SMARCA4-Deficient Undifferentiated Esophageal Carcinoma: A Clinical Case Series and Literature Review.

PURPOSE: Undifferentiated carcinoma of the esophagus (UEC) is a rare malignancy. Deficiency in SMARCA genes, critical for chromatin regulation, has been observed in cases of UEC. Research in UEC is sparse, however, and we present a case series along with a comprehensive review of the literature. CASE SERIES: Case 1 is a 49-year-old female with abdominal pain and dysphagia and esophagogastroduodenoscopy (EGD) showing a friable mass at the gastroesophageal (GE) junction. Biopsies showed a poorly differentiated neoplasm and immunohistochemistry showed loss for SMARCA4. With metastatic disease, she agreed to undergo palliative chemotherapy and radiation, passing away at 4 months. Case 2 is an 88-year-old male with dysphagia, nausea, vomiting, and distal esophageal mass with biopsy showing a malignancy with loss of SMARCA4 expression. Due to extensive metastases, he was counseled on hospice care. Case 3 is a 53-year-old male with extensive alcohol and smoking history presenting with hematemesis, passing away shortly. Posthumous histopathology consistent with undifferentiated SMARCA4-deficient carcinoma of the esophagus. Results of the literature review indicate a predilection towards males (75.0%) and a variable age range (39-88 years). Majority (76.2%) reported with a distal esophagus location. Metastatic disease was common at initial presentation. Median survival was 2.60 months. Some were managed with chemotherapy and radiation. CONCLUSIONS: Research in SMARCA-deficient UEC is very limited. It is more common in men, age is variable, and associated with Barret's esophagus. Further research is necessary to better understand it and to establish treatment guidelines; however, it is clear that SMARCA4-deficient UEC carries a significantly poor prognosis.

A Structural Perspective on Calprotectin as a Ligand of Receptors Mediating Inflammation and Potential Drug Target.

Calprotectin, a heterodimer of S100A8 and S100A9 EF-hand calcium-binding proteins, is an integral part of the innate immune response. Calprotectin (CP) serves as a ligand for several pattern recognition cell surface receptors including the receptor for advanced glycation end products (RAGE), toll-like receptor 4 (TLR4), and cluster of differentiation 33 (CD33). The receptors initiate kinase signaling cascades that activate inflammation through the NF-kB pathway. Receptor activation by CP leads to upregulation of both receptor and ligand, a positive feedback loop associated with specific chronic inflammatory syndromes. Hence, CP and its two constituent homodimers have been viewed as potential targets to suppress certain chronic inflammation pathologies. A variety of inhibitors of CP and other S100 proteins have been investigated for more than 30 years, but no candidates have advanced significantly into clinical trials. Here, current knowledge of the interactions of CP with its receptors is reviewed along with recent progress towards the development of CP-directed chemotherapeutics.

Comment on "How will induced seismicity in Oklahoma respond to decreased saltwater injection rates?" by C. Langenbruch and M. D. Zoback.

The state of Oklahoma has experienced an unprecedented increase in earthquake activity since 2009, likely driven by large-scale wastewater injection operations. Statewide injection rates peaked in early 2015 and steadily decreased thereafter, approximately coinciding with collapsing oil prices and regulatory action. If seismic activity is primarily driven by fluid injection, a noticeable seismogenic response to the decrease in injection rates is expected. Langenbruch and Zoback suggest that "the probability of potentially damaging larger events, should significantly decrease by the end of 2016 and approach historic levels within a few years." We agree that the rate of small earthquakes has decreased toward the second half of 2016. However, their specific predictions about seismic hazard require reexamination. We test the influence of the model parameters of Langenbruch and Zoback based on fits to observed seismicity distributions. The results suggest that a range of realistic aftershock decay rates and b values can lead to an increase in moderate earthquake probabilities from 37 to 80% in 2017 without any further alteration to the model. In addition, the observation that all four M ≥ 5 earthquakes to date occurred when injection rates were below the triggering threshold of Langenbruch and Zoback challenges the applicability of the model for the most societally significant events.

The Pawnee earthquake as a result of the interplay among injection, faults and foreshocks.

The Pawnee M5.8 earthquake is the largest event in Oklahoma instrument recorded history. It occurred near the edge of active seismic zones, similar to other M5+ earthquakes since 2011. It ruptured a previously unmapped fault and triggered aftershocks along a complex conjugate fault system. With a high-resolution earthquake catalog, we observe propagating foreshocks leading to the mainshock within 0.5 km distance, suggesting existence of precursory aseismic slip. At approximately 100 days before the mainshock, two M ≥ 3.5 earthquakes occurred along a mapped fault that is conjugate to the mainshock fault. At about 40 days before, two earthquakes clusters started, with one M3 earthquake occurred two days before the mainshock. The three M ≥ 3 foreshocks all produced positive Coulomb stress at the mainshock hypocenter. These foreshock activities within the conjugate fault system are near-instantaneously responding to variations in injection rates at 95% confidence. The short time delay between injection and seismicity differs from both the hypothetical expected time scale of diffusion process and the long time delay observed in this region prior to 2016, suggesting a possible role of elastic stress transfer and critical stress state of the fault. Our results suggest that the Pawnee earthquake is a result of interplay among injection, tectonic faults, and foreshocks.

An Intensive Observation of Calving at Helheim Glacier, East Greenland.

Calving of glacial ice into the ocean from the Greenland Ice Sheet is an important component of global sea level rise. The calving process itself is relatively poorly observed, understood, and modeled; as such, it represents a bottleneck in improving future global sea level estimates in climate models. We organized a pilot project to observe the calving process at Helheim Glacier in East Greenland in an effort to better understand it. During an intensive one-week survey, we deployed a suite of instrumentation including a terrestrial radar interferometer, GPS receivers, seismometers, tsunameters, and an automated weather station. This effort captured a calving process and measured various glaciological, oceanographic, and atmospheric parameters before, during, and after the event. One outcome of our observations is evidence that the calving process actually consists of a number of discrete events, spread out over time, in this instance over at least two days. This time span has implications for models of the process. Realistic projections of future global sea level will depend on accurate parametrization of calving, which will require more sustained observations.

Parathyroid Imaging with Simultaneous Acquisition of 99mTc-Sestamibi and 123I: The Relative Merits of Pinhole Collimation and SPECT/CT.

UNLABELLED: The objective of this study was to determine the relative utility of 3 state-of-the-art parathyroid imaging protocols: single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with pinhole collimation in the anterior and bilateral anterior oblique projections, single-time-point simultaneous acquisition of (99m)Tc-sestamibi and (123)I images with SPECT/CT, and the combination of the first and second protocols. METHODS: Fifty-nine patients with surgical proof of parathyroid adenomas were evaluated retrospectively. All 3 protocols included perfectly coregistered subtraction images created by subtracting the (123)I images from the (99m)Tc-sestamibi images, plus an anterior parallel-hole collimator image of the neck and upper chest. The pinhole protocol was performed first, followed by the SPECT/CT protocol. Three image sets were derived from each study in each patient according to the above protocols. Two experienced observers recorded the size, location, and degree of certainty of any identified lesion. RESULTS: The 59 patients had 61 adenomas. For the 2 observers combined, the localization success rate was 88% for the pinhole protocol, 69% for the SPECT/CT protocol, and 81% for the combined protocol. The pinhole protocol detected more adenomas than the SPECT/CT protocol and missed fewer adenomas than either the SPECT/CT protocol or the combined pinhole and SPECT/CT protocol (P < 0.01). The 2 protocols that included SPECT/CT provided superior anatomic information relative to the location and size of the parathyroid adenomas. CONCLUSION: The pinhole protocol localized significantly more adenomas than the SPECT/CT protocol. However, the protocols that included SPECT/CT provided more anatomic information than pinhole imaging alone.

Subglacial discharge at tidewater glaciers revealed by seismic tremor.

Subglacial discharge influences glacier basal motion and erodes and redeposits sediment. At tidewater glacier termini, discharge drives submarine terminus melting, affects fjord circulation, and is a central component of proglacial marine ecosystems. However, our present inability to track subglacial discharge and its variability significantly hinders our understanding of these processes. Here we report observations of hourly to seasonal variations in 1.5-10 Hz seismic tremor that strongly correlate with subglacial discharge but not with basal motion, weather, or discrete icequakes. Our data demonstrate that vigorous discharge occurs from tidewater glaciers during summer, in spite of fast basal motion that could limit the formation of subglacial conduits, and then abates during winter. Furthermore, tremor observations and a melt model demonstrate that drainage efficiency of tidewater glaciers evolves seasonally. Glaciohydraulic tremor provides a means by which to quantify subglacial discharge variations and offers a promising window into otherwise obscured glacierized environments.

A review of preclinical safety data for magnevist (gadopentetate dimeglumine) in the context of nephrogenic systemic fibrosis.

OBJECTIVES: Magnevist (gadopentetate dimeglumine, Bayer Healthcare, Bayer) is a gadolinium-based contrast agent (GBCA) for magnetic resonance imaging approved for clinical use in various indications since 1988. A possible association between the administration of GBCAs to patients with severe kidney impairment, and a condition first identified in 2000 and later described as "nephrogenic systemic fibrosis" (NSF), was published in early 2006. In the light of this reported association and the published histologic findings of certain NSF patients, Bayer, with support of external experts, reassessed the preclinical safety data from in vivo studies in healthy rats and dogs that were conducted with Magnevist during the drug development process in the mid-80s. These studies, which were performed according to standard regulatory requirements as defined in pertinent guidelines and which were conducted before the reported association between GBCAs and NSF, were not specifically designed to detect NSF-like lesions. Instead, the intention of this reassessment was to analyze whether the acquired knowledge on NSF would lead to a revised interpretation of the original preclinical data. MATERIALS AND METHODS: Studies on repeat-dose toxicity of Magnevist performed in the mid-80s with healthy rats and dogs were re-evaluated, with special emphasis on the retrospective analysis of morphologic findings which have come to be considered potentially suggestive of NSF. In particular, histologic slides of the skin of repeat-dose toxicity studies were re-examined by Bayer pathologists, with a special focus on the occurrence of morphologic lesions that have subsequently been identified as consistent with NSF. In addition, slides from selected studies were also subjected to a blinded external peer review by an independent international Pathology Working Group. RESULTS: A review of the preclinical data from the repeated-dose toxicity studies provided no evidence for toxicological effects after administration of Magnevist, which could be construed as suggestive of or consistent with NSF. More specifically, histopathology peer reviews of skin samples from repeated-dose toxicity studies with rats and dogs revealed no signs of skin lesions even after repeated high-dose administration to rats of 5.0 mmol Gd/kg of Magnevist (50 times the standard diagnostic dose). CONCLUSIONS: No findings were observed in any of the preclinical studies with Magnevist in healthy rats and dogs which could be characterized as similar to the types of morphologic lesions that have subsequently been identified as consistent with NSF. This preclinical assessment is in contrast to the reported clinical evidence of rare NSF cases in patients with severe kidney impairment after Magnevist administration. The differences between the preclinical models and their predictive limitations with regard to the clinical situation of renally impaired patients are discussed.