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| 2. |
- Campbell, Brittany B., et al.
(author)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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In: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Journal article (peer-reviewed)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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| 3. |
- Das, A., et al.
(author)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Journal article (peer-reviewed)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 4. |
- Faries, B., et al.
(author)
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Completion dissection or observation for sentinel-node metastasis in melanoma
- 2017
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In: New England Journal of Medicine. - 0028-4793. ; 376:23, s. 2211-2222
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Journal article (peer-reviewed)abstract
- BACKGROUND Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediatethickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS Immediate completion lymph-node dissection was not associated with increased melanomaspecific survival among 1934 patients with data that could be evaluated in an intention-Totreat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (-SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86-1.3% and 86-1.2%, respectively; P = 0.42 by the logrank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68-1.7% and 63-1.7%, respectively; P = 0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92-1.0% vs. 77-1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P = 0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases.
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| 5. |
- Johansson, Sveneric, et al.
(author)
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The FERRUM Project: New f-value Data for Fe II and Astrophysical Applications
- 2002
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In: Physica Scripta. - : Institute of Physics Publishing (IOPP). - 0281-1847 .- 0031-8949 .- 1402-4896. ; T100, s. 71-80
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Conference paper (peer-reviewed)abstract
- We present the FERRUM Project, an international collaboration aiming at a production and evaluation of oscillator strengths (transition probabilities) of selected spectral lines of singly ionized iron group elements, that are of astrophysical relevance. The results obtained include measurements and calculations of permitted and forbidden lines of Fe II. The data have been applied to both emission and absorption lines in astrophysical spectra. We make comparisons between experimental, theoretical and astrophysical f-values. We give a general review of the various measurements, and discuss the UV8 multiplet of Fe II around 1610 Šin detail.
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| 6. |
- D, Andesson, et al.
(author)
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Ergonomiskt utformning av styckningsarbete
- 1985
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Reports (other academic/artistic)abstract
- This research work was carried out together with the Department of Industrial Ergonomics at Linköping University, Linköping. A comment: Publishing consumer reports was the praxis during this (early) period of time at Chalmers University of Technology, as well as probably at some other universities. This means that frequent and vast academic publication by means of e.g. conference papers and refereed contributions to scientific journals was almost unheard of. At least so for some of the applied science disciplines. However, today are the situation indeed very different (i.e. earlier was the publication in many respects focused on trying to satisfy the executive administrator the research foundation in question etc.). To be more precise, this early praxis was definitively the case for the research and development work carried out at the Department of Transportation (a broadly applied science discipline), which was characterized by more practical strives to e.g. engineer research results. Rather than relying on truer scientific efforts in a narrower sense. Functional satisfaction (i.e. something engineered work as planned instead verification/falsification of a hypothesis) was judged as being a primary aim of this research and development work. Therefore are (in the context of the publications registered in Chalmers Public Library CPL) the author making distinctions between consumer reports, on one hand. And, one the other hand, reports and preprints (manuscripts), while instead the academically orientated publications are various sort of scientific contributions presented at conferences or published in scientific journals (actually it is somewhat more complex, but further explanations are omitted here). The consumer reports were aimed at a various external organization with who the authors cooperated, and these are in many cases not available in PDF format to be easily read by logging in at CPL. This particular approach has judged as being fair/relevant fair in order to mirror of work conducted by the author or authors during the passing decades. Besides, the competencies at Chalmers Library, who actually have been very helpful, have not managed to provide appropriate answers to the various questions implied being at hand just above (this despite trying to get hold of such answers, hence this very comment).
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| 7. |
- Durno, C., et al.
(author)
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Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance
- 2021
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In: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 39:25
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Journal article (peer-reviewed)abstract
- PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.
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| 8. |
- McFarlane, G., et al.
(author)
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Enamel daily secretion rates of deciduous molars from a global sample of children
- 2021
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In: Archives of Oral Biology. - : Elsevier BV. - 0003-9969. ; 132
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Journal article (peer-reviewed)abstract
- Objective: To investigate and describe the variation in enamel daily secretion rates (DSRs) of naturally exfoliated deciduous molars (n = 345) from five modern-day populations (Aotearoa New Zealand, Britain, Canada, France, and Sweden). Design: Each tooth was thin sectioned and examined using a high-powered Olympus BX51 microscope and DP25 digital microscope camera. Mean DSRs were recorded for the inner, mid, and outer regions of cuspal and lateral enamel, excluding enamel nearest the enamel-dentin junction and at the outermost crown surface. Results: Mean DSRs did not vary significantly between populations, or by sex. Cuspal enamel grew slightly faster than lateral enamel (mean difference 0.16 mu m per day; p < 0.001). The trajectory of DSRs remained relatively constant from inner to outer cuspal enamel and increased slightly in lateral enamel (p = 0.003). Conclusions: The DSRs of deciduous molars from modern-day children are remarkably consistent when compared among populations. While growth rates are faster in cuspal than lateral enamel, the trajectory of enamel formation changes only slightly from inner to outer regions. The trajectory of DSRs for deciduous molars differs to that of permanent molar enamel, which typically display a steep increase in matrix deposition from inner to outer enamel.
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| 9. |
- Rask, Olof, et al.
(author)
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Prospective registration of symptoms and times to diagnosis in children and adolescents with central nervous system tumors: A study of the Swedish Childhood Cancer Registry
- 2022
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In: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 69:11
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Journal article (peer-reviewed)abstract
- Background The elapsed time taken to diagnose tumors of the central nervous system in children and adolescents varies widely. The aim of the present study was to investigate such diagnostic time intervals at a national level in Sweden as they correlate with clinical features. Methods Data prospectively accumulated over a 4-year period in the Swedish Childhood Cancer Registry from patients aged 0-18 years were pooled, and diagnostic time intervals were analyzed considering tumor location, tumor type, patient age and sex, initial symptoms, and clinical timelines. All six pediatric oncology centers in Sweden contributed to collection of data. Time points for calculating the total diagnostic interval (TDI) defined as the time from symptom onset to diagnosis were reported in 257 of 319 patients (81%). Results The time from symptom onset to the first healthcare consultation, median 2.6 weeks, did not vary significantly between patients categorized according to tumor type or location. The median TDI was 8.3 weeks for the 4-year study period. Patients with optic pathway glioma (TDI 26.6 weeks), those with tumors of the spinal cord (TDI 25.9 weeks), and those with midline tumors (TDI 24.6 weeks) had the longest lead times. Additionally, older age, too few initial symptoms, and seeking initial redress outside an emergency ward were factors associated with a longer time to diagnosis. Conclusion This study identified several factors associated with delayed diagnosis of central nervous system tumors among Swedish children and adolescents. These novel data ought to help direct future efforts toward clinical improvement.
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