Conventional treatment of pulmonary metastatic sarcoma primarily involves surgery, with systemic therapy added in select patients. However, broader applications of radiation therapy techniques have ...prompted investigation into the use of stereotactic body radiotherapy (SBRT) for treatment of metastatic sarcoma, an attractive non-invasive intervention with potential for lower rates of adverse events than surgery. Current data are limited to retrospective analyses. This study analyzed 2-year local control and overall survival and adverse events in patients prospectively treated with SBRT to pulmonary sarcoma metastases.
Patients prospectively treated with SBRT to the lung for biopsy-proven metastatic sarcoma at a single institution from 2010 to 2022 were included. SBRT dose/fractionation treatment regimens ranged from 34 to 54 Gy in 1-10 fractions using photons. Local recurrence, local progression-free survival (LPFS) and overall survival (OS) were calculated from the end of SBRT. Univariable analysis (UVA) was performed using the log-rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazards model. Adverse events due to SBRT were graded based on the Common Terminology Criteria for Adverse Events, version 4.0.
Eighteen patients with metastatic sarcoma were treated to 26 pulmonary metastases. The median local progression-free survival was not met. The median overall survival was not met. The local control rate at 2 years was 96%. 2-year LPFS was 95.5% and OS was 74%. Three patients (16.7%) developed grade 1 adverse events from SBRT. There were no adverse events attributed to radiation that were grade 2 or higher.
We report prospective data demonstrating that SBRT for sarcoma pulmonary metastases affords a high rate of local control and low toxicity, consistent with prior sarcoma SBRT retrospective data. This study adds to the wealth of information on SBRT in a radioresistant tumor. Though largely limited to retrospective reviews, current data indicate high rates of local control with favorable toxicity profiles. Therefore, SBRT for pulmonary sarcoma metastases may be considered for properly selected patients.
Pazopanib, an oral angiogenesis inhibitor, is approved for the treatment of advanced renal cell carcinoma (RCC). Response to pazopanib monotherapy varies between patients, and no validated biomarkers ...predictive of treatment outcome have been identified. We tested the hypothesis that this variability is partially dependent on germline genetic variants that may affect pazopanib exposure or angiogenesis pathways.
Twenty-seven functional polymorphisms within 13 genes were evaluated in 397 patients with RCC. Genetic association with progression-free survival (PFS) and objective response rate (RR) was analyzed using the Cox proportional hazards model and proportional odds model, respectively.
Three polymorphisms in IL8 and HIF1A and five polymorphisms in HIF1A, NR1I2, and VEGFA showed nominally significant association (P ≤ .05) with PFS and RR, respectively. Compared with the wild-type AA genotype (median PFS, 48 weeks), the IL8 2767TT variant genotype showed inferior PFS (27 weeks, P = .009). The HIF1A 1790AG genotype was associated with inferior PFS and reduced RR, compared with the wild-type GG genotype (median PFS, 20 v 44 weeks; P = .03; RR, 30% v 43%, P = .02). Reductions in RR were detected for the NR1I2 -25385TT genotype, compared with the wild-type CC genotype (37% v 50%, P = .03), and for the VEGFA -1498CC genotype compared with the TT genotypes (33% v 51%).
Germline variants in angiogenesis- and exposure-related genes may predict treatment response to pazopanib monotherapy in patients with RCC. If validated, these markers may explain why certain patients fail antiangiogenesis therapy and they may support the use of alternative strategies to circumvent this issue.
Seroma development is a known complication following extremity and trunk soft-tissue sarcoma (STS) resection. The purpose of this study is to evaluate and characterize seroma outcomes and the ...development of associated complications.
A retrospective review of 123 patients who developed postoperative seromas following STS resection at a single institution was performed. Various patient and surgical factors were analyzed to determine their effect on overall seroma outcomes.
77/123 seromas (62.6%) were uncomplicated, 30/123 (24.4%) developed infection, and 16/123 (13.0%) were symptomatic and required aspiration or drainage for symptom relief at an average of 12.2 months postoperatively. 65/123 (52.8%) seromas resolved spontaneously at an average time of 12.41 months. Seromas in the lower extremity (p=0.028), surgical resection volume >864 cm3, (p=<0.001) and initial seroma volume >42 cm3 (p=<0.001) increased the likelihood of infection. 90% of infected seromas developed the infection within the first three months following initial resection. No seromas which were aspirated or drained ultimately developed an infection following these procedures, though 50% recurred.
Most seromas following STS resection are uncomplicated and do not require intervention, though a large resection cavity >864 cm3 and a large seroma volume >42 cm3 are risk factors for complications.
The Intergovernmental Panel on Climate Change (IPCC) confirmed that mean global warming was 0.6 +/- 0.2 degrees C during the 20th century and cited anthropogenic increases in greenhouse gases as the ...likely cause of temperature rise in the last 50 years. But this mean value conceals the substantial complexity of observed climate change, which is seasonally- and diurnally-biased, decadally-variable and geographically patchy. In particular, over the last 50 years three high-latitude areas have undergone recent rapid regional (RRR) warming, which was substantially more rapid than the global mean. However, each RRR warming occupies a different climatic regime and may have an entirely different underlying cause. We discuss the significance of RRR warming in one area, the Antarctic Peninsula. Here warming was much more rapid than in the rest of Antarctica where it was not significantly different to the global mean. We highlight climate proxies that appear to show that RRR warming on the Antarctic Peninsula is unprecedented over the last two millennia, and so unlikely to be a natural mode of variability. So while the station records do not indicate a ubiquitous polar amplification of global warming, the RRR warming on the Antarctic Peninsula might be a regional amplification of such warming. This, however, remains unproven since we cannot yet be sure what mechanism leads to such an amplification. We discuss several possible candidate mechanisms: changing oceanographic or changing atmospheric circulation, or a regional air-sea-ice feedback amplifying greenhouse warming. We can show that atmospheric warming and reduction in sea-ice duration coincide in a small area on the west of the Antarctic Peninsula, but here we cannot yet distinguish cause and effect. Thus for the present we cannot determine which process is the probable cause of RRR warming on the Antarctic Peninsula and until the mechanism initiating and sustaining the RRR warming is understood, and is convincingly reproduced in climate models, we lack a sound basis for predicting climate change in this region over the coming century. PUBLICATION ABSTRACT
An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, ...affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4- and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell deficiency.
To evaluate minimally invasive acetabular stabilization (MIAS) with thermal ablation and augmented screw fixation for impending or minimally displaced fractures of the acetabulum secondary to ...metastatic disease.
Between February 2011 and July 2014, 13 consecutive patients underwent thermal ablation, percutaneous screw fixation, and polymethyl methacrylate augmentation for impending or nondisplaced fractures of the acetabulum secondary to metastatic disease. Functional outcomes were evaluated before and after the procedure using the Musculoskeletal Tumor Society (MSTS) scoring system. Complications, hospital length of stay, and eligibility for chemotherapy and radiation therapy were assessed.
All procedures were technically successful with no major periprocedural complications. The mean total MSTS score improved from 23% ± 11 before MIAS to 51% ± 21 after MIAS (P < .05). The mean MSTS pain scores improved from 0% (all) to 32% ± 22 after MIAS (P < .05). The mean MSTS walking ability score improved from 22% ± 19 to 55% ± 26 after MIAS (P < .05). Two complications occurred; a patient had a minimally displaced fracture of the superior pubic ramus at the site of repair but remained ambulatory, and septic arthritis was diagnosed in another patient 12 months after repair. The average length of hospital stay was 2 days ± 3.6; six patients were discharged within 24 hours of the procedure. All patients were eligible for chemotherapy and radiation therapy immediately after the procedure.
MIAS is feasible, improves pain and mobility, and offers a minimally invasive alternative to open surgical reconstruction.
Aim
After environmental disasters, species with large population losses may need urgent protection to prevent extinction and support recovery. Following the 2019–2020 Australian megafires, we ...estimated population losses and recovery in fire‐affected fauna, to inform conservation status assessments and management.
Location
Temperate and subtropical Australia.
Time period
2019–2030 and beyond.
Major taxa
Australian terrestrial and freshwater vertebrates; one invertebrate group.
Methods
From > 1,050 fire‐affected taxa, we selected 173 whose distributions substantially overlapped the fire extent. We estimated the proportion of each taxon’s distribution affected by fires, using fire severity and aquatic impact mapping, and new distribution mapping. Using expert elicitation informed by evidence of responses to previous wildfires, we estimated local population responses to fires of varying severity. We combined the spatial and elicitation data to estimate overall population loss and recovery trajectories, and thus indicate potential eligibility for listing as threatened, or uplisting, under Australian legislation.
Results
We estimate that the 2019–2020 Australian megafires caused, or contributed to, population declines that make 70–82 taxa eligible for listing as threatened; and another 21–27 taxa eligible for uplisting. If so‐listed, this represents a 22–26% increase in Australian statutory lists of threatened terrestrial and freshwater vertebrates and spiny crayfish, and uplisting for 8–10% of threatened taxa. Such changes would cause an abrupt worsening of underlying trajectories in vertebrates, as measured by Red List Indices. We predict that 54–88% of 173 assessed taxa will not recover to pre‐fire population size within 10 years/three generations.
Main conclusions
We suggest the 2019–2020 Australian megafires have worsened the conservation prospects for many species. Of the 91 taxa recommended for listing/uplisting consideration, 84 are now under formal review through national processes. Improving predictions about taxon vulnerability with empirical data on population responses, reducing the likelihood of future catastrophic events and mitigating their impacts on biodiversity, are critical.
Background:
Metastatic bone disease in the periacetabular region represents a potentially devastating problem for patients. Surgical treatment can offer pain relief and restore function. We describe ...a series of patients treated with minimally invasive osteoplasty and screw fixation with or without ablation.
Methods:
Thirty-eight patients with 16 different metastatic tumor subtypes were managed with osteoplasty and screw fixation with or without ablation at a single institution. A retrospective review was performed to determine functional outcomes with use of the 1993 Musculoskeletal Tumor Society (MSTS) score as well as changes in narcotic usage.
Results:
MSTS scores improved for all patients following surgery. Narcotic usage decreased in >80% of patients. Approximately half of the operations were outpatient procedures. Complications were minimal, there were no delays in chemotherapy or radiation due to surgical wound concerns, and there were no surgery-related deaths. The mean duration of follow-up was 9 months, with a 39% survival rate at the time of writing. Six of the 12 patients who survived for >1 year required additional procedures at a mean of 12 months (range, 4 to 23 months).
Conclusions:
Treatment of periacetabular metastatic disease with minimally invasive stabilization with or without ablation provides pain relief and functional improvement with lower complication rates than previously reported open reconstruction techniques. The minimally invasive approach allows for rapid initiation of chemotherapy and radiation. Patients with particularly aggressive cancers that are poorly responsive to systemic therapies and radiation may have progression of disease and may require additional procedures. Conversion to total hip arthroplasty was uncomplicated, and the cement and screw constructs were retained, providing a stable base for the arthroplasty reconstruction.
Level of Evidence:
Therapeutic
Level IV
. See Instructions for Authors for a complete description of levels of evidence.
The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle ...immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.
Commencing in 1956, observations made at Halley Research Station in Antarctica provide one of the longest continuous series of near-surface temperature observations from the Antarctic continent. ...Since few other records of comparable length are available, the Halley record has been used extensively in studies of long-term Antarctic climate variability and change. The record does not, however, come from a single location but is a composite of observations from a sequence of seven stations, all situated on the Brunt Ice Shelf, that range from around 10 to 50 km in distance from the coast. Until now, it has generally been assumed that temperature data from all of these stations could be combined into a single composite record with no adjustment. Here, we examine this assumption of homogeneity. Application of a statistical changepoint algorithm to the composite record detects a sudden cooling associated with the move from Halley IV to Halley V station in 1992. We show that this temperature step is consistent with local temperature gradients measured by a network of automatic weather stations and with those simulated by a high-resolution atmospheric model. These temperature gradients are strongest in the coastal region and result from the onshore advection of maritime air. The detected inhomogeneity could account for the weak cooling trend seen in the uncorrected composite record. In future, studies that make use of the Halley record will need to account for its inhomogeneity.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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