Mutation-positive Group Research Articles

Analysis of Morphologic Classification System for Acute Promyelocytic Leukemia and Its Correlation with Laboratory Tests and FLT3-ITD Mutation

To establish a morphologic classification system for characterizing blast cells in patients with acute promyelocytic leukemia (APL) and analyze the correlation of different APL morphologic characteristics with conventional tests and genetic variants. Based on the morphological characteristics of APL blast cells, a classification system of 14 categories was established to characterize the inter- and intra-individual cellular morphological heterogeneity of patients. The classification system was used for the morphological analysis of 40 APL patients, and the classification results were statistically analyzed with the patients' conventional test indexes and gene variant characteristics to analyze the correlation of different APL blast cell morphological features with conventional test indexes and gene variants. In the FLT3-ITD mutation-positive group, there were significantly fewer cells with regular nuclear shape, hyper granularity, and missing Auer rods (category 1) than in the FLT3 mutation-negative group (P < 0.05). The activated partial thromboplastin (APTT) was significantly longer in the group with regular nucleus compared to the group with irregular nucleus (P < 0.05). In the hypo-granular group, the APTT was also significantly longer compared to the hyper-granular group (P < 0.01), and the proportion of myeloid blast cells was relatively lower (P < 0.05). The peripheral blood white blood cell counts, D-dimer, lactate dehydrogenase and proportion of bone marrow blast cells were significantly higher in the Auer rods (-) group than Auer rods increasing group (all P < 0.05). The newly established morphologic classification system in this study can objectively characterize different types of APL blast cells, which helps to better assess the intra- and inter-individual heterogeneity of APL blast cells, and further use in accurately analyzing the correlation of morphological phenotypes with biological properties of APL.

Impact of smoking on resected lung cancer depends on epidermal growth factor receptor mutation.

Smokers comprise the majority of surgical patients with primary lung cancer. Epidermal growth factor receptor (EGFR) mutation-negative status impacts the treatment of recurrence. However, the prognostic impact of cigarette smoking stratified by EGFR mutation status has not been reported. Therefore, we assessed its impact on patients with resected lung cancer. We retrospectively analysed 362 consecutive patients who underwent complete resection for stage 1 primary lung cancer at our institution between 2012 and 2021. The EGFR mutation status was evaluated using the real-time polymerase chain reaction. We compared the overall survival (OS) and disease-free survival (DFS) between patients with and without a history of smoking. The EGFR mutation-negative group included 194 patients, of whom 160 (83%) had a history of smoking. Male sex (P < 0.01), forced expiratory volume in 1 s (P < 0.01) and adenocarcinoma (P < 0.01) showed significant differences between the groups. In the EGFR mutation-positive group, the 5-year OS and DFS were similar regardless of smoking status (OS: 86% vs 75%; DFS: 73% vs 73%). In the EGFR mutation-negative group, the 5-year OS and DFS were significantly poorer in the smoking group (OS: 87% vs 65%, P = 0.05; DFS: 84% vs 54%, P = 0.01). Deaths from other diseases were relatively high (n = 19, 53%). Cigarette smoking may be associated with a poor prognosis in EGFR mutation-negative lung cancer but had no impact on the prognosis of the EGFR mutation-positive group. This finding underscores the potential influence of smoking on the treatment of lung cancer recurrence but also highlights its significance in contributing to death from other diseases.

Characterization of DNA damage repair mutations in lung cancer in an underserved urban patient population.

e20058 Background: DNA-damage repair (DDR) mutations in lung cancer have shown potential for use as therapeutic targets and predictive biomarkers. However, the relationship between DDR mutations and socioeconomic factors remains largely unknown. In this study, we characterize the distribution of DDR gene mutations in lung cancer patients at a single academic medical center serving a unique population consisting of primarily underserved, underinsured patients. Methods: All lung cancer patients seen at the University of Illinois Chicago (UIC) between 11/2/2015 and 9/11/2023 with TEMPUS genetic data available were included in the study (N = 235). DDR mutations of interest were ARID1A, ATM, ATR, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, ERCC3, FANCA, FANCC, MLH3, MRE11, MSH6, MUTYH, NBN, PALB2, and RAD50. The population was subdivided into a DDR mutation positive group and a DDR mutation negative group. Each group was compared with respect to lung cancer type, tumor mutational burden (TMB), and socioeconomic factors including sex, race, insurance category, and zip code. Results: The overall frequency of DDR mutations in the population was 28.5% (n = 67). The most common DDR mutations were ARID1A (20.7%), CHEK2 (12.8%), ATM (9.9%), BRCA2 (9.9%), ATRX (7.9%), and MUTYH (7.9%). The histological distribution of the DDR mutation positive group was adenocarcinoma (76.1%), squamous cell carcinoma (4.4%), adenosquamous carcinoma (2.9%), neuroendocrine carcinoma (5.9%), and other (10.4%). The histological distribution of the DDR negative group was adenocarcinoma (60.1%), squamous cell carcinoma (22.0%), adenosquamous carcinoma (1.1%), neuroendocrine carcinoma (4.1%), and other (12.5%). There was a significant effect in TMB, t(55) = 2.97, p = 0.004, with a higher mean TMB in the DDR positive group (M = 14.4, SD = 11.1) compared to the DDR negative group (M = 9.4, SD = 5.1). The most common zip codes in the DDR positive groupwere 60608 (9.0%), 60629 (9.0%), and 60616 (7.5%) compared to 60616 (8.3%), 60609 (5.3%), and 60624 (4.7%) in the DDR negative group. Demographic factors of the two groups are compared below. Conclusions: The frequency and distribution of DDR mutations in lung cancer at UIC appears similar to what has been previously reported in the literature. There is a higher tumor mutational burden in lung cancers with DDR mutations, which may suggest greater susceptibility to immunotherapy. There may be a correlation between the presence of DDR mutations and lung cancer type, insurance category, and patient geographic distribution. Future work will include obtaining further geographic data for the study population such as average income, pollution exposure, and smoking rate by neighborhood. [Table: see text]

TERT Promoter Mutations Increase Tumor Aggressiveness by Altering TERT mRNA Splicing in Papillary Thyroid Carcinoma.

Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis than TERT-p mutation-positive tumors. TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. We investigated the expression of 2 major variants, α deletion (dA) and β deletion (dB), in a series of 207 PTCs operated on between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into 3 groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A+B/dB ratio in mut+/exp+ was significantly higher than that in mut-/exp+ PTCs. Analysis with clinicopathological data revealed that +A+B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor-suppressive role. These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Gene Profile and Clinical Significance of Concomitant Mutations in CN-AML Patients with CEBPA Mutation

To analyze the occurrence of concomitant gene mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients with CEBPA mutation and its impact on the clinical characteristics and prognosis of the patients. 151 newly diagnosed patients with CN-AML in the Second Hospital of Shanxi Medical University from June 2013 to June 2020 were analyzed retrospectively. 34 common genetic mutations associated with hematologic malignancies were detected by next-generation sequencing technology. The occurrence of concomitant gene mutations in patients with CEBPA positive and negative groups was compared, and the correlation between concomitant mutations in different functional groups and the clinical characteristics and prognosis of CN-AML patients with CEBPA mutation was analyzed. In 151 patients with CN-AML, 55 (36.42%) were positive for CEBPA mutation (including 36 cases of CEBPAdm and 19 cases of CEBPAsm), of which 41 (74.55%) had co-mutations with other genes. The main mutated genes were GATA2 (25.45%, 14/55), TET2 (21.82%, 12/55), FLT3 (20.00%, 11/55), NRAS (12.73%, 7/55) and WT1 (9.09%, 9/55), etc. Some cases had two or more concomitant gene mutations. Grouping the mutant genes according to their functions showed that CEBPA+ group had lower mutation rates of histone methylation (P =0.002) and chromatin modification genes (P =0.002, P =0.033), and higher mutation rates of transcription factors (P =0.037) than CEBPA- group. In 55 patients with CEBPA+ CN-AML, the platelet count at diagnosis in signaling pathway gene mutation-positive group was lower than that in the mutation-negative group (P =0.005), the proportion of bone marrow blasts in transcription factor mutation-positive group was higher than that in the mutation-negative group (P =0.003), and the onset age in DNA methylation gene mutation-positive group and chromatin modifier mutation-positive group was older than that in the mutation-negative group, respectively (P =0.002, P =0.008). DFS of CEBPA+ CN-AML patients in signaling pathway gene mutation group was shorter than that in signaling pathway gene mutation-negative group (median DFS: 12 months vs not reached) (P =0.034). Compared with DNA methylation gene mutation-negative group, CEBPA+ CN-AML patients with DNA methylation gene mutation had lower CR rate (P =0.025) significantly shorter OS and DFS (median OS: 20 months vs not reached, P =0.006; median DFS: 15 months vs not reached, P =0.049). OS in patients with histone methylation gene mutation was significantly shorter than that in the histone methylation gene mutation-negative group (median OS: 12 months vs 40 months) (P =0.008). Multivariate analysis of prognostic factors showed that the proportion of bone marrow blasts (P =0.046), concomitant DNA methylation gene mutation (P =0.006) and histone methylation gene mutation (P =0.036) were independent risk factors affecting the prognosis. CN-AML patients with CEBPA mutation have specific concomitant gene profile, and the concomitant mutations of different functional genes have a certain impact on the clinical characteristics and prognosis of the patients.

TP53 and/or BRCA1 Mutations Based on CtDNA Analysis as Prognostic Biomarkers for Primary Triple-Negative Breast Cancer.

Precise biomarkers for predicting the therapeutic efficacy of molecularly targeted drugs are limited at the protein level; thus, it has been important to broadly scrutinize individual cancer driver gene mutations for effective cancer treatments. Multiplex cancer genome profiling can comprehensively identify gene mutations that are therapeutic targets using next-generation sequencing (NGS). In addition, circulating tumor DNA (ctDNA) is a DNA fragment released into the blood by tumor cell-derived cell death or apoptosis. Liquid biopsy with ctDNA is a novel clinical test for identifying genetic mutations in an entire population noninvasively, in real-time, and heterogeneously. Although there are several reports on ctDNA, fewer have evaluated ctDNA with NGS before an initial treatment for breast cancer patients. Therefore, we examined whether analyzing tumor-associated gene mutations in primary breast cancer based on ctDNA could serve as a biomarker for prognosis and optimal treatment selection. Ninety-five primary breast cancer patients treated at our department from January 2017 to October 2020 were included. Pretreatment plasma samples were subjected to NGS analysis of ctDNA, and correlations with patients' clinicopathological characteristics were evaluated. Fifty-nine (62.1%) patients were positive for ctDNA. ctDNA tended to be positive in hormone receptor-negative, and TP53 (34%), BRCA1 (20%), and BRCA2 (17%) gene mutations were more frequent. Regarding recurrence-free survival, the prognosis was poor in the TP53 and/or BRCA1 mutation-positive groups, especially in triple-negative breast cancer (TNBC) patients. In conclusion, the results of this study indicate that ctDNA with liquid biopsy could identify the poor prognosis group before treatment among TNBC patients and for those for whom optimal treatment selection is desirable; additionally, optimal treatment could be selected according to the ctDNA analysis results.

MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results.

159 Background: MK-5684 (previously ODM-208) is a first-in-class, oral, non-steroidal, selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. MK-5684 suppresses the production of all steroid hormones and precursors that may activate the androgen receptor (AR) signaling pathway. Initial phase 1 (ASCO-GU 2022) and phase 2 results in AR-LBD mutation-positive (ESMO 2022) mCRPC patients were previously presented. Now we report phase 2 results for both AR-LBD mutation-positive and negative patients. Methods: MK-5684 5mg BID (with dexamethasone and fludrocortisone) was evaluated in an open-label expansion cohort in patients with progressing mCRPC who had previously received ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy. An initial expansion cohort enrolled 45 patients with an activating AR-LBD mutation identified in cell-free DNA (Guardant360 assay, 74-gene panel), a subsequent extension cohort included mainly AR-LBD mutation-negative patients to attain comparable groups of about 60 patients each, with and without AR-LBD mutations. Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. MK-5684 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA. Data are based on a 17 July 2023 data cut-off. Results: A total of 66 AR-LBD mutation-positive and 68 AR-LBD mutation-negative patients (median age 68.3 years) were enrolled and received MK-5684 treatment. 53% and 33.8% of patients had previously received both abiraterone and enzalutamide, and 63.6% and 55.9% patients had received cabazitaxel in AR-LBD mutation positive and negative groups respectively. MK-5684 profoundly suppressed androgen synthesis resulting in PSA50 responses in 55.6% and 16.7% of patients and PSA30 responses in 69.8% and 30.0% of patients, with and without AR-LBD mutations respectively. At the time of abstract data cut-off, objective responses by RECIST had occurred in 8 patients, all with AR-LBD mutations (ORR 20.5% for AR-LBD positive). MK-5684 was well-tolerated: the most common treatment-related adverse events were related to adrenal suppression with the rate of hospitalization for adrenal insufficiency being much lower than in phase 1 when typically higher MK-5684 doses were administered (3.0% vs. 33% respectively). Data with a minimum follow up of approximately 4 months after last patient enrolment will be presented. Conclusions: Administration of MK-5684 to heavily pre-treated mCRPC patients showed promising antitumor activity. PSA50 responses were most frequent among patients harboring activating AR-LBD mutations. Clinical trial information: NCT03436485 .

Clinical, genomic and immune microenvironmental determinants of nivolumab response in head and neck squamous cell carcinoma.

In view of improving biomarkers predicting the efficacy of immunotherapy for head and neck squamous cell carcinoma (R/M HNSCC), this multicenter retrospective study aimed to identify clinical, tumor microenvironmental, and genomic factors that are related to therapeutic response to the anti- Programmed cell death protein 1 (PD-1) antibody, nivolumab, in patients with R/M HNSCC. The study compared 53 responders and 47 non-responders, analyzing formalin-fixed paraffin-embedded samples using 14-marker multiplex immunohistochemistry and targeted gene sequencing. Of 100 patients included, responders had significantly lower smoking and alcohol index, higher incidence of immune related adverse events, and higher PD-1 ligand (PD-L1) expression in immune cells as well as PD-L1 combined positive score (CPS) than non-responders. The frequency of natural killer cells was associated with nivolumab response in patients with prior cetuximab use, but not in cetuximab-naïve status. Age-stratified analysis showed nivolumab response was linked to high CPS and lymphoid-inflamed profiles in patients aged ≥ 65. In contrast, lower NLR in peripheral blood counts was associated with response in patients aged < 65. Notably, TP53 mutation-positive group had lower CPS and T cell densities, suggesting an immune-excluded microenvironment. Patients with altered tumor suppressor gene pathways, including TP53, CDKN2A, and SMAD4 mutations, had lower CPS, higher smoking index, and were associated with poor responses. Nivolumab treatment efficacy in HNSCC is influenced by a combination of clinical factors, age, prior treatment, immune environmental characteristics, and gene mutation profiles.

Prevalence and prognosis of PIK3CA mutations in Bulgarian patients with metastatic breast cancer receiving endocrine therapy in first-line setting.

In approximately 40% of patients with HER2-negative/HR-positive breast cancer tumors, the PIK3CA gene is mutated. Despite this, clinical outcomes vary between studies in this cohort. We aimed to ascertain the prevalence of PIK3CA mutations in patients with metastatic HR+/HER2- breast in Bulgaria, as well the evaluation and comparison of progression free survival (PFS) between wild-type (WT) and mutation-positive groups in the real-world setting. Three oncology centers in Bulgaria collected 250 tissue samples between 2016 and 2022 for this multicentric retrospective study. PIK3CA mutations were identified using Real-Time qPCR. The median follow-up period was 35 months. The mean age of the mutant cohort was 57.6 ± 11.6 years, compared to 56.5 ± 12.2 years for the WT cohort (p = .52). The percentage of patients with visceral metastasis was 58.8% (n = 147). Approximately 84.3% (n = 210) of the patients had reached postmenopause. 29.2% (n = 73) of the patients had PIK3CA mutations. The predominant mutation was present in exon 20, H1047R (46.5%). We found a significant correlation only between the presence of a mutation and the metastatic diseases at diagnosis (p = .002). As first-line therapy, 67.1% of patients received endocrine therapy (ET) plus cyclin dependent kinase (CDK4/6) inhibitor, while the remainder received ET alone. The median PFS of patients in the group with the mutation was 32 months (95%, CI: 22-40) compared to 24 months in the WT cohort ((95%, CI: 21-36) (p = .45)); HR = 0.86 (95%, CI: 0.5-1.3) (p = .46). We corroborated our conclusion using propensity matching score analysis, (36 months [95% CI: 20-40] vs. 26 months [95% CI: 21-38], [p = .69]). We found that the prevalence of PIK3CA mutations in our patients was comparable to what has been reported in other nations. Our results suggest that PIK3CA mutational status has no bearing to ET efficacy in first-line setting.

Genetic Mutation and Outcome of Venetoclax-Based Therapy in Newly Diagnosed AML in the Real World: Hokkaido Leukemia Net Study

Introduction Venetoclax (VEN) had been approved in Japan since March 2021 for acute myeloid leukemia (AML), and VEN-based regimens were widely used as initial therapy predominantly for elderly or unfit patients. Genetic mutations affect therapeutic outcomes of VEN-based therapy (CD DiNardo, et al. Blood. 2020). We performed gene panel sequencing using a next-generation sequencer for the newly diagnosed AML patients who were initially treated by VEN-based regimen and analyzed the relationship between gene mutations and outcomes in our regional cohort. Patients and Methods Hokkaido Leukemia Net (HLN) is prospective cohort study collecting acute leukemia samples from affiliated hospitals of the North Japan Hematology Study Group (NJHSG) covering Hokkaido and Iwate, Japan. We developed a compact AML panel covering mutation hot spots of 14 genes including TP53, CEBPA, NPM1, FLT3, KIT, NRAS, KRAS, CBL, PTPN11, DNMT3A, IDH1, IDH2, RUNX1 and ASXL1. Treatment efficacy was determined based on European LeukemiaNet 2017 response criteria in AML. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional review boards. Results A total of 89 AML cases registered in HLN from May 2021 to April 2023 were initially treated by VEN-based therapy (age range, 57-90 years; median age, 75 years; 49 males and 40 females, VEN+AZA 85, VEN+AraC 4). The median overall survival (OS) for all patients was 367 days (range 12-636). Patients who achieved complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR) during the observation period and had no relapse were designated as Group 1, those who relapsed as Group 2, and those who became Stable disease (SD) or Progressive disease (PD) as Group 3. IDH2 mutations were significantly more frequent in Group 1 (P=0.010), and NPM1 mutations also tended to be more frequent in Group 1 and 2 (P=0.064). Furthermore, the ratio of CR or CRi was more than 80% in the patients with mutation of CEBPA-bZIP, DNMT3A, IDH1, IDH2, and NPM1 mutation-positive groups, respectively. These response groups clearly stratified prognosis. On the other hand, prognostic stratification according to biological disease factors depending on National Comprehensive Cancer Network (NCCN) 2017 stratification could not stratify the VEN-treated cohort (P=0.26) (Figure 1). Next, the mutations with high CR+CRi rate ( CEBPA-bZIP, DNMT3A, IDH1, IDH2, and NPM1) were classified as “high-sensitivity mutations”. Patients with high-sensitivity mutations were significantly less likely to have complex karyotypes (P=0.026), but other patient characteristics such as age, sex, performance status, WBC count, other genetic mutations were not statistically different. Patients with high-sensitivity mutations had a significantly favorable OS than those without (median OS not reached; 95% CI, 367 - NA vs 331 days; 95% CI, 259-430, p=0.0022). Univariate analysis was carried out for age, sex, karyotype, each gene mutation and “high-sensitivity mutations”. IDH2 mutation and high-sensitivity mutations were associated with favorable OS (P=0.016, 0.0022, log-rank test). As previously reported, complex karyotypes and TP53 mutations were associated with poor OS (p&amp;lt;0.001, &amp;lt;0.001, log-rank test). Multivariate analysis including age, sex, “complex karyotype and/or TP53 mutation” and “high-sensitivity mutations” showed that the high-sensitivity mutations were independently associated with favorable OS (HR, 0.16; 95% CI, 0.053 to 0.62, p=0.0067; cox regression). Complex karyotype and/or TP53 mutation was independently associated with poor OS (HR, 2.39; 95% CI, 1.12 to 5.09, p=0.024; cox regression). Based on these results, we were able to stratify the prognosis by dividing the patients into three groups according to the presence of high-sensitivity mutations, complex karyotype and/or TP53 mutations (Figure 2). Conclusion VEN-based therapy abrogates the efficacy of NCCN2017 stratification, however, the genetic mutation profile of the initial disease successfully stratified prognosis.

131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML

Background : Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial. Results: In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p&amp;lt;0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI [0.37, 1.18]; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI [0.12, 0.67]; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) [(HR=0.23; 95% CI [0.10, 0.52]; p=0.0002) (Figure 1)]. Conclusion: Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.

BRAF V600E mutation in papillary thyroid microcarcinoma: is it a predictor for the prognosis of patients with intermediate to high recurrence risk?

The BRAFV600E mutation is the universal genetic mutation in papillary thyroid microcarcinoma (PTMC). The present study is to estimate the role of the BRAFV600E mutation in the clinical outcome of PTMC with intermediate to high recurrence risk after radioactive iodine (RAI) therapy, which is considered to be an indolent tumor. We conducted a single-center retrospective study. Between May 2016 and March 2019, PTMC patients with known BRAFV600E status who received RAI therapy were reviewed at the Second Hospital of Shandong University. Treatment and follow-up were defined according to criteria used in the 2015 ATA guidelines. The association between the BRAFV600E mutation and clinicopathological characteristics, response to RAI therapy, and recurrence after a period of follow-up were analyzed. Propensity score matching (PSM) and logistic regression were used to control confounding variables. Of the 322 patients with intermediate to high recurrence risk in PTMC, the mean age of the patients were 43.7 ± 12.2 years, and 72.1% were women. BRAFV600E mutation was found in 64.9% (209/322). After PSM, 112 pairs of patients were matched, and except for multifocality (P = 0.001), extrathyroidal invasion (P = 0.003) and tumor size (P = 0.03), there was no significant difference in all baseline characteristics between the two groups. An excellent response (ER) to RAI therapy was observed in 273 patients (84.7%). At the end of the study, 17(5.2%) and 6(1.8%) patients showed structural incomplete response (SIR) and biochemical incomplete response (BIR) status. The proportion of patients who achieved ER status in the BRAFV600E mutation positive and negative groups was 86.6% and 81.4%, respectively. Kaplan-Meier analyses showed that the BRAFV600E mutation was not related to lower ER reached time. The median follow-up was 51 months. We found the BRAFV600E mutation was associated with multifocality, extrathyroidal invasion, and tumor size in papillary thyroid microcarcinoma. However, the BRAFV600E mutation had no significant association with clinical outcomes in patients with intermediate to high recurrence risk after RAI therapy. Furthermore, the extra-thyroid uptake results and distant metastasis had been proven to be independent factor predicting the clinical response. ChiCTR2200062911.

Clinical role of CYP1B1 gene polymorphism in prediction of postoperative chemotherapy efficacy in NSCLC based on individualized health model.

Non-small cell lung cancer (NSCLC) is one of the most common cancers worldwide, and chemotherapy is one of its main treatment methods. However, there are significant differences in patients' reactions to chemotherapy, leading to unsatisfactory treatment outcomes. Therefore, identifying relevant factors that affect the efficacy of chemotherapy can help doctors better develop personalized treatment plans, improve the treatment effectiveness, and quality of life of patients. This article aims to understand the specific clinical role of CYP1B1 gene in NSCLC. Therefore, based on the individualized health model of CYP1B1 gene polymorphism, this article analyzes the prediction of postoperative chemotherapy efficacy for NSCLC. Through a study on the control variables of postoperative recovery of stage III NSCLC in a hospital, according to the findings of this study, 14 of the 32 patients in the EGFR mutation-positive group relapsed. In the EGFR-negative group, 13 of the 36 patients relapsed. It can be considered that CYP1B1 gene polymorphism has a good curative effect in postoperative chemotherapy of NSCLC, and it can effectively control the recurrence rate of cancer.

Difference in Radiosensitivity Depending on the Presence and Absence of EGFR Mutations: Clinical and In Vitro Analyses

For stage IV non-small cell lung cancer (NSCLC), the treatment drug is selected based on the gene mutation status. However, the dose or field of radiation therapy is not change based on the genetic status. We evaluated both clinical and in vitro data, showing that the presence or absence of epidermal growth factor receptor (EGFR) mutations affects radiosensitivity in patients with brain metastases (BM) from NSCLC. Patients with BM from NSCLC who received whole brain radiotherapy (WBRT) were enrolled in this study. Patient characteristics are shown in the Table. EGFR mutations were observed in 13 (31.0%) patients. The prescribed dose was 30 Gy in 10 fractions (85.7%). The A549, VMRC-LCD, NCI-H1975, and HCC4006 cell lines were used for the in vitro study. EGFR mutation was negative in A549 and VMRC-LCD and positive in NCI-H1975 (exon21) and HCC4006 (exon19). After irradiation of these cell lines with 0, 2, 4, and 8 Gy, a colony formation assay was performed. DNA double-strand breaks (DSBs) were assessed 30 min and 24 h after 4 Gy irradiation using γH2AX. The median follow-up period was 4 months (range, 1-35). Intracranial recurrence was observed in 14 (33.3%) patients during the follow-up period. Thirty-nine (92.9%) patients died during the follow-up period. Patients with EGFR mutation-positive tumors had significantly better intracranial control rates than those with EGFR mutation-negative tumors (p = 0.0213). A similar tendency was observed in the analysis conducted, except for the cases in which tyrosine kinase inhibitor (TKI) was administered after WBRT. In the EGFR mutation-positive group, no significant difference was observed between patients who received TKI after WBRT and those who did not (p = 0.527). In the colony formation assay, EGFR mutation-positive cell lines showed a significantly lower number of colonies formed after irradiation with 2 and 4 Gy than mutation-negative cell lines (p = 0.00018 and 0.0000291, respectively). EGFR mutation-positive cell lines had significantly more DNA-DSBs remaining 24 h after irradiation than mutation-negative cell lines (p = 0.0000000312). Our data suggest that patients with EGFR mutation-positive NSCLC are more radiosensitive than those with negative EGFR mutations.

Clinical and genetic characteristics of children with primary dilated cardiomyopathy

To study the genetic characteristics, clinical characteristics, and prognosis of children with primary dilated cardiomyopathy (DCM). A retrospective analysis was performed on the medical data of 44 children who were diagnosed with DCM in Hebei Children's Hospital from July 2018 to February 2023. According to the genetic testing results, they were divided into two groups: gene mutation-positive group (n=17) and gene mutation-negative group (n=27). The two groups were compared in terms of clinical data at initial diagnosis and follow-up data. Among the 44 children with DCM, there were 21 boys (48%) and 23 girls (52%). Respiratory symptoms including cough and shortness of breath were the most common symptom at initial diagnosis (34%, 15/44). The detection rate of gene mutations was 39% (17/44). There were no significant differences between the two groups in clinical characteristics, proportion of children with cardiac function grade Ⅲ or Ⅳ, brain natriuretic peptide levels, left ventricular ejection fraction, and left ventricular fractional shortening at initial diagnosis (P>0.05). The median follow-up time was 23 months, and 9 children (20%) died, including 8 children from the gene mutation-positive group, among whom 3 had TTN gene mutation, 2 had LMNA gene mutation, 2 had TAZ gene mutation, and 1 had ATAD3A gene mutation. The gene mutation-positive group had a significantly higher mortality rate than the gene mutation-negative group (P<0.05). There is no correlation between the severity of DCM at initial diagnosis and gene mutations in children. However, children with gene mutations may have a poorer prognosis.

Differential Distribution of Brain Metastases from Non-Small Cell Lung Cancer Based on Mutation Status.

Non-small cell lung cancer (NSCLC) has a high rate of brain metastasis. The purpose of this study was to assess the differential distribution of brain metastases from primary NSCLC based on mutation status. Brain MRI scans of patients with brain metastases from primary NSCLC were retrospectively analyzed. Brain metastatic tumors were grouped according to mutation status of their primary NSCLC and the neuroimaging features of these brain metastases were analyzed. A total of 110 patients with 1386 brain metastases from primary NSCLC were included in this study. Gray matter density at the tumor center peaked at ~0.6 for all mutations. The median depths of tumors were 7.9 mm, 8.7 mm and 9.1 mm for EGFR, ALK and KRAS mutation groups, respectively (p = 0.044). Brain metastases for the EGFR mutation-positive group were more frequently located in the left cerebellum, left cuneus, left precuneus and right precentral gyrus. In the ALK mutation-positive group, brain metastases were more frequently located in the right middle occipital gyrus, right posterior cingulate, right precuneus, right precentral gyrus and right parietal lobe. In the KRAS mutation-positive patient group, brain metastases were more frequently located in the posterior left cerebellum. Our study showed differential spatial distribution of brain metastases in patients with NSCLC according to their mutation status. Information regarding distribution of brain metastases is clinically relevant as it could be helpful to guide treatment planning for targeted therapy, and for predicting prognosis.

Association between DIAPH1 variant and posterior circulation involvement with Moyamoya disease

Moyamoya disease (MMD) is a chronic and progressive cerebrovascular stenosis or occlusive disease that occurs near Willis blood vessels. The aim of this study was to investigate the mutation of DIAPH1 in Asian population, and to compare the angiographic features of MMD patients with and without the mutation of the DIAPH1 gene. Blood samples of 50 patients with MMD were collected, and DIAPH1 gene mutation was detected. The angiographic involvement of the posterior cerebral artery was compared between the mutant group and the non-mutant group. The independent risk factors of posterior cerebral artery involvement were determined by multivariate logistic regression analysis. DIAPH1 gene mutation was detected in 9 (18%) of 50 patients, including 7 synonymous mutations and 2 missense mutations. However, the incidence of posterior cerebral artery involvement in mutation positive group was very higher than that in mutation negative group (77.8% versus 12%; p = 0.001). There is an association between DIAPH1 mutation and PCA involvement (odds ratio 29.483, 95% confidence interval 3.920–221.736; p = 0.001). DIAPH1 gene mutation is not a major genetic risk gene for Asian patients with moyamoya disease but may play an important role in the involvement of posterior cerebral artery.

Significance of the determination of DNA load of drug-resistant mycoplasma pneumoniae and 23sRNA gene mutation locus in children

Purpose: To determine the significance of the detection of Mycoplasma pneumoniae (MP)-DNA load and 23sRNA gene mutation locus in children with drug-resistant MP pneumonia. &#x0D; Methods: A total of 158 children with MP pneumonia received drug sensitivity tests. The patients were divided into resistance group and non-resistance group. The MP-DNA load index (MPLI) and mutation rate of 23sRNA gene at 2063 locus were assessed and compared between the two groups: the MPLI-negative group and the MPLI-positive group, based on whether MPLI was greater than 6.12. The association of MPLI of all the patients and the 23sRNA gene mutation at 2063 locus in the resistance group, as well as clinical indicators were analyzed. &#x0D; Results: The MPLI of the resistance group was lower than that of the non-resistance group. In the MPLI-positive group, the duration of disease, defervescence time, disappearance time of cough and expectoration, disappearance time of chest opacity, and length of stay were all longer than those of the MPLI-negative group, while the proportion of cases with extrapulmonary complications and the white blood cell (WBC) count were higher than those of the MPLI-negative group. The mutation rate of 23sRNA gene at 2063 locus in the resistance group was higher than that in non-resistance group (p &lt; 0.05). The defervescence time, disappearance time of cough and expectoration, disappearance time of chest opacity and length of stay were longer in the mutation-positive group than those in the mutation-negative group (p &lt; 0.05). &#x0D; Conclusion: The mutation rate of 23sRNA gene at 2063 locus is higher in children with drug-resistant MP pneumonia. Furthermore, low MPLI and 23sRNA gene mutations at 2063 locus are associated with the duration of disease, disappearance time of clinical symptoms and other clinical indicators.

Genomic landscape of pancreatic cancer in the Japanese version of the Cancer Genome Atlas.

Pancreatic cancer (PC) is one of the most aggressive cancers worldwide. Although many studies have investigated genomic alterations, the genomic landscape of Japanese PC patients has not been fully elucidated. We used whole-exome sequencing, cancer gene panel deep-sequencing, and microarray gene expression profiling data derived from the Japanese version of the Cancer Genome Atlas (JCGA) in 93 PC cases. Somatic driver mutations were identified in 65.6% of samples in 19 genes. The median tumor mutation burden (TMB) value was 0.24 Muts/Mb (interquartile range, 0.15-0.64 Muts/Mb). The commonly mutated genes were KRAS (58%), TP53 (40%), CDKN2A (10%), SMAD4 (10%), FGFR2 (9%), and PKHD1 (9%). Frequent germline variation genes were BRCA1 (8%), CDH1 (5%), MET (5%), MSH6 (5%), and TEK (5%). Frequent chromosomal arm alterations included copy number gains in 2q (42%), 7q (24%), and 3q (24%), and copy number losses in 19p (62%), 19q (47%), 12q (34%), and 7q (30%). A prognostic analysis according to the presence of driver mutations showed that overall survival (OS) in the driver mutation-positive group was significantly worse in comparison to that of the driver mutation-negative group (median, 23.1 vs 46.7 mo; P=.010). A Cox proportional hazards analysis for OS identified driver mutation (hazard ratio [HR], 1.89; P=.025) and lymph node metastasis (HR, 3.27; P=.002) as independent prognostic factors. The present results from the JCGA dataset constitute a fundamental resource for genomic medicine for PC patients, especially in Japan.

Von Willebrand factor activity levels are influenced by driver mutation status in polycythemia vera and essential thrombocythemia patients with well-controlled platelet counts.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (<600 × 109 /L), low vWF activity (<50%) was more frequently observed in JAK2+ PV patients than in JAK2+ ET (p=.013) or CALR+ ET (p=.013) groups, and in PV and ET patients with ≥50% JAK2+ allele burden than in those with allele burden <50% (p=.015). High vWF activity (>150%) was more frequent in the JAK2+ ET group than in the CALR+ ET group (p=.005), and often associated with vasomotor symptoms (p=.002). This study suggests that some patients with JAK2+ PV or ET have vWF activity outside the standard range even with well-controlled PLT, and that the measurement of vWF activity is useful for assessing the risk of thrombosis and hemorrhage.