Diagnostic utility of combining PRAME and HMB-45 stains in primary melanocytic tumors.

BACKGROUND: Pathologists face ongoing challenges distinguishing between benign and malignant melanocytic tumors. PRAME (PReferentially expressed Antigen in Melanoma) has a demonstrated value distinguishing between these types of lesions. However, the sensitivity of single immunohistochemistry is variable. HMB-45 is another valuable marker, but on its own, has a limited ability in setting of primary melanocytic tumors. This study sought to evaluate the diagnostic potential of a dual panel combining PRAME and HMB-45 in the assessment of primary melanocytic tumors. METHODS: 259 tumors, of which 141 were benign nevi, 31 dysplastic nevi (either low- or high grade dysplasia), and further 87 malignant melanomas, were retrieved from the department's archives and assessed by two experienced dermatopathologists. New sections were stained with PRAME and HMB-45, respectively. For PRAME, a nuclear, and for HMB-45, a cytoplasmic staining, was considered positive and scored as described in the literature on a scale from 0 to 4+. Only dermal component was assessed on HMB-45 stain. RESULTS: PRAME was diffusely expressed in only 1 benign nevus, with focal expression in further 28 compared to 22 diffusely and 103 focally HMB-45-positive benign nevi. 5 high-grade dysplastic nevi showed diffuse PRAME expression in epidermal component, with varying degree of positivity in adjacent dermal compartment, and further 8 dysplastic nevi showed only focal expression. HMB-45 was diffusely expressed in only 2, with focal expression in 23, and no apparent positivity in remaining 6 dysplastic nevi. In invasive melanoma group, PRAME stained >75 % cells in 64/87 tumors, however, 10/87 melanomas were completely negative. HMB-45 was captured diffusely in 49/87 melanomas, 32 showed patchy expression, and 6 tumors were blank negative. Diffuse 4+ PRAME positivity showed superior sensitivity and specificity of 73,6 % and 96,5 %, respectively, compared to HMB-45, 56,3 % and 86,0 %, respectively. No nevi showed double 4+ positivity, however, the sensitivity for double positivity was only 49,4 %. CONCLUSION: Our results confirm the superiority of PRAME over HMB-45 in the differential diagnosis of melanocytic tumors. However, combined staining can significantly increase specificity, rendering a benign diagnosis more unlikely in a double 4+ diffuse positivity setting.

Spatial and temporal distribution of mass loss from the Greenland Ice Sheet since AD 1900.

The response of the Greenland Ice Sheet (GIS) to changes in temperature during the twentieth century remains contentious, largely owing to difficulties in estimating the spatial and temporal distribution of ice mass changes before 1992, when Greenland-wide observations first became available. The only previous estimates of change during the twentieth century are based on empirical modelling and energy balance modelling. Consequently, no observation-based estimates of the contribution from the GIS to the global-mean sea level budget before 1990 are included in the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. Here we calculate spatial ice mass loss around the entire GIS from 1900 to the present using aerial imagery from the 1980s. This allows accurate high-resolution mapping of geomorphic features related to the maximum extent of the GIS during the Little Ice Age at the end of the nineteenth century. We estimate the total ice mass loss and its spatial distribution for three periods: 1900-1983 (75.1 ± 29.4 gigatonnes per year), 1983-2003 (73.8 ± 40.5 gigatonnes per year), and 2003-2010 (186.4 ± 18.9 gigatonnes per year). Furthermore, using two surface mass balance models we partition the mass balance into a term for surface mass balance (that is, total precipitation minus total sublimation minus runoff) and a dynamic term. We find that many areas currently undergoing change are identical to those that experienced considerable thinning throughout the twentieth century. We also reveal that the surface mass balance term shows a considerable decrease since 2003, whereas the dynamic term is constant over the past 110 years. Overall, our observation-based findings show that during the twentieth century the GIS contributed at least 25.0 ± 9.4 millimetres of global-mean sea level rise. Our result will help to close the twentieth-century sea level budget, which remains crucial for evaluating the reliability of models used to predict global sea level rise.

Reducing workload in malignant melanoma sentinel node examination: a national study of pathology reports from 507 melanoma patients.

AIMS: Even though extensive melanoma sentinel node (SN) pathology protocols increase metastasis detection, there is a need for balancing high detection rates with reasonable workload. A newly tested Danish protocol recommended examining nodes at six levels 150 µm apart (six-level model) and using SOX10 and Melan-A immunohistochemistry (IHC). We explored if a protocol examining 3 levels 300 µm apart (three-level model) combined with IHC would compromise metastasis detection. The study aim was to optimise the protocol to reduce workload without compromising detection rate. METHODS: 8 months after protocol implementation, we reviewed the pathology reports of SNs from 507 melanoma patients nationwide, including 117 SN-positive patients. Each report was reviewed to determine histopathological features, including detection of metastasis, exact levels with metastasis, exact levels with metastasis >1 mm in diameter and IHC results. RESULTS: The six-level model detected metastases in 23% of patients, whereas the three-level model would have detected metastases in 22% of patients. The three-level model would have missed a few small metastases (n=4), measuring <0.1 mm, 0.1 mm, 0.4 mm and 0.1 mm, respectively. The six-level model detected metastases >1 mm in 7% of patients. One of these metastases (measuring 1.1 mm) would have been detected by the three-level model, but not as >1 mm. SOX10 and Melan-A had equal sensitivity. CONCLUSIONS: Reducing the number of levels examined to three levels 300 µm apart combined with IHC does not have significant impact on metastasis detection rate, and we will therefore recommend that the future melanoma SN guideline takes this into consideration to reduce overall workload.

Uncovering a 70-year-old permafrost degradation induced disaster in the Arctic, the 1952 Niiortuut landslide-tsunami in central West Greenland.

On December 15th 1952, at approximately 14:00 local time a mass of 5.9 × 106 m3 of permafrozen talus deposits failed in a landslide close to the Niiortuut mountain on the south coast of the Nuussuaq peninsula, central West Greenland. Between 1.8 and 4.5 × 106 m3 of the material entered the sea and generated a tsunami that propagated through the Vaigat strait (Sullorsuaq). Here we describe this catastrophic event for the first time by analysis of historical material supplemented by recent fieldwork and discuss the implications for the state of contemporary permafrozen slopes. The tsunami killed a fisherman working on the shore of southern Nuussuaq, 10 km south-east of the landslide. In the mining town of Qullissat, 30 km south of the landslide, it had a runup height of 2.2-2.7 m and caused minor material damage. Morphological evidence show that the basal surface of rupture was 80 m inside the permafrost cemented talus slope, whose degradation was a dynamic conditioning factor for the landslide. The 1952 Niiortuut landslide is the first historically recorded event of permafrost degradation induced landslide-tsunamis in the Arctic. We infer that the landslide and its cascading consequences occurred due to the early-twentieth century warming that started in the late 1910's in the Arctic. Warming is now increasingly affecting this region, as shown by an enhanced recent landslide activity.

[Digital pathology].

Digitalisation of pathology slides allows pathologists to make diagnoses using a high-resolution computer screen instead of a conventional microscope. In 2020/21, the four pathology departments in the Region of Southern Denmark implemented digital pathology for all histologic samples. Going digital necessitated optimisation of workflows and training of pathologists, avoiding a reduction in diagnostic quality. This review describes the process for realisation of digital pathology and its future perspectives, including artificial intelligence algorithms to be implemented.

A first constraint on basal melt-water production of the Greenland ice sheet.

The Greenland ice sheet has been one of the largest sources of sea-level rise since the early 2000s. However, basal melt has not been included explicitly in assessments of ice-sheet mass loss so far. Here, we present the first estimate of the total and regional basal melt produced by the ice sheet and the recent change in basal melt through time. We find that the ice sheet's present basal melt production is 21.4 +4.4/-4.0 Gt per year, and that melt generated by basal friction is responsible for about half of this volume. We estimate that basal melting has increased by 2.9 ± 5.2 Gt during the first decade of the 2000s. As the Arctic warms, we anticipate that basal melt will continue to increase due to faster ice flow and more surface melting thus compounding current mass loss trends, enhancing solid ice discharge, and modifying fjord circulation.

Centennial response of Greenland's three largest outlet glaciers.

The Greenland Ice Sheet is the largest land ice contributor to sea level rise. This will continue in the future but at an uncertain rate and observational estimates are limited to the last few decades. Understanding the long-term glacier response to external forcing is key to improving projections. Here we use historical photographs to calculate ice loss from 1880-2012 for Jakobshavn, Helheim, and Kangerlussuaq glacier. We estimate ice loss corresponding to a sea level rise of 8.1 ± 1.1 millimetres from these three glaciers. Projections of mass loss for these glaciers, using the worst-case scenario, Representative Concentration Pathways 8.5, suggest a sea level contribution of 9.1-14.9 mm by 2100. RCP8.5 implies an additional global temperature increase of 3.7 °C by 2100, approximately four times larger than that which has taken place since 1880. We infer that projections forced by RCP8.5 underestimate glacier mass loss which could exceed this worst-case scenario.

Postglacial relative sea level change and glacier activity in the early and late Holocene: Wahlenbergfjorden, Nordaustlandet, Svalbard.

Sediment cores from Kløverbladvatna, a threshold lake in Wahlenbergfjorden, Nordaustlandet, Svalbard were used to reconstruct Holocene glacier fluctuations. Meltwater from Etonbreen spills over a threshold to the lake, only when the glacier is significantly larger than at present. Lithological logging, loss-on-ignition, ITRAX scanning and radiocarbon dating of the cores show that Kløverbladvatna became isolated from Wahlenbergfjorden c. 5.4 cal. kyr BP due to glacioisostatic rebound. During the Late Holocene, laminated clayey gyttja from lacustrine organic production and surface runoff from the catchment accumulated in the lake. The lacustrine sedimentary record suggests that meltwater only spilled over the threshold at the peak of the surge of Etonbreen in AD 1938. Hence, we suggest that this was the largest extent of Etonbreen in the (mid-late) Holocene. In Palanderbukta, a tributary fjord to Wahlenbergfjorden, raised beaches were surveyed and organic material collected to determine the age of the beaches and reconstruct postglacial relative sea level change. The age of the postglacial raised beaches ranges from 10.7 cal. kyr BP at 50 m a.s.l. to 3.13 cal. kyr BP at 2 m a.s.l. The reconstructed postglacial relative sea level curve adds valuable spatial and chronological data to the relative sea level record of Nordaustlandet.

Younger Dryas ice margin retreat triggered by ocean surface warming in central-eastern Baffin Bay.

The transition from the last ice age to the present-day interglacial was interrupted by the Younger Dryas (YD) cold period. While many studies exist on this climate event, only few include high-resolution marine records that span the YD. In order to better understand the interactions between ocean, atmosphere and ice sheet stability during the YD, more high-resolution proxy records from the Arctic, located proximal to ice sheet outlet glaciers, are required. Here we present the first diatom-based high-resolution quantitative reconstruction of sea surface conditions from central-eastern Baffin Bay, covering the period 14.0-10.2 kyr BP. Our record reveals warmer sea surface conditions and strong interactions between the ocean and the West Greenland ice margin during the YD. These warmer conditions were caused by increased Atlantic-sourced water inflow combined with amplified seasonality. Our results emphasize the importance of the ocean for ice sheet stability under the current changing climate.

Digital elevation model and orthophotographs of Greenland based on aerial photographs from 1978-1987.

Digital Elevation Models (DEMs) play a prominent role in glaciological studies for the mass balance of glaciers and ice sheets. By providing a time snapshot of glacier geometry, DEMs are crucial for most glacier evolution modelling studies, but are also important for cryospheric modelling in general. We present a historical medium-resolution DEM and orthophotographs that consistently cover the entire surroundings and margins of the Greenland Ice Sheet 1978-1987. About 3,500 aerial photographs of Greenland are combined with field surveyed geodetic ground control to produce a 25 m gridded DEM and a 2 m black-and-white digital orthophotograph. Supporting data consist of a reliability mask and a photo footprint coverage with recording dates. Through one internal and two external validation tests, this DEM shows an accuracy better than 10 m horizontally and 6 m vertically while the precision is better than 4 m. This dataset proved successful for topographical mapping and geodetic mass balance. Other uses include control and calibration of remotely sensed data such as imagery or InSAR velocity maps.

Shared decision-making in treatment of Merkel cell carcinoma.

An 82-year-old woman presented with an asymptomatic mass, rapidly growing on her left cheek for the previous 3 months. Punch biopsy of the tumour was performed, and the pathology was compatible with Merkel cell carcinoma. A resection margin of more than 1 cm would involve left oral commissura, potentially damaging speech, eating and drinking ability. The patient had a strong wish of keeping surgery simple in order to maintain quality of life. Tumour excision was performed with 1 cm resection margin, and postoperatively the patient was referred to adjuvant radiation therapy. Sensibility of upper and lower lip remained unaffected, while motor innervation of left upper lip was impaired. Despite this, the patient's ability to talk and eat was unaffected. Surgery, with adjunctive radiation therapy, is the first-line of treatment for the primary tumour. The option for a more conservative treatment is not first choice, but can be considered upon individual assessment.

Aerial photographs reveal late-20th-century dynamic ice loss in northwestern Greenland.

Global warming is predicted to have a profound impact on the Greenland Ice Sheet and its contribution to global sea-level rise. Recent mass loss in the northwest of Greenland has been substantial. Using aerial photographs, we produced digital elevation models and extended the time record of recent observed marginal dynamic thinning back to the mid-1980s. We reveal two independent dynamic ice loss events on the northwestern Greenland Ice Sheet margin: from 1985 to 1993 and 2005 to 2010, which were separated by limited mass changes. Our results suggest that the ice mass changes in this sector were primarily caused by short-lived dynamic ice loss events rather than changes in the surface mass balance. This finding challenges predictions about the future response of the Greenland Ice Sheet to increasing global temperatures.

A 10,000-year record of Arctic Ocean sea-ice variability--view from the beach.

We present a sea-ice record from northern Greenland covering the past 10,000 years. Multiyear sea ice reached a minimum between ~8500 and 6000 years ago, when the limit of year-round sea ice at the coast of Greenland was located ~1000 kilometers to the north of its present position. The subsequent increase in multiyear sea ice culminated during the past 2500 years and is linked to an increase in ice export from the western Arctic and higher variability of ice-drift routes. When the ice was at its minimum in northern Greenland, it greatly increased at Ellesmere Island to the west. The lack of uniformity in past sea-ice changes, which is probably related to large-scale atmospheric anomalies such as the Arctic Oscillation, is not well reproduced in models. This needs to be further explored, as it is likely to have an impact on predictions of future sea-ice distribution.

Synthesis and pharmacological evaluation of novel cis-3,4-diaryl-hydroxychromanes as high affinity partial agonists for the estrogen receptor.

The syntheses and in vitro pharmacological evaluation of a number of cis-3,4-diaryl-hydroxy-chromanes are reported, along with the results of a thorough in vivo profiling of the tissue-selective estrogen partial-agonist NNC 45-0781 [3, (-)-(3S,4R)-7-hydroxy-3-phenyl-4-(4-(2-pyrrolidinoethoxy)phenyl)chromane]. These studies showed that NNC 45-0781 is a very promising candidate for the prevention of post-menopausal osteoporosis, and the treatment of other health issues related to the loss of endogenous estrogen production.