Synthesis and evaluation of druglike parameters via in silico techniques for a series of heterocyclic monosquarate-amide derivatives as potential carboxylic acid bioisosteres.

Herein, we present a synthetic compound library comprising of 13 structurally diverse heterocyclic monosquarate-amide derivatives. The compounds featured in this library were designed as potential bioisosteric replacements carboxylic acid moiety's. A good selection of the compounds presented exhibit unique molecular architecture and have shown promising results following in silico evaluation of 'druglike properties' using Swiss ADME. The research presented in this work focuses on the preparation of derivatives of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

Does autoimmune hypothyroidism increase the risk of neurovascular complications in type 1 diabetes?

BACKGROUND: Type 1 diabetes (T1DM) often coexists with other autoimmune diseases, most commonly with hypothyroidism. To date, the influence of coexisting autoimmune hypothyroidism (AHT) on the course of chronic neurovascular complications of autoimmune diabetes has not been established. The aim of the study was to assess the relationship between AHT and the occurrence of chronic T1DM complications. METHODS: The study group comprised 332 European Caucasian participants with T1DM [165 (49.7%) men]. AHT was recognized in subclinical and overt hypothyroidism and confirmed by the presence of anti-thyroid autoantibodies: anti-peroxidase (ATPO) and/or anti-thyroglobulin (ATg) and ultrasonography (hypoechogenicity, parenchymal heterogeneity, lymph nodes assessment). RESULTS: In the analyzed group, 48.5% of patients were diagnosed with at least one neurovascular complication. At the time of enrollment, 16.3% of participants were diagnosed with AHT. Patients with AHT, compared to those without AHT, were characterized by a higher prevalence of neurovascular complications (64.8 vs. 45.3%; P = 0.009) and retinopathy (55.6 vs. 38.9%; P = 0.02). There were significant differences between groups with and without neurovascular complications, with regard to classic risk factors for chronic diabetes complications: age, T1DM duration, SBP, DBP, HbA1c, TG, eGFR and hypertension prevalence. In the multivariate logistic regression analysis, AHT was an independent predictor of neurovascular complications after adjusting for age, DBP, HbA1c and TG (odds ratio, 2.40; 95% confidence interval, 1.17-4.92; P = 0.02). CONCLUSIONS: AHT coexisting with T1DM was associated with a higher incidence of neurovascular complications.

Activity and safety of crizotinib in patients with alveolar soft part sarcoma with rearrangement of TFE3: European Organization for Research and Treatment of Cancer (EORTC) phase II trial 90101 'CREATE'.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET- sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET- patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET- cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. Clinical trial number: EORTC 90101, NCT01524926.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Influence of Cytochrome P450, ABC and SLC Gene Polymorphisms on Imatinib Therapy Outcome of Patients with Gastrointestinal Stromal Tumours (GIST).

The efficacy of imatinib-based therapy depends on the proteins involved in its metabolism and transportation. Therefore, the aim of our study was to investigate the possible correlation of selected P450, ABC and SLC polymorphic variants and the outcome of imatinib therapy. A total of 101 patients with advanced, KIT/PDGFRA(+) GIST treated with imatinib were enrolled to the study. DNA was extracted from peripheral blood samples and genotypes were determined by PCR-RFLP and direct sequencing. Deviation from the Hardy-Weinberg equilibrium was only observed for rs2740574. None of the studied SNPs was associated with GIST time to progression. No significant correlation between any specific variant and time to progression was found in the group with KIT exon 11 mutation. However, individuals of at least three potentially unfavourable genotypes presented significantly shorter time to progression in comparison to patients with two or less unfavourable genotypes.

Morphological assessment of thin basement membrane disease.

Thin basement membrane disease is more common than IgA nephropathy or Alport syndrome, which are also associated with the presence of erythrocyturia. Very few reports on the disorder are available in the Polish literature. The objective of this work was to analyze the results from 83 patients with thin basement membrane syndrome as well as to formulate a proposal of strict morphological assessment criteria for the disorder. Attention was drawn to the requirement of thickness of the lamina densa rather than the entire basement membrane thickness and a sufficiently high number of loops featuring thinned lamina densa, namely at least 80% of loops, being taken into account. Occurrence of other morphological changes associated with the disorder and clinical symptoms other than erythrocyturia was also highlighted.

Oxidative stress in blood of healthy people after diving.

AIM: The aim of this study was to investigate the effect of diving on the level of lipid peroxidation products and the activity of antioxidant enzyme in blood of healthy volunteers. METHODS: The studied group consisted of 11 experienced divers, who spent 40 min submerged in water, at an average depth of 6.2 m with water temperature of 13ºC. Blood samples were taken before diving and immediately after surfacing. The concentration of conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) was assayed both in blood plasma and erythrocytes, while the activity of superoxide dismutase (SOD) in erythrocytes. RESULTS: A statistically significant increase of CD level in blood plasma and an increasing tendency in erythrocytes with concomitant decrease of SOD activity was observed after diving. No statistically significant changes in concentration of TBARS both in blood plasma and erythrocytes were revealed. CONCLUSION: The changes in environmental conditions during diving cause the oxidant-antioxidant imbalance, as it is evidenced by observed increase of CD level, which are the primary markers of lipid peroxidation and the decrease of SOD activity. No changes in the level of secondary products of lipid peroxidation - TBARS, may suggest that in studied subjects inhibition of free-radical processes occurs and/or the products of lipid peroxidation are quickly removed due to adaptation, what protect the divers against damages on cellular level.

IGC investigation of the effect of the length of the n-alkyl substituent in 5-alkylsubstituted norbornenes on solute retention.

Polymerization of 5-n-alkyl-substituted 2-norbornenes synthesized a series of polymers having the same structure of the main polymer chain, but differing in the length of the alkyl substituent (up to 14 methylene units). The obtained polymers were studied by the capillary IGC method as a stationary phase during separation of a mixture of normal hydrocarbons C6-C10. Retention data in the form of a logarithm of the retention factor lnk were correlated with the size of the sorbate (via the carbon number of the alkane ZS) and with the size of the n-alkyl substituent in the polymer chain (via the carbon number of the polymer ZP). Correlation of lnk vs. ZS turned out to be linear for all polymers, but the angle of the slope of linear dependence dlnk/dZS increases with a decrease in the carbon number of the polymer ZP. Dependency of dlnk/dZS vs. ZP is not linear and indicates an increase in the retention of sorbates by the stationary phase with a decrease in the length of the alkyl substituent in the polymer chain. The correlation of the retention of lnk analytes with the carbon number of the polymer ZP is not linear and indicates an increase in the sorbate/sorbent interaction with a decrease in the length of the alkyl substituent. Inflection points were found at both correlations with ZP in the region of ZP = 8, which indicates a possible change in the sorption mechanism or a change in the phase state of the polymer. In polymer chemistry, the phase state of a polymer is characterized by the glass transition temperature Tg, the dependence of which vs. ZP turned out to be nonlinear with an inflection point at ZP ∼11. Thus, a decrease in the length of the alkyl substituent leads to the transition of the polymer from a rubbery state to a glassy one at ZP ∼ 11, which in turn, with a further decrease in the carbon number of the polymer to ZP ∼ 8, causes a change in the sorption mechanism from bulk sorption to surface sorption. The change in the sorption mechanism is accompanied by an increase in the interaction of the sorbate with the stationary phase, which manifests itself both in an increase in the retention time of analytes and in an increase in the enthalpy and entropy of sorption. The reason for this increase can be seen in the formation of a microporous structure in 5-alkyl-substituted polynorbornenes in a glassy state.

MiR-17-92 and miR-221/222 cluster members target KIT and ETV1 in human gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are characterised by high expression of KIT and ETV1, which cooperate in GIST oncogenesis. Our aim was to identify microRNAs that are deregulated in GIST, have a role in GIST pathogenesis, and could potentially be used as therapeutic tool. METHODS: Differentially expressed microRNAs between primary GIST (n=50) and gastrointestinal leiomyosarcomas (GI-LMS, n=10) were determined using microarrays. Selected microRNA mimics were transfected into GIST-882 and GIST-T1 cell lines to study the effects of microRNA overexpression on GIST cells. Luciferase reporter assays were used to establish regulation of target genes by selected microRNAs. RESULTS: MiR-17-92 and miR-221/222 cluster members were significantly (P<0.01) lower expressed in GIST vs GI-LMS and normal gastrointestinal control tissues. MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and--to a lesser extent--mRNA levels of their predicted target genes KIT and ETV1. Luciferase reporter assays confirmed direct regulation of KIT and ETV1 by miR-222 and miR-17/20a, respectively. CONCLUSION: MicroRNAs that may have an essential role in GIST pathogenesis were identified, in particular miR-17/20a/222 that target KIT and ETV1. Delivering these microRNAs therapeutically could hold great potential for GIST management, especially in imatinib-resistant disease.

Defining pseudoprogression in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Pseudoprogression is a frequent phenomenon observed since the introduction of postoperative therapy with radiotherapy and temozolomide (RT/TMZ) in glioblastoma multiforme (GBM) patients. However, the criteria defining pseudoprogression, its incidence, the time of occurrence and its impact on therapy and outcome remain poorly defined. METHODS: The objective of this study is to compare two sets of criteria (liberal and stringent), defining pseudoprogression, in a cohort of patients treated before and after the introduction of RT/TMZ in the standard postoperative treatment. This retrospective review includes 136 unselected and consecutively treated patients with pathologically diagnosed GBM. RESULTS: Pseudoprogression was observed in 10 (12%) cases applying the stringent criteria, and in 18 (23%) patients when using the liberal criteria, in the cohort treated with RT/TMZ. Pseudoprogression was observed in only one patient treated with RT alone. The median time to pseudoprogression was 4 weeks after the end of RT. Patients with pseudoprogression had a median survival time of 28 months, compared with 12 months for patients without pseudoprogression. CONCLUSIONS: The incidence of pseudoprogression after RT/TMZ strongly depends on the applied criteria. However, regardless of the stringency of the criteria, the impact on survival remains the same.

A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience.

BACKGROUND: Majority of gastrointestinal stromal tumours (GISTs) are characterised by KIT-immunopositivity and the presence of KIT/platelet-derived growth factor receptor alpha (PDGFRA) activating mutations. PATIENTS AND METHODS: Spectrum and frequency of KIT and PDGFRA mutations were investigated in 427 GISTs. Univariate and multivariate analysis of relapse-free survival (RFS) was conducted in relation to tumours' clinicopathologic features and genotype. RESULTS: Mutations were found in 351 (82.2%) cases, including 296 (69.3%) KIT and 55 (12.9%) PDGFRA isoforms. Univariate analysis revealed higher 5-year RFS rate in women (37.9%; P = 0.028) and in patients with gastric tumours (46.3%; P < 0.001). In addition a better 5-year RFS correlated with smaller tumour size ≤ 5 cm (62.7%; P < 0.001), tumours with mitotic index ≤ 5/50 high-power fields (60%; P < 0.001), and characterised by (very) low/moderate risk (70.2%; P = 0.006). Patients with GISTs bearing deletions encompassing KIT codons 557/558 had worse 5-year RFS rate (23.8%) than those with any other KIT exon 11 mutations (41.8%; P < 0.001) or deletions not involving codons 557/558 (33.3%; P = 0.007). Better 5-year RFS characterised patients with KIT exon 11 point mutations (50.7%) or duplications (40%). By multivariate analysis, tumours with PDGFRA mutations and KIT exon 11 point mutations/other than 557/558 deletions had lower risk of progression than with KIT exon 11 557/558 deletions (both Ps = 0.001). CONCLUSIONS: KIT/PDGFRA mutational status has prognostic significance for patients' outcome and may help in management of patients with GISTs.

Safety of central venous catheter placement at diagnosis of acute lymphoblastic leukemia in children.

BACKGROUND: Central venous catheters (CVC) facilitate the management of patients with cancer. Optimal timing for placement of a CVC is controversial. We sought to determine whether early placement in children with acute lymphoblastic leukemia (ALL), a group at high risk for infection and thrombosis, was associated with an increased rate of surgical complications. PROCEDURE: We evaluated the incidence and risk factors for early surgical complications in children with ALL diagnosed between 2004 and 2009 at a single pediatric cancer center. RESULTS: One hundred seventy-two patients were studied. There were 17 episodes of bloodstream infection, for a 30-day incidence of 9.8% (95% CI, 5.9-15%). There were no surgical site infections and no CVC was removed due to infection. Early thrombosis occurred in only one patient, 3 days after CVC placement. Infection was not influenced by catheter type, patient age, body mass index, or fever at the time of placement. The infection rate was not statistically higher when the ANC was <500/mm(3) at the time of CVC placement (14.2% vs. 6.8%; P = 0.12). CONCLUSION: Early CVC placement at the time of diagnosis of ALL was associated with a low surgical complication rate with no catheters requiring removal due to infection. Utilizing our current methods of preoperative preparation, surgical management and postoperative CVC care, early placement of a CVC is safe in children with ALL even when their ANC is <500/mm(3) , but larger cohort studies would be helpful to further clarify this issue.

M-protein gene-type distribution and hyaluronic acid capsule in group A Streptococcus clinical isolates in Chile: association of emm gene markers with csrR alleles.

Streptococcus pyogenes causes a variety of infections because of virulence factors such as capsular hyaluronic acid and M protein. The aim of this study was to determine emm types and capsule phenotype in 110 isolates of S. pyogenes from patients with invasive (sterile sites) and non-invasive (mainly pharyngitis) infections in Chile, and the relationship between both virulence factors. The most abundant types found were emm12, emm1, emm4 and emm28 and their distribution was similar to that seen in Latin America and developed countries, but very different from that in Asia and Pacific Island countries. Ten of 16 emm types identified in pharyngeal isolates were found in sterile-site isolates, and three of nine emm types of sterile-site isolates occurred in pharyngeal isolates; three emm subtypes were novel. The amount of hyaluronic acid was significantly higher in sterile-site isolates but did not differ substantially among emm types. Only three isolates were markedly capsulate and two of them had mutations in the csrR gene that codes for a repressor of capsule synthesis genes. We found a non-random association between emm types and csrR gene alleles suggesting that horizontal gene transfer is not freely occurring in the population.

Development and inter-laboratory validation of the VISAGE enhanced tool for age estimation from semen using quantitative DNA methylation analysis.

The analysis of DNA methylation has become an established method for chronological age estimation. This has triggered interest in the forensic community to develop new methods for age estimation from biological crime scene material. Various assays are available for age estimation from somatic tissues, the majority from blood. Age prediction from semen requires different DNA methylation markers and the only assays currently developed for forensic analysis are based on SNaPshot or pyrosequencing. Here, we describe a new assay using massively parallel sequencing to analyse 13 candidate CpG sites targeted in two multiplex PCRs. The assay has been validated by five consortium laboratories of the VISible Attributes through GEnomics (VISAGE) project within a collaborative exercise and was tested for reproducible quantification of DNA methylation levels and sensitivity with DNA methylation controls. Furthermore, DNA extracts and stains on Whatman FTA cards from two semen samples were used to evaluate concordance and mimic casework samples. Overall, the assay yielded high read depths (> 1000 reads) at all 13 marker positions. The methylation values obtained indicated robust quantification with an average standard deviation of 2.8% at the expected methylation level of 50% across the 13 markers and a good performance with 50 ng DNA input into bisulfite conversion. The absolute difference of quantifications from one participating laboratory to the mean quantifications of concordance and semen stains of remaining laboratories was approximately 1%. These results demonstrated the assay to be robust and suitable for age estimation from semen in forensic investigations. In addition to the 13-marker assay, a more streamlined protocol combining only five age markers in one multiplex PCR was developed. Preliminary results showed no substantial differences in DNA methylation quantification between the two assays, indicating its applicability with the VISAGE age model for semen developed with data from the complete 13-marker tool.

How does osteonecrosis about the knee progress in young patients with leukemia?: a 2- to 7-year study.

BACKGROUND: Osteonecrosis is a major treatment complication of pediatric leukemias owing to its potential to cause joint deterioration. Because of potential long-term effects of osteonecrosis on joints, information regarding its progression and collapse in different patients can be used to identify high-risk groups, advise the patients and parents of this complication, and potentially consider the risk for development of osteonecrosis in planning primary treatment. QUESTIONS/PURPOSES: We therefore determined: (1) the incidence of joint collapse and/or pain in young patients with hematologic malignancies diagnosed with ON of the knee; (2) risk factors associated with collapse; and (3) the relationship between size and location of osteonecrotic knee lesions and the likelihood of joint collapse. PATIENTS AND METHODS: We retrospectively reviewed 109 patients with hematologic malignancies and MRI-confirmed knee osteonecrosis. The median age was 11.5 years (range, 2.3-18.8 years) at primary diagnosis of hematologic malignancy and a median age of 13.4 years (range, 2.7-23.3 years) at diagnosis of osteonecrosis of the knee. For analyses, we used the first and last MR images. Minimum clinical followup was 2.3 years after diagnosis of knee osteonecrosis (median, 6 years; range, 2.3-7.17 years). RESULTS: Joint collapse occurred in 22% (24 of 109). Older age, pain at osteonecrosis presentation, and lesions extending to the articular surface of distal femoral epiphyses were associated with joint collapse. CONCLUSIONS: Younger patients and those without extensive femoral epiphyseal involvement have a better prognosis for osteonecrosis of the knee. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Anti-tumor activity of the MDM2-TP53 inhibitor BI-907828 in dedifferentiated liposarcoma patient-derived xenograft models harboring MDM2 amplification.

PURPOSE: Dedifferentiated liposarcoma (DDLPS) is a soft tissue malignancy characterized by amplification of the mouse double minute 2 homolog (MDM2) gene. MDM2 is a negative regulator of tumor protein 53 (TP53). We tested the in vivo efficacy of BI-907828, a small molecule inhibitor of the MDM2-TP53 interaction, in two DDLPS patient-derived xenografts (PDX). METHODS: Partially immunodeficient mice were bilaterally engrafted with UZLX-STS3 (n = 24) and UZLX-STS5 (n = 24) human DDLPS tissue harboring MDM2 amplifications. Mice were grouped as follows: (a) vehicle (0.5% hydroxyethylcellullose) 10 ml/kg daily per os (p.o.); (b) doxorubicin 5 mg/kg weekly intraperitoneally (i.p.); (c) BI-907828 2.5 mg/kg daily p.o. and (d) BI-907828 10 mg/kg daily p.o. The treatment lasted for 15 days, all mice treated with BI-907828 were followed for 37 days post-treatment. Efficacy was assessed by tumor volume and histopathological evaluation. RESULTS: The 15-day treatment with 2.5 mg/kg and 10 mg/kg BI-907828 significantly inhibited tumor growth in UZLX-STS5 and -STS3 (p < 0.0001 compared to control for both models). All UZLX-STS5 and -STS3 tumors treated with BI-907828 decreased in size during treatment, and BI-907828-treated UZLX-STS5 tumors even disappeared completely. During the follow-up period, no tumor regrowth was observed in the UZLX-STS5 model and both doses of BI-907828 led to a pathological complete response, whereas a dose-dependent regrowth was seen in the UZLX-STS3 model. CONCLUSION: BI-907828 showed significant anti-tumor activity in DDLPS PDX harboring MDM2 amplifications, providing a strong rationale for early clinical testing of BI-907828 in a DDLPS patient population.

Reliability of the Modified TICI Score among Endovascular Neurosurgeons.

BACKGROUND AND PURPOSE: The modified TICI score is the benchmark for quantifying reperfusion after mechanical thrombectomy. There has been limited investigation into the reliability of this score. We aim to identify intra-rater and inter-rater reliability of the mTICI score among endovascular neurosurgeons. MATERIALS AND METHODS: Four independent endovascular neurosurgeons (raters) reviewed angiograms of 67 patients at 2 time points. κ statistics assessed inter- and intrarater reliability and compared raters'-versus-proceduralists' scores. Reliability was also assessed for occlusion location and by dichotomizing modified TICI scores (0-2a versus 2b-3). RESULTS: Interrater reliability was moderate-to-substantial, weighted κ = 0.417-0.703, overall κ = 0.374 (P < .001). The dichotomized modified TICI score had moderate-to-substantial interrater agreement, κ statistics = 0.468-0.715, overall κ = 0.582 (P < .001). Intrarater reliability was moderate-to-almost perfect, weighted κ = 0.594-0.81. The dichotomized modified TICI score had substantial-to-almost perfect reliability, κ = 0.632-0.82. Proceduralists had fair-to-moderate agreement with raters, weighted κ = 0.348-0.574, and the dichotomized modified TICI score had fair-to-moderate agreement, κ = 0.365-0.544. When proceduralists and raters disagreed, proceduralists' scores were higher in 79.6% of cases. M1 followed by ICA occlusions had the highest agreement. CONCLUSIONS: The modified TICI score is a practical metric for assessing reperfusion after mechanical thrombectomy, though not without limitations. Agreement improved when scores were dichotomized around the clinically relevant threshold of successful revascularization. Interrater reliability improved with time, suggesting that formal training of interventionalists may improve reporting reliability. Agreement of the modified TICI scale is best with M1 and ICA occlusion and becomes less reliable with more distal or posterior circulation occlusions. These findings should be considered when developing research trials.

A Comparison of Forensic Age Prediction Models Using Data From Four DNA Methylation Technologies.

Individual age estimation can be applied to criminal, legal, and anthropological investigations. DNA methylation has been established as the biomarker of choice for age prediction, since it was observed that specific CpG positions in the genome show systematic changes during an individual's lifetime, with progressive increases or decreases in methylation levels. Subsequently, several forensic age prediction models have been reported, providing average age prediction error ranges of ±3-4 years, using a broad spectrum of technologies and underlying statistical analyses. DNA methylation assessment is not categorical but quantitative. Therefore, the detection platform used plays a pivotal role, since quantitative and semi-quantitative technologies could potentially result in differences in detected DNA methylation levels. In the present study, we analyzed as a shared sample pool, 84 blood-based DNA controls ranging from 18 to 99 years old using four different technologies: EpiTYPER®, pyrosequencing, MiSeq, and SNaPshotTM. The DNA methylation levels detected for CpG sites from ELOVL2, FHL2, and MIR29B2 with each system were compared. A restricted three CpG-site age prediction model was rebuilt for each system, as well as for a combination of technologies, based on previous training datasets, and age predictions were calculated accordingly for all the samples detected with the previous technologies. While the DNA methylation patterns and subsequent age predictions from EpiTYPER®, pyrosequencing, and MiSeq systems are largely comparable for the CpG sites studied, SNaPshotTM gives bigger differences reflected in higher predictive errors. However, these differences can be reduced by applying a z-score data transformation.