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.

Glioblastoma multiforme metastasizing to the skin, a case report and literature review.

Glioblastoma Multiforme (GBM) is the most common primary central nervous system (CNS) malignancy in adults. It is very aggressive and is notorious for its fast and local invasion of nearby brain parenchyma. Consequently, the overall survival (OS) of patients with GBM is short despite resection, radiotherapy and chemotherapy regimens. The most common sites of metastasis of GBM are the lungs and pleura, cervical lymph nodes, and bone. Metastasis to the skin is a rare event and to our knowledge, there are less than 30 cases of GBM metastasizing to cutaneous or subcutaneous tissue described in the literature. None of these cases were diagnosed and/or treated in the Middle East region; and the majority of the metastases found were adjacent to the site of surgery undergone to remove the primary malignancy. We present the case of a 53-year-old male diagnosed with GBM and later showing signs of metastases at the anterio-auricular side of his face near-distant from the site of previous surgery done to remove the primary tumor.

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.

Corrigendum: Genomic Assays in Node Positive Breast Cancer Patients: A Review.

[This corrects the article DOI: 10.3389/fonc.2020.609100.].

The burden of Arcanobacterium haemolyticum pharyngitis: A systematic review and management algorithm.

INTRODUCTION: Arcanobacterium haemolyticum causes pharyngotonsillitis in children and young adults. It is rarely isolated in pharyngeal swabs as testing for it is not routine. Data on complications, management, and antibiotic susceptibility testing is limited. We sought to review the available literature on the presentation and management of A. haemolyticum pharyngotonsillitis in this age group. METHODS: A systematic review of eligible studies reporting pharyngotonsillitis and related complications in children and young adults caused by A. haemolyticum was conducted. Literature from case reports, case series, and available cohorts was compiled. Data were analyzed using descriptive statistics. RESULTS: The initial database search yielded 63 articles, after applying exclusion criteria 17 studies were included. 191 patients were identified with a median age of 16.5 years. The most common presentation was throat pain reported in 93.7% of patients. Tonsillar exudates, fever at presentation and rash were present in more than half of the reviewed cases. The diagnosis was established by a positive culture on a pharyngeal swab in 98.8% of swabs collected. Complications described included peritonsillar abscesses, Lemierre's syndrome, pneumonia, and sepsis. Penicillin was the first line antibiotic in 81% of patients followed by macrolides in 19 patients (18%). CONCLUSIONS: A. haemolyticum occurs in children and young adults and may result in complications. Our review supports its susceptibility to penicillin. We suggest a diagnostic and management algorithm to guide clinicians in targeted testing and aid with decision making regarding timely and appropriate antibiotic therapy, in an effort to reduce the burden of its complications.

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.

Genomic Assays in Node Positive Breast Cancer Patients: A Review.

In recent years, developments in breast cancer have allowed yet another realization of individualized medicine in the field of oncology. One of these advances is genomic assays, which are considered elements of standard clinical practice in the management of breast cancer. These assays are widely used today not only to measure recurrence risk in breast cancer patients at an early stage but also to tailor treatment as well and minimize avoidable treatment side effects. At present, genomic tests are applied extensively in node negative disease. In this article, we review the use of these tests in node positive disease, explore their ramifications on neoadjuvant chemotherapy decisions, highlight sufficiently powered recent studies emphasizing their use and review the most recent guidelines.

Coordinating the Provision of Health Services in Humanitarian Crises: a Systematic Review of Suggested Models.

BACKGROUND: Our objective was to identify published models of coordination between entities funding or delivering health services in humanitarian crises, whether the coordination took place during or after the crises. METHODS: We included reports describing models of coordination in sufficient detail to allow reproducibility. We also included reports describing implementation of identified models, as case studies. We searched Medline, PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and the WHO Global Health Library. We also searched websites of relevant organizations. We followed standard systematic review methodology. RESULTS: Our search captured 14,309 citations. The screening process identified 34 eligible papers describing five models of coordination of delivering health services: the "Cluster Approach" (with 16 case studies), the 4Ws "Who is Where, When, doing What" mapping tool (with four case studies), the "Sphere Project" (with two case studies), the "5x5" model (with one case study), and the "model of information coordination" (with one case study). The 4Ws and the 5x5 focus on coordination of services for mental health, the remaining models do not focus on a specific health topic. The Cluster approach appears to be the most widely used. One case study was a mixed implementation of the Cluster approach and the Sphere model. We identified no model of coordination for funding of health service. CONCLUSION: This systematic review identified five proposed coordination models that have been implemented by entities funding or delivering health service in humanitarian crises. There is a need to compare the effect of these different models on outcomes such as availability of and access to health services.