme pathway that have been well-described in the literature. However, very little is known about the heme pathway with exposure to ELS or chronic psychosocial stress. Utilizing a mouse model of ELS, maternal separation with early weaning (MSEW), we previously reported that MSEW induces endothelial dysfunction via increased superoxide production. We reasoned that heme dysregulation may be one of the culprits induced by MSEW and sustained throughout adulthood; thus, we hypothesized that MSEW induces heme dysfunction. We investigated whether circulating levels of heme, a circulating pro-oxidant mediator, are increased by MSEW and examined the role of the heme metabolic pathway and heme homeostasis in this process. We found that circulating levels of heme are increased in mice exposed to MSEW and that plasma from MSEW mice stimulated higher superoxide production in cultured mouse aortic endothelial cells (MAECs) compared to plasma from normally reared mice. The heme scavenger hemopexin blunted this enhanced superoxide production. Splenic haptoglobin abundance was significantly lower and hemoglobin levels per red blood cell were significantly higher in MSEW versus control mice. These findings lead us to propose that ELS induces increased circulating heme through dysregulation of the haptoglobin-hemoglobin system representing a mechanistic link between ELS and CVD risk in adulthood.

Intraventricular metastatic melanoma: A case report and review of the literature.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

Cerebellar Arteriovenous Malformation Rupture Despite Apparent Angiographic Obliteration.

BACKGROUND: Arteriovenous malformations (AVMs) can occur in all regions of the brain and spinal cord, with clinical consequences and risks varying by location. Delayed AVM rupture despite digital subtraction angiography-confirmed obliteration post-radiation is exceedingly rare. CASE DESCRIPTION: To our knowledge, we present the first documented case of delayed hemorrhage associated with a cerebellar AVM 5 years after linear accelerator-based radiation in a man aged 31 years despite apparent angiographic obliteration. CONCLUSIONS: Intracranial hemorrhage after radiosurgery in digital subtraction angiography-confirmed obliterated AVMs is rare, with limited understanding of risk factors, appropriate preventative management, and mechanisms of occurrence. This case serves to demonstrate the need for greater awareness of this rare complication, as well as the need for appropriate surveillance and management strategies.

Hyperfiltration predicts long-term renal outcomes in humanized sickle cell mice.

We previously reported that humanized sickle cell (HbSS) mice develop spontaneous nephropathy, a major cause of morbidity and mortality in sickle cell disease (SCD). Because sex-dependent protective mechanisms in SCD have been reported, we examined the course of nephropathy in male and female HbSS mice to determine contributors and/or predictors of disease severity. In male HbSS mice, glomerular filtration rate was characterized by a rapid onset of hyperfiltration and subsequent progressive decline of renal function over 20 weeks. Early tubular injury presented with increased excretion of kidney injury marker 1 (KIM-1), progressive loss of tubular brush border, and interstitial fibrosis that preceded the onset of glomerular damage, suggesting a tubuloglomerular mechanism of kidney injury in these mice. Additionally, we observed a strong association between the magnitude of hyperfiltration and the degree of long-term kidney injury in male HbSS mice. Unlike males, female HbSS mice did not demonstrate a significant loss of renal function or severe kidney damage during the time course of the study. These results suggest that magnitude of hyperfiltration predicts the onset of chronic kidney damage in male HbSS mice, whereas protective mechanisms in female HbSS mice delay the onset of SCD nephropathy.

Endothelial Dysfunction in Cystic Fibrosis: Role of Oxidative Stress.

Oxidative stress and vascular endothelial dysfunction are established characteristics of cystic fibrosis (CF). Oxidative stress may contribute to vascular dysfunction via inhibition of nitric oxide (NO) bioavailability. Purpose. To determine if ingestion of a single antioxidant cocktail (AOC) improves vascular endothelial function in patients with CF. Methods. In 18 patients with CF (age 8-39 y), brachial artery flow-mediated dilation (FMD) was assessed using a Doppler ultrasound prior to and two hours following either an AOC (n = 18; 1,000 mg vitamin C, 600 IU vitamin E, and 600 mg α-lipoic acid) or a placebo (n = 9). In a subgroup of patients (n = 9), changes in serum concentrations of α-tocopherol and lipid hydroperoxide (LOOH) were assessed following AOC and placebo. Results. A significant (p = 0.032) increase in FMD was observed following AOC (Δ1.9 ± 3.3%), compared to no change following placebo (Δ - 0.8 ± 1.9%). Moreover, compared with placebo, AOC prevented the decrease in α-tocopherol (Δ0.48 ± 2.91 vs. -1.98 ± 2.32 µM, p = 0.024) and tended to decrease LOOH (Δ - 0.2 ± 0.1 vs. 0.1 ± 0.1 µM, p = 0.063). Conclusions. These data demonstrate that ingestion of an antioxidant cocktail can improve vascular endothelial function and improve oxidative stress in patients with CF, providing evidence that oxidative stress is a key contributor to vascular endothelial dysfunction in CF.

Oncolytic herpes simplex virus immunotherapy for brain tumors: current pitfalls and emerging strategies to overcome therapeutic resistance.

Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.