The convergence of tumor suppressors on the type I interferon pathway in clear cell renal cell carcinoma and its therapeutic implications.

In clear cell renal cell carcinoma (ccRCC), the von Hippel-Lindau tumor suppressor gene/hypoxia inducible factor (VHL/HIF) axis lays the groundwork for tumorigenesis and is the target of many therapeutic agents. HIF activation alone, however, is largely insufficient for kidney tumor development, and secondary mutations in PBRM1, BAP1, SETD2, KDM5C, or other tumor suppressor genes are strong enablers of tumorigenesis. Interestingly, it has been discovered that VHL loss and subsequent HIF activation results in upregulation of a negative feedback loop mediated by ISGF3, a transcription factor activated by type I interferon (IFN). Secondary mutations in the aforementioned tumor suppressor genes all partially disable this negative feedback loop to facilitate tumor growth. The convergence of several cancer genes on this pathway suggests that it plays an important role in ccRCC development and maintenance. Tumors with secondary mutations that dampen the negative feedback loop may be exquisitely sensitive to its reactivation, and pharmacological activation of ISGF3 either alone or in combination with other therapies could be an effective method to treat patients with ccRCC. In this review, we examine the relevance of the type I IFN pathway to ccRCC, synthesize our current knowledge of the ccRCC tumor suppressors in its regulation, and explore how this may impact the future treatment of patients with ccRCC.

Carbapenemase Inhibitors: Updates on Developments in 2021.

Carbapenem resistance, an emerging global health problem, compromises the treatment of infections caused by nosocomial pathogens. Preclinical and clinical trials demonstrate that a new generation of carbapenemases inhibitors, together with the recently approved avibactam, relebactam and vaborbactam, would address this resistance. Our review summarizes the latest developments related to carbapenemase inhibitors synthesized to date, as well as their spectrum of activity and their current stage of development. A particular focus will be on ß-lactam/ß-lactamase inhibitor combinations that could potentially be used to treat infections caused by carbapenemase-producer pathogens. These new combinations mark a critical step forward the fight against antimicrobial resistance.

BAP1 maintains HIF-dependent interferon beta induction to suppress tumor growth in clear cell renal cell carcinoma.

BRCA1-associated protein 1 (BAP1) is a deubiquitinase that is mutated in 10-15% of clear cell renal cell carcinomas (ccRCC). Despite the association between BAP1 loss and poor clinical outcome, the critical tumor suppressor function(s) of BAP1 in ccRCC remains unclear. Previously, we found that hypoxia-inducible factor 2α (HIF2α) and BAP1 activate interferon-stimulated gene factor 3 (ISGF3), a transcription factor activated by type I interferons and a tumor suppressor in ccRCC xenograft models. Here, we aimed to determine the mechanism(s) through which HIF and BAP1 regulate ISGF3. We found that in ccRCC cells, loss of the von Hippel-Lindau tumor suppressor (VHL) activated interferon beta (IFN-ß) expression in a HIF2α-dependent manner. IFN-ß was required for ISGF3 activation and suppressed the growth of Ren-02 tumors in xenografts. BAP1 enhanced the expression of IFN-ß and stimulator of interferon genes (STING), both of which activate ISGF3. Both ISGF3 overexpression and STING agonist treatment increased ISGF3 activity and suppressed BAP1-deficient tumor growth in Ren-02 xenografts. Our results indicate that BAP1 loss reduces type I interferon signaling, and reactivating this pathway may be a novel therapeutic strategy for treating ccRCC.

Clipping Could Be the Best Treatment Modality for Recurring Anterior Communicating Artery Aneurysms Treated Endovascularly.

BACKGROUND: The anterior communicating artery (AcoA) is the most common location for intracranial aneurysms. OBJECTIVE: To present occlusion outcomes, complication rate, recurrence rate, and predictors of recurrence in a large cohort with AcoA aneurysms treated primarily with endosaccular embolization. We also attempt to present data on the most effective treatment modality for recurrent AcoA aneurysms. METHODS: This is a retrospective, single-center study, reviewing the outcomes of 463 AcoA aneurysms treated endovascularly between 2003 and 2018. RESULTS: The study cohort consisted of 463 patients. Adequate immediate occlusion was achieved in 418 (90.3%). Independent functional status at discharge was observed in 269 patients (58.0%), and the mortality rate was 6.8% (31). At 6 months, adequate occlusion was achieved in 418 (90.4%). Of all the patients, recurrence was observed in 101 cases (21.8%), and of those, 98 (22.4%) underwent retreatment. The combined frequency of retreatment for the coiling group was 42.4%, which was significantly higher than the 0 incident of retreatment in the clipping group (P < .0001). Among the retreatment cohort, there was a significantly higher subsequent retreatment rate in the endovascular group (0% in the clipping group vs 42.4% in the endovascular group, P < .0001). CONCLUSION: Coiling with and without stent/balloon assistance is a relatively safe and effective modality for the treatment of AcoA aneurysms; however, in the setting of recurrence, microsurgical reconstruction leads to improved outcomes regarding durable occlusion, thus avoiding the potential for multiple interventions in the future.

Telemedicine during and post-COVID 19: The insights of neurosurgery patients and physicians.

OBJECTIVE: COVID-19 has caused a massive surge in telemedicine utilization as patients and physicians tried to minimize in-person contact to avoid the spread and impact of the pandemic. This study aims to expand on the knowledge of telemedicine during and beyond the COVID-19 era as it pertains to its use, efficacy, and patient and provider satisfaction through surveys. METHODS: This is a retrospective study involving 93 patients and 33 Neurosurgery physicians who anonymously participated in the survey about their experience with telemedicine visits. RESULTS: Most respondents indicated extreme satisfaction with their telemedicine encounters during the pandemic (77%). As for how comfortable physicians are in providing a diagnosis via telemedicine compared to clinic visits, 7 (21.9%) physicians felt extremely comfortable, 13 (40.6%) felt somewhat comfortable, 2 (6.4%) were neutral, 9 (28.1%) felt somewhat uncomfortable and 1 (3.1%) felt extremely uncomfortable. Physical examination was the main tool that telemedicine didn't provide (n = 21, 100%). CONCLUSION: Telemedicine has become a major force in the health care system under the circumstances the world is witnessing. Physicians and patients have displayed high levels of satisfaction with telemedicine which could be pivotal to improving healthcare access to underprivileged areas beyond the pandemic.

Preoperative Ultrasound-Guided Percutaneous Embolization of Orbital Lymphaticovenous Malformations Using Onyx.

The treatment of orbital lymphaticovenous malformations (OLVMs) has evolved from simple surgical resection to a multimodal approach consisting of sclerosing agents, embolization, and resection depending on the specific components that compose the lesion. Here we present a representative case series of 5 nonconsecutive patients who underwent percutaneous embolization of OLVMs with the Onyx Liquid Embolic System (Medtronic, Dublin, Ireland) before surgical resection between 2019 and 2021. OLVMs are rare, benign, congenital lesions that grow with age and can become symptomatic and disabling. Treatment can be conservative or invasive; depending on the clinical presentation and characteristics of the lesions, treatment modalities can vary. Preoperative percutaneous embolization of OLVMs with the Onyx system is a promising technique, as demonstrated in this case series.