Oncogenic mutations in KEAP1 disturbing inhibitory Nrf2-Keap1 interaction: Activation of antioxidative pathway in papillary thyroid carcinoma

Abstract

Background

Nuclear factor erythroid 2-like 2 (NFE2L2) encodes Nrf2, transcription factor of antioxidative genes. In the presence of reactive oxygen species, Keap1 (Kelch-ECH-associating protein-1) inhibitor complex undergoes conformational changes disrupting Keap1-Nrf2 binding and Nrf2 translocates into nucleus. We evaluated the presence of mutations in NFE2L2 and KEAP1 in papillary thyroid carcinomas (PTCs) and correlated them with clinical presentation.

Methods

Coding regions of NFE2L2 and KEAP1 were sequenced in 131 patients with PTC. Clinical and histopathological features were analyzed. Immunohistochemical analysis of Nrf2 expression was performed in mutated carcinomas.

Results

Although no mutations were found in NFE2L2, missense mutations in KEAP1 were observed in 6 patients with PTC (4.6%). Immunohistochemistry showed increased Nrf2 expression in nuclei of all mutated carcinomas, which presented poor prognostic features in histopathology.

Conclusion

We identified mutations in KEAP1 associated with Nrf2 overexpression in PTC. Mutations favored disruption of inhibitory interaction Nrf2-Keap1 to enable increased antioxidant Nrf2 activity, possibly with prognostic consequences.

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Long-term experience with intranasal bevacizumab therapy

Objectives/Hypothesis

Long-term follow-up of intranasal bevacizumab therapy in hereditary hemorrhagic telangiectasia (HHT).

Study Design

Prospective, noncomparative study.

Methods

Patients treated for HHT-associated epistaxis by intranasal submucosal bevacizumab injections between June 2011 and August 2013 were included and followed prospectively. The effectiveness of the treatment was evaluated by the epistaxis severity score (ESS); the epistaxis intensity, frequency, and the need of blood transfusion (IFT) score; and hemoglobin levels.

Results

Thirty-three patients were included. The total number of treatments with intranasal bevacizumab injection was 210. The mean number of treatments per patient was 6.2 ± 4.6 (range, 1–16), and the mean treatment and observation period was 38.8 ± 21.8 months (range, 2–66 months). Four patients showed no improvement after treatment. Eleven patients (33.3%) showed initial improvement in both ESS and IFT, but the treatment was discontinued before the end of the study because the effect became gradually shorter lasting despite repeated injections. Twelve patients (36.3%) continued to have a positive response to the treatment at the end of the study. No local adverse effects were observed, but one patient developed osteonecrosis in both knees during the treatment period.

Conclusions

Intranasal bevacizumab injection is an effective treatment for most of the moderate and severe grades of HHT-associated epistaxis. The duration of the effect of the treatment was variable. Primary and late resistance phenomena to the treatment were quite common.

Level of Evidence

4. Laryngoscope, 2018

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How old is too old for cochlear implantation for congenital bilateral sensorineural hearing loss?

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Cancer Risk Associated With Key Epigenetic Changes Occurring Through Normal Aging Process

Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration process called senescence. Now, researchers at the Johns Hopkins Kimmel Cancer Center demonstrated that instead, tumor-associated epigenetic states evolve erratically during early stages of tumor development, eventually selecting for a subset of genes that undergo the most changes during normal aging and in early tumor development.

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Combined Nd:YAG laser and bleomycin sclerotherapy under the same anesthesia for cervicofacial venous malformations: A safe and effective treatment option

Publication date: May 2018
Source:International Journal of Pediatric Otorhinolaryngology, Volume 108
Author(s): Stacie Gregory, Patricia E. Burrows, Herodotos Ellinas, Michael Stadler, Robert H. Chun
IntroductionExtensive cervicofacial venous malformations (VM) pose significant challenges to a patient's quality of life (altered breathing, dysphagia, dysarthria). Treatment options include: 1) Surgical debulking; 2) Sclerotherapy; 3) laser therapy; or 4) Combined modalities. Recent studies have demonstrated the importance of multimodality and multidisciplinary management of these patients. However, no studies have described combined single anesthetic laser and sclerotherapy treatment. We sought to demonstrate the safety and efficacy of combined Nd:YAG laser and sclerotherapy under the same anesthetic administration.MethodsRetrospective review of 8 patients (Age 6 mo −74 yrs, x͂ 31) with extensive cervicofacial VM with significant airway involvement. Patients were treated with combined suspension laryngoscopy with Nd:YAG laser of airway VM followed by image guided direct puncture sclerotherapy using bleomycin in the airway VM and sodium tetradecyl sulfate (STS) foam in the cervicofacial VM during the same anesthetic encounter.ResultsAll 8 patients had extensive cervicofacial VMs that were symptomatic with snoring or orthopnea. Four of the patients had previously been treated at outside institutions with residual disease or significant complications. All patients remained intubated post procedure (Avg. 1.07 days) and tolerated extubation without re-intubation or any major complications. The average length of hospital stay was 3.2 days, of which 1.9 days were spent in the ICU. Patients reported symptomatic improvement or had decreased VM disease on MRI follow up.ConclusionCombined Nd:YAG laser therapy and sclerotherapy allows treatment of both superficial and deep components of VMs in a safe and efficient manner. In addition, suspension laryngoscopy provides improved visualization and access for the interventional radiologist in difficult to reach areas for sclerotherapy.



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Effect of Tumor Size on Risk of Metastatic Disease and Survival for Thyroid Cancer: Implications for Biopsy Guidelines

Thyroid , Vol. 0, No. 0.


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Mycobacterium ChelonaeDeveloping Multidrug Resistance

Mycobacterium chelonae is a rapidly growing mycobacterium which is known to respond well to standard antibiotic treatment regimen. There are no specific guidelines for treatment. Antibiotics are chosen based on the bacterial sensitivity. Here we present a 47-year-old man with hip replacement who developed bright red papular generalised skin lesions and bilateral hip abscess. On workup, it was confirmed that M. chelonae was the causative organism. He was given 8 weeks of antibiotics; however, there was worsening of the hip abscess on interval imaging. The progression was most likely due to M. chelonae developing antibiotic resistance. Physicians should be aware of the rising resistance of this organism, and guide antibiotic therapy based on bacterial sensitivity to yield better outcomes.

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