New insights from field observations of the Younger giant dyke complex and mafic lamprophyres of the gardar province on Tuttutooq island, South Greenland

LK, RW, RC, LM and AM received funding from the Mining Institute of Scotland, Institute of Materials, Minerals and Mining, the Edinburgh Geological Society, the Augustine Courtauld Trust and the Scott Polar Research Institute. LK received funding from the Society of Economic Geology Hickok-Radford Fund.The Gardar Province of south Greenland is defined by the products of alkaline igneous magmatism during the Mesoproterozoic. The most laterally extensive Gardar intrusions are a series of giant dyke complexes best exposed on the Tuttutooq archipelago. We present new field observations and a geological map of north-east Tuttutooq island that provide fresh insights into the temporal evolution of the Younger giant dyke complex and two associated ultramafic lamprophyres. Our data demonstrate that distinctive crystallisation regimes occurred in different sectors of the dyke complex, leading to the formation of marginal gabbros and ovoid pod-like domains displaying lamination, modal layering and/or more evolved differentiates. We infer that at least two pulses of magma contributed to the formation of the Younger giant dyke complex. In addition, the relative ages of two ultramafic lamprophyre diatremes are constrained and attributed to two distinct phases of rifting in the Gardar Province.Publisher PDFPeer reviewe

First experiences with Lu-177-PSMA-617 therapy for recurrent or metastatic salivary gland cancer

BACKGROUND: Advanced salivary gland cancers become difficult to treat when they are technically irresectable and radiotherapy limits are exceeded. There is also an unmet need to improve palliative systemic therapy. Salivary glands depict the Prostate-Specific Membrane Antigen (PSMA) on (68)Ga-PSMA-PET/CT, a transmembrane protein that is targeted for diagnosis and treatment of advanced prostate cancer. Some salivary gland carcinomas also express PSMA. METHODS: This study aimed to retrospectively evaluate the effectiveness of (177)Lu-PSMA-617 therapy for recurrent or metastatic salivary gland cancers, as a last resort treatment. Patients with serious tumour-related discomfort for whom no regular option was available were selected and critically re-assessed by the tumour board. Radionuclide therapy eligibility was confirmed when tumour targeting was greater than liver SUVmax on (68)Ga-PSMA-PET/CT. The protocol aimed at four cycles of 6.0–7.4 GBq (177)Lu-PSMA-617 every 6–8 weeks. Clinical response was evaluated by questionnaires and radiological response by (68)Ga-PSMA-PET/CT. RESULTS: Six patients were treated with (177)Lu-PSMA: four adenoid cystic carcinomas, one adenocarcinoma NOS and one acinic cell carcinoma. In two patients, radiological response was observed, showing either stable disease or a partial response, and four patients reported immediate relief of tumour-related symptoms. Most reported side effects were grade 1–2 fatigue, nausea, bone pain and xerostomia. Four patients prematurely discontinued therapy: three due to disease progression and one due to demotivating (grade 1) side-effects. CONCLUSIONS: Palliative (177)Lu-PSMA therapy for salivary gland cancer may lead to rapid relief of tumour-associated discomfort and may even induce disease stabilization. It is safe, relatively well tolerated and can be considered when regular treatment options fail

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas.Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation.Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC.Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation.</p

Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification

Background: Organoids are in vitro three-dimensional structures that can be grown from patient tissue. Head and neck cancer (HNC) is a collective term used for multiple tumor types including squamous cell carcinomas and salivary gland adenocarcinomas. Methods: Organoids were established from HNC patient tumor tissue and characterized using immunohistochemistry and DNA sequencing. Organoids were exposed to chemo- and radiotherapy and a panel of targeted agents. Organoid response was correlated with patient clinical response. CRISPR-Cas9-based gene editing of organoids was applied for biomarker validation. Findings: A HNC biobank consisting of 110 models, including 65 tumor models, was generated. Organoids retained DNA alterations found in HNC. Comparison of organoid and patient response to radiotherapy (primary [n = 6] and adjuvant [n = 15]) indicated potential for guiding treatment options in the adjuvant setting. In organoids, the radio-sensitizing potential of cisplatin and carboplatin could be validated. However, cetuximab conveyed radioprotection in most models. HNC-targeted treatments were tested on 31 models, indicating possible novel treatment options with the potential for treatment stratification in the future. Activating PIK3CA mutations did not predict alpelisib response in organoids. Protein arginine methyltransferase 5 (PRMT5) inhibitors were identified as a potential treatment option for cyclin-dependent kinase inhibitor 2A (CDKN2A) null HNC. Conclusions: Organoids hold potential as a diagnostic tool in personalized medicine for HNC. In vitro organoid response to radiotherapy (RT) showed a trend that mimics clinical response, indicating the predictive potential of patient-derived organoids. Moreover, organoids could be used for biomarker discovery and validation

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Differences in the association of time to treatment initiation and survival according to various head and neck cancer sites in a nationwide cohort

Objectives: To assess whether there are differences in the effects of time to treatment interval (TTI) on patient survival for head and neck cancer (HNC) sites in order to provide evidence that can support decision-making regarding prioritizing treatment. Materials and methods: Patients in the Netherlands with a first primary HNC without distant metastasis between 2010 and 2014 were included for analysis (N = 10,486). TTI was defined as the time from pathologic diagnosis to the start of initial treatment. Overall survival (OS), cox regression analyses and cubic spline hazard models were calculated and visualized. Results: Overall, the hazard of dying was higher (HR = 1.003; 95 % CI 1.001–1.005) with each additional day until treatment initiation. The pattern, as visualized in cubic spline graphs, differed by site the hazard increased more steeply with increasing TTI for oral cavity cancer. For oropharyngeal and laryngeal cancer, a slight increase commenced after a longer TTI than for oral cavity cancer, while there was hardly an increase in hazard with increasing TTI for hypopharyngeal cancer. Conclusion: The relationship between longer TTI and decreased survival was confirmed, but slight variations in the pattern of the hazard of dying by TTI by tumour site were observed. These findings could support decisions on prioritizing treatment. However, other aspects such as extent of treatment and quality of life should be investigated further so this can also be included.</p

The formation of lithium-rich pegmatites through multi-stage melting

Lithium-cesium-tantalum−type pegmatites (the primary source of lithium) crystallize from highly evolved, volatile felsic melts that incorporated crustal material in their source. Pegmatites are classically thought to form either from extreme fractionation of a parental granite body or via low-degree partial melting of a metamorphic rock (anatectic origin). However, the processes that lead to the formation of economic lithium pegmatite deposits remain enigmatic, because precipitation of lithium ore minerals requires melt lithium concentrations in excess of 5000 ppm—∼500 times upper crustal abundances. We use petrological modeling to quantify lithium enrichment in an anatectic-origin scenario and show that it is primarily driven by the relative stability of residual biotite and muscovite at medium to high pressures (∼8 kbar), and biotite and cordierite at low pressures (∼3 kbar). We show anatexis of an average lithium-enriched metasedimentary source cannot sufficiently elevate the lithium content of the ensuing melt to form economic deposits; however, if this first-generation melt—now crystallized as granitic crust—is re-melted, the second-generation melt will be sufficiently concentrated in lithium to crystallize lithium ore minerals. We propose a petrogenetic model for anatectic-origin lithium pegmatites, in which a region experiences at least two stages of partial melting, ultimately generating lithium-rich melts without invoking extensive fractional crystallization. This mechanism can both account for the occurrence of unzoned lithium pegmatites and explain why economic pegmatites in many terranes are younger than their inferred source granites

First experiences with Lu-177-PSMA-617 therapy for recurrent or metastatic salivary gland cancer

Background Advanced salivary gland cancers become difficult to treat when they are technically irresectable and radiotherapy limits are exceeded. There is also an unmet need to improve palliative systemic therapy. Salivary glands depict the Prostate-Specific Membrane Antigen (PSMA) on Ga-68-PSMA-PET/CT, a transmembrane protein that is targeted for diagnosis and treatment of advanced prostate cancer. Some salivary gland carcinomas also express PSMA. Methods This study aimed to retrospectively evaluate the effectiveness of Lu-177-PSMA-617 therapy for recurrent or metastatic salivary gland cancers, as a last resort treatment. Patients with serious tumour-related discomfort for whom no regular option was available were selected and critically re-assessed by the tumour board. Radionuclide therapy eligibility was confirmed when tumour targeting was greater than liver SUVmax on Ga-68-PSMA-PET/CT. The protocol aimed at four cycles of 6.0-7.4 GBq Lu-177-PSMA-617 every 6-8 weeks. Clinical response was evaluated by questionnaires and radiological response by Ga-68-PSMA-PET/CT. Results Six patients were treated with Lu-177-PSMA: four adenoid cystic carcinomas, one adenocarcinoma NOS and one acinic cell carcinoma. In two patients, radiological response was observed, showing either stable disease or a partial response, and four patients reported immediate relief of tumour-related symptoms. Most reported side effects were grade 1-2 fatigue, nausea, bone pain and xerostomia. Four patients prematurely discontinued therapy: three due to disease progression and one due to demotivating (grade 1) side-effects. Conclusions Palliative Lu-177-PSMA therapy for salivary gland cancer may lead to rapid relief of tumour-associated discomfort and may even induce disease stabilization. It is safe, relatively well tolerated and can be considered when regular treatment options fail