Background Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic ...effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. Methods This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without norepinephrine, norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. Results A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. Conclusions In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation.
•Improved cancer survival with use of antihistamines desloratadine and loratadine.•Improved survival seen in tumors that respond to immune checkpoint therapy.•A – potentially immunological – ...anti-tumor effect of desloratadine and loratadine.
We have previously shown an association with substantially improved survival in breast cancer and melanoma for desloratadine and loratadine users, and set out to find whether an improved survival can be seen in tumors with and without a known response to immune checkpoint therapy, such as anti-CTLA-4 or anti-PD-1.
We investigated survival and use of six common H1-antihistamines (cetirizine, clemastine, desloratadine, ebastine, fexofenadine and loratadine) in a nation-wide cohort of all 429,198 Swedish patients with ten types of immunogenic (gastric, colorectal/anal, pancreatic, lung, breast, prostate, kidney, and bladder cancer, melanoma and Hodgkin lymphoma) and six non-immunogenic (liver, uterine, ovarian, brain/CNS, and thyroid cancer and non-Hodgkin lymphoma) tumors diagnosed 2006–2017. Follow-up was until 2019–02–24.
Desloratadine use was associated with an improved survival for all immunogenic tumors, but not for the non-immunogenic ones. Loratadine use was associated with improved survival for some tumors. Use of the other antihistamines could not be shown to be consistently associated with improved survival to a statistically significant degree.
Our hypothesis is that our findings result from immune checkpoint inhibition, and we believe both desloratadine and loratadine should be tested in randomized clinical trials as treatment of immunogenic tumors, with priority given to trials of desloratadine as treatment of tumors with few therapy options and dismal prognoses, such as pancreatic cancer. If our results can be confirmed in a clinical setting, new, potentially curative, therapies could result for several tumors, including ones with dire prognoses and limited treatment options.
Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed ...autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.
Sun exposure in combination with skin pigmentation is the main determinant for vitamin D status. Human skin color seems to be adapted and optimized for regional sun ultraviolet (UV) intensity. ...However, we do not know if fair, UV-sensitive skin is a survival advantage in regions with low UV radiation.
A population-based nested case-control study of 29,518 Caucasian women, ages 25 to 64 years from Southern Sweden who responded to a questionnaire regarding risk-factors for malignant melanoma in 1990 and followed for 25 years. For each fair woman, defined as having red hair or freckles (n = 11,993), a control was randomly selected from all non-fair women from within the cohort of similar age, smoking habits, education, marital status, income, and comorbidity, i.e., 11,993 pairs. The main outcome was the difference in all-cause mortality between fair and non-fair women in a low UV milieu, defined as living in Sweden and having low-to-moderate sun exposure habits. Secondary outcomes were mortality by sun exposure, and among those non-overweight.
In a low UV milieu, fair women were at a significantly lower all-cause mortality risk as compared to non-fair women (log rank test p = 0.04) with an 8% lower all-cause mortality rate (hazard ratio HR = 0.92, 95% CI 0.84‒1.0), including a 59% greater risk of dying from skin cancer among fair women (HR 1.59, 95% CI 1.26‒2.0). Thus, it seem that the beneficial health effect from low skin coloration outweigh the risk of skin cancer at high latitudes.
In a region with low UV milieu, evolution seems to improve all-cause survival by selecting a fair skin phenotype, i.e., comprising fair women with a survival advantage.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Airborne Laser Scanning (ALS) has implied a disruptive transformation of how data are gathered for forest management planning in Nordic countries. We show in this study that the accuracy of ALS ...predictions of growing stock volume can be maintained and even improved over time if they are forecasted and assimilated with more frequent but less accurate remote sensing data sources like satellite images, digital photogrammetry, and InSAR. We obtained these results by introducing important methodological adaptations to data assimilation compared to previous forestry studies in Sweden. On a test site in the southwest of Sweden (58°27′N, 13°39′E), we evaluated the performance of the extended Kalman filter and a proposed modified filter that accounts for error correlations. We also applied classical calibration to the remote sensing predictions. We evaluated the developed methods using a dataset with nine different acquisitions of remotely sensed data from a mix of sensors over four years, starting and ending with ALS-based predictions of growing stock volume. The results showed that the modified filter and the calibrated predictions performed better than the standard extended Kalman filter and that at the endpoint the prediction based on data assimilation implied an improved accuracy (25.0% RMSE), compared to a new ALS-based prediction (27.5% RMSE).
Data assimilation (DA) is often used for merging observations to improve the predictions of the current and future states of characteristics of interest. In forest inventory, DA has so far found ...limited use, although dense time series of remotely sensed (RS) data have become available for estimating forest characteristics. A problem in forest inventory applications based on RS data is that errors from subsequent predictions tend to be strongly correlated, which limits the efficiency of DA. One reason for such a correlation is that model-based predictions, using techniques such as parametric or non-parametric regression, are normally biased conditional on the actual ground conditions, although they are unbiased conditional on the RS predictor variables. A typical case is that predictions are shifted towards the mean, i.e., small true values are overestimated, and large true values are underestimated. In this study, we evaluated if the classical calibration of RS-based predictions could remove this type of bias and improve DA results. Through a simulation study, we mimicked growing stock volume predictions from two different sensors: one from a metric strongly correlated with growing stock volume, mimicking airborne laser scanning, and one from a metric slightly less correlated with growing stock volume, mimicking data obtained from 3D digital photogrammetry. Consistent with previous findings, in areas such as chemistry, we found that classical calibration made the predictions approximately unbiased. Further, in most cases, calibration improved the DA results, evaluated in terms of the root mean square error of predicted volumes, evaluated at the end of a series of ten RS-based predictions.
In general, melanoma can be considered as a UV‐driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by ...sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen‐activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple‐wild‐type status and correlated with tumor and patient characteristics. We found that the NF1‐mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co‐occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain‐containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1‐mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease‐specific survival, DSS; HR, 1.9; 95% CI, 1.21–3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28–2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
Melanoma is stratified based on somatic mutations in BRAF, NRAS, or NF1 genes. However, the clinical significance of this classification is unknown. Here, Cirenajwis et al. in silico combined in‐house mutation data with data from three published studies. Collectively, the NF1‐mutated subtype had a higher mutational burden, was enriched for male patients and older patients as well as an increased risk of death from melanoma. This highlights the need for improved characterization of this group.
Purpose
In Sweden, a Traceback approach, i.e., a retrospective genetic outreach activity, among cancer patients is not normally used in clinical practice. In this pilot study, we wanted to evaluate a ...Traceback strategy for possible future clinical implementation and investigate why not all women with early-onset breast cancer underwent genetic testing when they were first diagnosed.
Methods
Out of all women (
n
= 409) diagnosed with breast cancer at ≤ 35 years in Southern Sweden between 2000 and 2017, 63 had not previously been tested. These women were offered an analysis of the genes
BRCA1
,
BRCA2
,
PALB2
,
CHEK2
, and
ATM
through a standardized letter. Subsequently, women with normal test results were informed through a letter and carriers of pathogenic variants were contacted through a telephone call and offered in-person genetic counseling. All tested women were asked to complete a follow-up questionnaire regarding previously not having attended genetic counseling and testing and their experiences of the current retrospective approach.
Results
Out of the invited women, 29 (46%) underwent genetic testing and 27 (43%) answered the questionnaire. Pathogenic variants were identified in
BRCA1
(
n
= 2),
CHEK
2 (
n
= 1), and
ATM
(
n
= 1). The main reason for previously not having undergone genetic testing was not having received any information from their physicians. Most study participants were satisfied with both written pre- and post-test information.
Conclusion
The process with retrospective identification, written pre-test information, and genetic testing, followed by in-person counseling for carriers of pathogenic variants only, was well accepted. This has implications for future Traceback implementation programs.
The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, ...characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type‐specific genes extracted from genome‐wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss‐of‐function events for melanomas unresponsive to immunotherapies (immune‐low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low‐dimensional projection based on immune cell type‐specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type‐specific methylation differed across tumor and cell types. However, in melanomas immune cell type‐specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan‐cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.
The importance of the tumor immune microenvironment has been highlighted in multiple cancers, but information regarding the contribution of individual immune cell types is lacking for melanoma. In this study, we have sought to fill the gap by identifying distinct DNA methylation patterns for specifc immune cells. These were corroborated by other molecular correlates and found to be shared across other types of solid tomors.
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