MLN8237 plus eribulin eradicates metastases via autophagy

Recent findings suggest that the inhibition of Aurora A (AURKA) kinase may offer a novel treatment strategy against metastatic cancers. In the current study, we determined the effects of AURKA inhibition by the small molecule inhibitor MLN8237 both as a monotherapy and in combination with the microtubule targeting drug eribulin on different stages of metastasis in triple negative breast cancer (TNBC) and defined the potential mechanism of its action. MLN8237 as a single agent and in combination with eribulin affected multiple steps in the metastatic process including migration, attachment, and proliferation in distant organs, resulting in suppression of metastatic colonization and recurrence of cancer. Eribulin application induces accumulation of active AURKA in TNBC cells providing foundation for the combination therapy. Mechanistically, AURKA inhibition induced cytotoxic autophagy via activation of the LC3B/p62 axis and inhibition of pAKT, leading to eradication of metastases, but has no effect on growth of mammary tumor. Combination of MLN8237 with eribulin leads to a synergistic increase in apoptosis in mammary tumors, as well as cytotoxic autophagy in metastases. This preclinical data provides a new understanding of the mechanisms by which MLN8237 mediates its anti-metastatic effects and advocates for its combination with eribulin in future clinical trials for metastatic breast cancer and early stage solid tumors.

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De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival

Background: Although 20% to 30% of melanomas are histopathologically 'nevus associated,' the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival.

Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided.

Results: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus-associated tumors.

Conclusions: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in melanoma outcomes.

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CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial)

CEA response may be a surrogate for response and long term outcome in (K)RAS wild-type mCRC receiving first-line targeted therapy. In the FIRE-3 trial, FOLFIRI and cetuximab induced a faster and greater CEA response than FOLFIRI and bevacizumab. CEA response correlated with longer PFS and OS. Hypothesizing that CEA reflects tumor burden greater CEA response may indicate greater antitumor efficacy.

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The Time To Progression Ratio: a new individualized volumetric parameter for early detection of clinical benefit of targeted therapies

Detecting signs of efficacy in early phase clinical trials is essential for efficient drug development. The TTP ratio is a novel endpoint that incorporates volumetrics and an intra-patients control to determine treatment efficacy. Response according to TTP ratio was correlated to Overall Survival and identified patients within the RECIST Stable Disease group who had a longer Overall Survival.

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The role of oral hygiene in head and neck cancer: Results from International Head and Neck Cancer Epidemiology (INHANCE) Consortium

This pooled analysis describes the largest and most comprehensive assessment of the association between oral hygiene indicators and HNCs to date, including oral cavity, laryngeal, hypopharyngeal, and oropharyngeal cancers. We found good oral hygiene is associated with higher lower risk of HNC. Improvements in oral hygiene by increasing oral hygiene literacy, particularly for annual dentist visits and daily tooth brushing, may be protective against HNC.

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Key concepts in MR spectroscopy and practical approaches to gaining biochemical information in children

Abstract

Magnetic resonance spectroscopy (MRS) provides independent biochemical information and has become an invaluable adjunct to MRI and other imaging modalities. This review introduces key concepts and presents basic methodological steps regarding the acquisition and the interpretation of proton MRS. We review major brain metabolites and discuss MRS dependence on age, location, echo time and field strength.

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The radiology report: a guide to thoughtful communication for radiologists and other medical professionals, by Curtis P. Langlotz

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