Patient reported outcomes following MR-guided radiotherapy for prostate cancer: a systematic review and meta-analysis.

PURPOSE: This systematic review provides an overview of literature on the impact of MR-guided radiotherapy (MRgRT) on patient reported outcomes (PROs) in patients with prostate cancer (PC). METHODS: A systematic search was performed in October 2023 in PubMed, EMBASE and Cochrane Library. The PICOS framework (i.e., patient, intervention, comparison, outcome, study design) was used to determine eligibility criteria. Included were studies assessing PROs following MRgRT for PC with sample size >10. Methodological quality was assessed using the ROBINS-I and RoB 2. Relevant mean differences (MD) compared to pre-RT were interpreted using minimal important differences (MID). Meta-analyses were performed using random-effects models. Between-study heterogeneity was assessed using the I2-statistic. RESULTS: Eleven observational studies and one randomized controlled trial (n=897) were included. Nine studies included patients with primary PC with MRgRT as first-line treatment (n=813) and three with MRgRT as second-line treatment (n=84). Substantial risk of bias was found in five studies. EORTC QLQ-C30 and EORTC QLQ-PR25 scores were pooled from three studies, and EPIC-26 scores from four studies. Relevant MDs for the urinary domain were found with the EPIC-26 (MD-10.0 [95%CI -12.0 - -8.1]; I20%) and the EORTC QLQ-PR25 (MD8.6 [95%CI -4.7-22.0]; I297%), both at end-RT to one month follow-up. Relevant MDs for the bowel domain were found with the EPIC-26 (MD-4.7 [95%CI -9.2 - -0.2]; I282%), at end-RT or one month follow-up, but not with the EORTC QLQ-PR25. For both domains, no relevant MDs were found after three months of follow-up. No relevant MDs were found in the general QoL domains of the EORTC QLQ-C30. CONCLUSION: MRgRT for PC results in a temporarily worsening of patient-reported urinary and bowel symptoms during the first month after treatment compared to pre-RT, resolving at 3 months. No clinically relevant changes were found for general QoL domains. These results provide important information for patient counseling and can serve as a benchmark for future studies.

Frequency of GCH1 deletions in Dopa-responsive dystonia.

We performed a systematic study on the frequency of point mutations and deletions of the gene GCH1 in dopa-responsive dystonia (DRD). A total of 136 dystonia patients were studied. Fifty of these had a sustained response to oral L-Dopa therapy (group 1: definite diagnosis of DRD), whereas the response to L-Dopa was incomplete or not tested in 86 patients (group 2: possible diagnosis of DRD). We found a GCH1 point mutation in 27 patients of group 1 (54%) and in four patients of group 2 (5%). Of these, nine single and one double mutation have not been described before. GCH1 deletions were detected in four patients of group 1 (8%) and in one patient of group 2 (1%). Among GCH1 point-mutation-negative patients with a definite diagnosis of DRD (group 1), the frequency of GCH1 deletions was 17% (4/23). We conclude that GCH1 deletion analysis should be incorporated into the routine molecular diagnosis of all patients with DRD with a sustained response to L-Dopa.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience.

AIMS: Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS: We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS: Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION: MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

Specificity of head-up tilt testing in adolescents: effect of various degrees of tilt challenge in normal control subjects.

OBJECTIVES: This study sought to determine the specificity of commonly used tilt protocols in children. BACKGROUND: Tilt table testing is commonly utilized in the evaluation of children and adolescents with syncope despite a lack of uniformity in tilt protocols and a lack of studies of specificity in normal control subjects. METHODS: Sixty-nine normal control volunteers (12 to 18 years old, 38 male, 31 female) with no previous history of syncope, presyncope or arrhythmia underwent tilting to 80 degrees, 70 degrees or 60 degrees for a maximum of 30 min on a motorized table with a footboard support. Autonomic maneuvers, including deep breathing, carotid massage, Valsalva maneuver and diving reflex, were performed before tilt testing to determine whether the response to these maneuvers could identify subjects prone to fainting during tilt testing. RESULTS: Symptoms of presyncope and frank syncope were elicited in 24 of 69 subjects (13 male, 11 female): 6 (60%) of 10 were tilted at 80 degrees, 9 (29%) of 31 at 70 degrees and 9 (32%) of 28 at 60 degrees. Tilt testing at 80 degrees was terminated after the tenth subject by the institutional review board. The mean time to a positive test response was 10.5 min at 80 degrees, 14.2 min at 70 degrees and 13.2 min at 60 degrees. In the 80 degrees tilt, 4 of 10 subjects had a positive response within 10 minutes, whereas only 3 of 31 and 2 of 28 had a positive response within < 10 min at 70 degrees and 60 degrees tilt angles, respectively. Subjects with and without a positive response to tilt testing were similar with respect to age; gender; PR, QRS and QT intervals; and baseline heart rate and blood pressure. Likewise, responses to other autonomic function tests performed were similar in tilt-positive and tilt-negative patients. The power for detecting a significant difference between patients tilted at 80 degrees versus 60 degrees and 70 degrees was 0.45 and for detecting differences in autonomic tone between tilt-positive (n = 24) and tilt-negative (n = 45) subjects was 0.8. CONCLUSIONS: Children appear to be more susceptible to orthostatic stress than adults. Therefore, tilt protocols commonly used in adults lack specificity in teenage patients. A specificity > 85% may be obtained by performing the tilt test at 60 degrees or 70 degrees for no longer than 10 min.

Population genetic data determined for five different single locus minisatellite probes.

We report on the population genetic data (frequencies of restriction fragments, heterozygosity rates, and mutation rates) obtained by analysis of approximately 1100 Hinfl-digested DNAs from West Germans. Probe G3 detects a common 1.7 kb DNA fragment showing a population frequency of about 13%. All the other fragments detected with probes MS1, MS31, MS43, G3 and YNH24 show frequencies of less than 8%. These data suggest that single locus DNA probes can provide valuable information for parentage evaluation and individualization.

Human autosomal short tandem repeat types in Jat Sikhs from North India.

This study provides Jat Sikhs population data in North India for nine short tandem repeat (STR) loci.

Gm and Km frequencies in West Germans: usefulness of typing Gm(1,2,3,10,21) and Km(1,3) in paternity cases.

The immunoglobulin allotypes G1m(1,2,3) and G3m(10,21) were typed in 2855 unrelated West German adult individuals. 1455 individuals were typed for the factors Km(1,3). Phenotype and haplotype frequencies are reported. The usefulness of this routine typing programme in paternity tests is demonstrated in three case reports.

Sequence analysis and population data on the 'new' short tandem repeat locus D5S2360.

We have studied the sequence structure and population genetics of a 'new' short tandem repeat polymorphism at locus D5S2360 in German Caucasians. Sequencing at this locus revealed a considerable variation, which is characterized by a tetranucleotide (AGAT)(n) repeat pattern with (GAT), (AGATT), and (AG) repeats dispersed throughout the alleles. These microvariations do not necessarily alter the size of the alleles. They may vary by one or two pairs or they may remain unchanged in size. At locus D5S2360 we observed 33 allelic lengths comprising at least 36 different alleles. Population data revealed a high polymorphism with a heterozygosity rate of approximately 92.5%.

Usefulness of conventional blood groups, DNA-minisatellites, and short tandem repeat polymorphisms in paternity testing: a comparison.

A total of 215 paternity cases were analysed after testing 24 marker systems. Despite technical advantages of polymerase chain reaction related polymorphisms (automatisation, employment of robots, lesser requirements concerning of quality and quantity of DNA) it could be shown that the exclusive employment of a parentage testing kit is compromised by an increased risk of erroneous conclusions. It is estimated that in about 3-4% of the cases ambiguous situations have to be expected which are caused by the occurrence of single or double exclusions. In these cases it is impossible to decide whether the exclusions indicate either true nonpaternity or a de novo mutation. The situation might become even more complicated if an involvement of a close relative of the alleged father cannot be ruled out. We cautiously advance the hypothesis that in parentage testing DNA minisatellite polymorphisms from an optimal set of tools.

Size calculation of restriction enzyme HaeIII-generated fragments detected by probe YNH24 by comparison of data from two laboratories: the generation of fragment-size frequencies.

Restriction fragment-length polymorphism of locus D2S44 detected by the highly polymorphic probe YNH24 and restriction endonuclease HaeIII can be used to improve parentage testing when representative fragment-size frequencies can be obtained. By joining the results of different laboratories, it is possible to set up a meaningful databank. Therefore, the same randomly chosen samples were tested for the HaeIII RFLP detected by probe YNH24 in Düsseldorf (DUS) and Amsterdam (AMS). The results of the different fragment-size calculations obtained by using internal markers and a computerized system (DUS-cad and AMS-cad), and by using external markers and manual calculations (DUS-man), were analyzed. Comparing these results, no statistically significant differences were seen. The results obtained with probe YNH24 and enzyme HaeIII in Düsseldorf and Amsterdam can be used to attain a sufficient number of samples to generate relevant fragment-size frequencies.

Biostatistical basis of individualization and segregation analysis using the multilocus DNA probe MZ 1.3: results of a collaborative study.

A collaborative study using the multilocus minisatellite DNA probe MZ 1.3 was carried out to investigate segregation information, mutation rate, DNA fragment frequencies as well as band sharing characteristics. The fingerprint patterns of 393 children as well as 694 unrelated individuals were analysed after digestion of DNA with the restriction enzyme HinfI. A mutation rate of 1% per meiosis or 0.04% per band was found with a mean number of 26 bands/individual. It was shown that maternal and paternal fragments are inherited in equal proportions. Population frequencies of restriction fragments demonstrated a distribution with increasing frequencies in the small fragment size range below 10 kb as well as the absence of very common or very rare fragments. Our data can be used to calculate simple exclusion probabilities based on the number of non-maternal bands in the child.

A new method for the evaluation of matches in non-recombining genomes: application to Y-chromosomal short tandem repeat (STR) haplotypes in European males.

A 9-locus microsatellite framework (minimal haplotype), previously developed for forensic purposes so as to facilitate stain analysis, personal identification and kinship testing, has been adopted for the establishment of a large reference database of male European Y-chromosomal haplotypes. The extent of population stratification pertaining to this database, an issue crucial for its practical forensic application, was assessed through analysis of molecular variance (AMOVA) of the 20 regional samples included. Despite the notion of some significant haplotype frequency differences, which were found to correlate with known demographic and historic features of Europeans, AMOVA generally revealed a high level of genetic homogeneity among the populations analyzed. Owing to their high diversity, however, accurate frequency estimation is difficult for Y-STR haplotypes when realistic (i.e. moderately sized) datasets are being used. As expected, strong pair-wise and higher order allelic associations were found to exist between all markers studied, implying that haplotype frequencies cannot be estimated as products of allele frequencies. A new extrapolation method was therefore developed which treats haplotype frequencies as random variables and generates estimates of the underlying distribution functions on the basis of closely related haplotypes. This approach, termed frequency 'surveying', is based upon standard population genetics theory and can in principle be applied to any combination of markers located on the Y-chromosome or in the mitochondrial genome. Application of the method to the quality assured reference Y-STR haplotype database described herein will prove very useful for the evaluation of positive trace-donor matches in forensic casework.

Online reference database of European Y-chromosomal short tandem repeat (STR) haplotypes.

The reference database of highly informative Y-chromosomal short tandem repeat (STR) haplotypes (YHRD), available online at http://ystr.charite.de, represents the largest collection of male-specific genetic profiles currently available for European populations. By September 2000, YHRD contained 4688 9-locus (so-called "minimal") haplotypes, 40% of which have been extended further to include two additional loci. Establishment of YHRD has been facilitated by the joint efforts of 31 forensic and anthropological institutions. All contributing laboratories have agreed to standardize their Y-STR haplotyping protocols and to participate in a quality assurance exercise prior to the inclusion of any data. In view of its collaborative character, and in order to put YHRD to its intended use, viz. the support of forensic caseworkers in their routine decision-making process, the database has been made publicly available via the Internet in February 2000. Online searches for complete or partial Y-STR haplotypes from evidentiary or non-probative material can be performed on a non-commercial basis, and yield observed haplotype counts as well as extrapolated population frequency estimates. In addition, the YHRD website provides information about the quality control test, genotyping protocols, haplotype formats and informativity, population genetic analysis, literature references, and a list of contact addresses of the contributing laboratories.

Human orosomucoid (ORM1) subtyping: further population genetic data and reports on the feasibility to type aged blood samples and stains.

Genetic polymorphism of serum orosomucoid (ORM1) was investigated in 1072 unrelated German Caucasians using isoelectric focusing followed by Western blotting and EIA. The estimated allele frequencies were ORM1 *F1 = 0.5690, ORM1 *S = 0.3927, ORM1 *F2 = 0.0368, ORM1 *F2S = 0.0009 and ORM1 *F5 = 0.0005. The method was successfully applied to determine ORM1 phenotypes in aged blood samples and blood stains. The results indicated that the ORM protein is a informative and remarkably robust blood group system.

[Significance and testimonial value of hemo-genetic legal identification with special reference to DNA analysis]. / Zur Bedeutung und Aussagekraft des hämogenetischen Identitätsgutachtens unter besonderer Berücksichtigung der DNA-Analyse.

175 hemogenetic expertises on the identity of ostensibly jumbled blood samples were analysed. In 4.5% of the cases a genetically qualified non-identity was found, although an erronous mixing-up of samples could be excluded. A major problem may arise when the expert witness has to find out whether a non-identity is due to either genetic or to artificial reasons. A battery of conventional blood group systems as well as highly informative DNA polymorphisms is a powerful tool in discriminating between both reasons and enables the expert to reach a decision.

Distribution of two Asian-related coding SNPs in the MC1R and OCA2 genes.

Very little is known about the genes and mechanisms affecting skin lightening in Asian populations. In this study, two coding SNPs, c.G1129A (R163Q) at the MC1R (melanocortin 1 receptor) gene and c.A1962G (H615R) at the OCA2 (oculocutaneous albinism type II) gene, were investigated in a total of 1,809 individuals in 16 populations from various areas. The Q163 and R615 alleles prevailed almost exclusively in East and Southeast Asian populations. Wright's F (ST) was 0.445 for R163Q and 0.385 for H615R among the 16 populations. The frequency of the Q163 allele was higher in Northeast Asians than in Southeast Asians. The frequency of the R615 allele was highest in South China and unlikely to be associated with levels of ultraviolet radiation. This allele may be a good marker to study the genetic affinity among East Asians because of its restricted distribution and marked difference in allele frequency.