BRAF–MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas

Brastianos, Priscilla K.; Twohy, Erin; Geyer, Susan; Gerstner, Elizabeth R.; Kaufmann, Timothy J.; Tabrizi, Shervin; Kabat, Brian; Thierauf, Julia; Ruff, Michael W.; Bota, Daniela A.; Reardon, David A.; Cohen, Adam L.; Fuente, Macarena I. de la; Lesser, Glenn J.; Campian, Jian; Agarwalla, Pankaj K.; Kumthekar, Priya; Mann, Bhupinder; Vora, Shivangi; Knopp, Michael; Iafrate, A. John; Curry, William T.; Cahill, Daniel P.; Shih, Helen A.; Brown, Paul D.; Santagata, Sandro; Barker, Fred G.; Galanis, Evanthia

doi:10.1056/nejmoa2213329

Cited by 35 publications

(15 citation statements)

References 36 publications

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“…Craniopharyngiomas in adults are most frequently driven by BRAF V600E mutations 18 . These mutations may have therapeutic consequences, 19 but were excluded by molecular methods in the present case. A family history of craniopharyngioma was absent.…”

Section: Discussionmentioning

confidence: 83%

A fortunate bitten tongue—Hypothyroidism despite repeatedly normal plasma thyrotropin levels

Djukic,

Gossner,

Larsen

et al. 2024

Clinical Case Reports

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Key Clinical MessageHypophyseal dysfunction may be overlooked by the currently generally accepted laboratory routine for the differential diagnosis in patients suffering from symptoms of depression or dementia.AbstractHypothyroidism is an important cause of depression and potentially reversible cognitive impairment. Whereas the determination of the plasma concentration of thyrotropin (TSH) is generally considered part of the laboratory screening tests for dementia, the measurement of total or free triiodothyronine (T3, FT3), thyroxine (T4, FT4) and cortisol in plasma does not belong to the routine diagnostic workup in patients with depression or suspected dementia. In an 87‐year‐old lady suffering from increasingly poor general health, decreased fluid and food intake, mood depression and lack of energy, three measurements of plasma TSH produced normal values. A cranial computed tomography (cCT) 2 days prior to hospital admission had been assessed as apparently normal. A second cCT performed following a loss of consciousness complicated by tongue bite showed a hypophyseal tumor. Then, low plasma levels of FT3, FT4 and cortisol were found. Following hormone replacement and transsphenoidal tumor resection, the patient recovered rapidly. The present case report illustrates the pitfalls of measuring merely the TSH level in the detection of thyroid and hypophyseal dysfunction.

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Section: Discussionmentioning

confidence: 83%

A fortunate bitten tongue—Hypothyroidism despite repeatedly normal plasma thyrotropin levels

Djukic,

Gossner,

Larsen

et al. 2024

Clinical Case Reports

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“…Notably, several of these compounds have shown promising anti-tumor activities in GBM or other cancers. For example, vemurafenib, a BRAF inhibitor, has demonstrated efficacy in BRAF V600E-mutant GBM patients and is undergoing clinical investigation (50). PLX-4720, another BRAF inhibitor, exhibits potent anti-proliferative effects in GBM cell lines and xenograft models (51).…”

Section: Discussionmentioning

confidence: 99%

Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity

Xie,

Du,

Ghosh

et al. 2024

Preprint

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Histone H3 Lysine 9 dimethylation or trimethylation (H3K9me2 or H3K9me3) marks more than half of the human genome, particularly in heterochromatin regions and specific genes within euchromatic regions. Enzymes catalyzing the methylation of H3K9 have individually been associated with the modulation of gene expression patterns involved in cancer progression, including suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, euchromatic histone-lysine N-methyltransferase 1 and 2 (EHMT1/2). However, a comprehensive comparison and understanding of the characteristics and mechanisms of these chromatin-modifying enzymes in cancers remains incompletely understood. In this study, we demonstrated that these six H3K9 methyltransferases differentially expressed in tumors and correlated expression with somatic copy number variations (CNVs) and DNA methylation patterns. Through integrative multi-omics analyses, we identified SUV39H1, SUV39H2, and SETDB1 as the key players among the six H3K9 methyltransferases that exhibited the most significant associations with cancer phenotypes. By incorporating SUV39H1, SUV39H2, and SETDB1, we developed a novel signature termed "H3K9me3 MtSig" (H3K9me3 methyltransferases signature). H3K9me3 MtSig was unique for various tumor types, had prognostic implications and was linked to significant signaling pathways, particularly in glioblastoma (GBM). Furthermore, elevated H3K9me3 MtSig was confirmed in GBM patient-derived cells and tissues. In addition, single-cell expression analysis of H3K9me3 MtSig in GBM tissues demonstrated a pattern related to the G2/M cell cycle and was negatively correlated with immune responses. H3K9me3-mediated repetitive sequence silencing by H3K9me3 MtSig, determined using ChIP-sequencing, contributed to these phenotypes, and inhibiting H3K9me3 MtSig in patient-derived GBM cells suppressed proliferation and increased immune responses. Translationally, H3K9me3 MtSig performed as an independent prognostic factor in a clinical prediction model, and drug susceptibility screening integrating H3K9me3 MtSig identified potential biomarkers and therapeutics for GBM. In summary, H3K9me3 MtSig has the potential to elucidate novel prognostic markers, therapeutic targets, and predictors of treatment response in GBM and other cancer types for clinical intervention.

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“… 3 10 Despite their histologically benign grade, craniopharyngiomas have the potential to cause significant morbidity due to the involvement of regional neurovascular structures and the challenge of obtaining a complete resection without deficits. 3 13 Nuanced management of craniopharyngiomas is beyond the scope of the review, in particular given the profound advances recently reported in the application of proton beam therapy 14 and BRAF inhibitors 15 for the treatment of appropriately selected lesions.…”

Section: Discussionmentioning

confidence: 99%

Decision-Making in Clival Mass Lesions: Risk Factors for Malignant Disease and an Illustrative Case Example

Baier,

Cheong,

Shi

et al. 2023

J Neurol Surg Rep

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Introduction Clival tumors are rare and heterogeneous. Although some benign prototypical sellar lesions may present as clival tumors, the likelihood of malignant disease is higher. Here we define a novel algorithm for the workup and management of clival masses through an illustrative case of colorectal adenocarcinoma metastasis to the clivus. Methods In this case report, the best practice guidelines for managing clival masses are described through a literature review and refined by senior author consensus. We conducted a focused systematic review to characterize the present case in the context of clival metastasis from gastrointestinal malignancy. Results An 83-year-old woman presented with 4 weeks of headaches and blurry vision. Examination revealed partial right abducens and left oculomotor palsies. Magnetic resonance imaging (MRI) identified a large, weakly enhancing sellar and clival mass with sphenoid sinus extension. An aggressive subtotal endoscopic endonasal resection was performed with removal of all sphenoid, clival, and sellar disease without cavernous sinus wall resection. Pathology confirmed colorectal adenocarcinoma; computed tomography (CT) imaging identified an ascending colon mass with metastases to the liver and mesenteric nodes. Palliative oncologic therapies were recommended, but she elected hospice, and died 3 months after initial presentation. Gastrointestinal clival metastases are exceedingly rare among sellar and clival pathologies, with eight prior cases reported, most of which presented with diplopia from abducens nerve involvement. Conclusion Clival masses are uncommon skull base lesions that are associated with more aggressive diseases. We present a consolidated framework for decision-making in these challenging patients, alongside an unusual case example that illustrates the importance of increased suspicion for malignant clinical entities in this setting.

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BRAF–MEK Inhibition in Newly Diagnosed Papillary Craniopharyngiomas

Cited by 35 publications

References 36 publications

A fortunate bitten tongue—Hypothyroidism despite repeatedly normal plasma thyrotropin levels

A fortunate bitten tongue—Hypothyroidism despite repeatedly normal plasma thyrotropin levels

Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity

Decision-Making in Clival Mass Lesions: Risk Factors for Malignant Disease and an Illustrative Case Example

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