bluuebunny/crossref_metadata_2025 huggingface dataset:
MRI features and tumor-infiltrating CD8 + T cells-based nomogram for predicting meningioma recurrence risk
Authors: Han Tao , Liu Xianwang , Long Changyou , Li Shenglin , Zhou Fengyu , Zhang Peng , Zhang Bin , Jing Mengyuan , Deng Liangna , Zhang Yuting , Zhou Junlin
Published: June 2024

Objective

This study was based on MRI features and number of tumor-infiltrating CD8 + T cells in post-operative pathology, in predicting meningioma recurrence risk.

Methods

Clinical, pathological, and imaging data of 102 patients with surgically and pathologically confirmed meningiomas were retrospectively analyzed. Patients were divided into recurrence and non-recurrence groups based on follow-up. Tumor-infiltrating CD8 + T cells in tissue samples were quantitatively assessed with immunohistochemical staining. Apparent diffusion coefficient (ADC) histogram parameters from preoperative MRI were quantified in MaZda. Considering the high correlation between ADC histogram parameters, we only chose ADC histogram parameter that had the best predictive efficacy for COX regression analysis further. A visual nomogram was then constructed and the recurrence probability at 1- and 2-years was determined. Finally, subgroup analysis was performed with the nomogram.

Results

The risk factors for meningioma recurrence were ADCp1 (hazard ratio [HR] = 0.961, 95% confidence interval [95% CI]: 0.937 ~ 0.986, p = 0.002) and CD8 + T cells (HR = 0.026, 95%CI: 0.001 ~ 0.609, p = 0.023). The resultant nomogram had AUC values of 0.779 and 0.784 for 1- and 2-years predicted recurrence rates, respectively. The survival analysis revealed that patients with low CD8 + T cells counts or ADCp1 had higher recurrence rates than those with high CD8 + T cells counts or ADCp1. Subgroup analysis revealed that the AUC of nomogram for predicting 1-year and 2-year recurrence of WHO grade 1 and WHO grade 2 meningiomas was 0.872 (0.652) and 0.828 (0.751), respectively.

Conclusions

Preoperative ADC histogram parameters and tumor-infiltrating CD8 + T cells may be potential biomarkers in predicting meningioma recurrence risk.

Clinical relevance statement

The findings will improve prognostic accuracy for patients with meningioma and potentially allow for targeted treatment of individuals who have the recurrent form.
Prevalence, distribution and factors associated with modern contraceptive use among women of reproductive age in Uganda: evidence from UDHS 2016
Authors: Towongo Moses Festo , Kelepile Matlhogonolo
Published: June 2024

Background

Unintended pregnancies pose significant health risks, particularly in sub-Saharan Africa, where millions of cases are recorded annually, disproportionately affecting adolescent women. Utilization of modern contraceptives is crucial in managing fertility and reducing unintended pregnancies, abortions, and associated health complications. This study aimed to assess the prevalence, distribution and factors associated with modern contraceptives utilization among women aged 15–49 in Uganda.

Methods

The study used secondary data from the 2016 Uganda Demographic and Health Survey (UDHS). The study sample comprise of 9,235 women aged 15–49 who used any method to prevent pregnancy in the five years preceding 2016 UDHS survey. The outcome variable for this study is utilization of modern contraceptives. Univariate, bivariate, and multilevel binary logistic regression was used to examine the relationship between individual and contextual factors on the modern contraceptive use among women aged 15–49 in Uganda. Choropleth mapping and network analysis in ArcGIS 10.8.2 was used to visualize spatial distribution of modern contraceptive use and measure community access to health facilities respectively.

Results

The prevalence of modern contraceptive use was 53.19% (n = 4,919) in Uganda, with significant spatial variation by district. Higher prevalence (23.18%) was observed among women aged 20–29 compared to adolescents (4.1%). Only 21.9% of married women reported using modern contraceptives. At the individual-level, the factors that positively influenced use of modern contraceptives included: women’s marital status, wealth index and level of education while sex of the household head, ever terminated a pregnancy and religion negatively affected the use of modern contraceptives. At community-level, community access to health facilities was found to have negative influence on the use of modern contraceptives among women. In communities where women frequently visited health facilities in the 12 months preceding the survey, the use of modern contraceptives reduced by 3.9%. Accessibility analysis revealed challenges, with women in northeastern districts (rural districts) facing travel times exceeding four hours to reach health facilities.

Conclusion

Utilization of modern contraceptives are essential for promoting women’s health and well-being, particularly concerning maternal healthcare. This study highlights disparities in modern contraceptive use across age groups and the districts, emphasizing the need for targeted interventions. Policymakers and stakeholders must prioritize strategies that promote utilization of modern contraceptives and maternal healthcare services to address these disparities effectively. Such efforts are crucial for improving reproductive health outcomes and reducing the burden of unintended pregnancies and related complications in Uganda.
Iparomlimab (QL1604) in patients (pts) with unresectable/metastatic deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) solid tumors: A single-arm, multicenter, pivotal, phase II study.
Authors: Guo Weijian , Bi Feng , Dong Jian , Jin Chuan , Niu Zuoxing , Wang Yusheng , Sun Meili , Wang Teng , Yu Dajun , He Yifu , Zhang Ruixing , Yin Xianli , Feng Wenlei , Zhang Meijiang , Zhang Baihui , Li Lingyan , Kang Xiaoyan
Published: June 2024

3578

Background: Iparomlimab, a novel anti-PD-1 antibody, demonstrated robust anti-tumor activity and well tolerated safety in pts with unresectable/metastatic dMMR/MSI-H solid tumors. At median follow-up of 17 mo, iparomlimab treatment demonstrated durable clinical benefit. Methods: This phase II study (NCT04326829) enrolled pts pathologically diagnosed as dMMR/MSI-H unresectable/metastatic solid tumors. Pts received iparomlimab (200 mg, iv, Q3W; 3 mg/kg for pts with body weight <40 kg). The primary endpoint was confirmed objective response rate (ORR) assessed by independent radiological review committee (IRRC) per RECIST 1.1. Eligible pts, who were enrolled and received at least 1 cycle of treatment, were included in the intention to treat (ITT) set. Among them, relapsed/refractory pts were included in the full analysis set (FAS) as primary efficacy analysis population. The FAS included pts with advanced colorectal cancer (CRC) failed from fluoropyrimidine, oxaliplatin, and irinotecan, pts with gastric cancer failed from at least two lines of standard of care, and other solid tumors failed from at least one prior treatment. Results: From Jun 19, 2020 to Jan 12, 2023, 120 pts were enrolled in ITT, with 60 pts in FAS. 117 (97.5%) pts were featured with stage IV disease. The median prior therapy lines were 2.0 in both ITT and FAS, respectively. CRC was diagnosed in 80 (66.7%) pts in ITT and 38 (63.3%) pts in FAS. As of Jan 20, 2024, the ORR were 58/120 (48.3%; 95% CI: 39.1%–57.6%) with 12 (10.0%) complete response (CR) and 46 (38.3%) partial response (PR) in ITT, and 30/60 (50.0%, 36.8%–63.2%) with 3 (5.0%) CR and 27 (45.0%) PR in FAS. In CRC pts, the ORR per IRRC were 37/80 (46.3%) and 22/38 (57.9%) in ITT and FAS, respectively. (Efficacy shown in Table) TRAEs of any grade occurred in 95 (79.2%) pts. The most frequent TRAE of any grade and grade ≥3 TRAE were both anemia, with incidence of 26.7% and 5.0%, respectively. irAEs of any grade were reported in 39/120 (32.5%) pts, with the most common occurring irAEs of hpothyroidism (12/120, 10.0%). TRSAEs occurred in 13/120 (10.8%) patients. No iparomlimab-related death occurred. Conclusions: At 17-mo follow-up, iparomlimab showed encouraging efficacy with durable response and tolerable safety in patients with unresectable/metastatic dMMR/MSI-H solid tumors in ITT and FAS. Clinical trial information: NCT04326829 . [Table: see text]
Impact of Latino ethnicity on the gut microbiome composition of patients with metastatic renal cell cancer (mRCC).
Authors: Barragán Carrillo Regina , Dizman Nazli , Ebrahimi Hedyeh , Meza Luis A , Bergerot Paulo Gustavo , Dorff Tanya B. , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Chehrazi-Raffle Alex , Tripathi Abhishek , Castro Daniela V. , Mercier Benjamin , Caporaso Gregory , Lee Keehoon , Pal Sumanta Kumar
Published: June 2024

4521

Background: Latinos with mRCC may have poorer outcomes with frontline immune checkpoint inhibition (ICI) compared to their non-Latino counterparts (Chehrazi-Raffle et alOncologist 2023). Recent studies have shown that the composition of the gut microbiome can impact outcomes with ICI (Routy et alScience 2018). Therefore, we aimed to investigate the differences in gut microbiome composition between Latino and non-Latino patients (pts) with mRCC. Methods: Stool specimens were prospectively collected in treatment-naïve pts with mRCC. We dichotomized pts into Latino vs non-Latino groups. Pts provided a stool sample (OMNIgene Gut) at baseline. Whole metagenome sequencing was performed on stool specimens collected. Taxonomic profiling was conducted using MetaPhlAn 4. ANCOM-BC analysis was used to identify differences in the relative abundance of bacterial species between groups. Alpha-diversity was evaluated using the Shannon diversity index and Evenness analysis, employing the Kruskal-Wallis test. Beta-diversity was assessed using the Bray-Curtis and Jaccard dissimilarity measures. The ratio of Firmicutes/Bacteroidetes (F/B), a measure of gut dysbiosis, was computed at baseline in the two cohorts. Results: Among 59 pts assessed, 27 and 32 were Latino and non-Latino, respectively. Median age of the cohort was 60 (range, 36-90). Most were male (71%), had clear cell RCC (88%) and had intermediate/poor risk disease (79%). ANCOM-BC analysis showed an enrichment of 14 bacterial species and a depletion in 3 species at baseline in the Latino group (p ≤ 0.05). Three Roseburiaspp. were enriched in the Latino pts, namely R. faecis (log-fold change [LFC]: 2.6), R. hominis (LFC: 2.0) and R. inulinivorans (LFC: 1.8). Additionally, Eubacterium rectalewas also enriched in the Latino group (LFC: 2.0). In contrast, in non-Latino pts Methylobacterium spp. was enriched (LFC: 1.3). The F/B ratio was higher in the Latino group as compared to the non-Latino group (1.00 vs 0.92). We did not observe any differences in alpha and beta diversity. A detailed analysis of simultaneously collected dietary logs is ongoing. Conclusions: Our examination of the gut microbiota of pts with mRCC revealed significant differences based on ethnicity at baseline. Specifically, the Latino group exhibited an enhancement of Roseburia spp. and E. rectale, species previously linked to favorable outcomes with ICIs, despite a higher F/B ratio (suggesting a greater degree of dysbiosis). Our findings advocate that clinical trials related to the microbiome should potentially account for baseline differences in ethnicity.
Lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in advanced renal cell carcinoma (aRCC): Patterns of progression and subsequent therapy in the CLEAR trial.
Authors: Grünwald Viktor , Motzer Robert J. , Keizman Daniel , Bedke Jens , Schmidinger Manuela , Staehler Michael D. , Matveev Vsevolod B. , George Saby , Hutson Thomas E. , Vaishampayan Ulka N. , Merchan Jaime R. , Eto Masatoshi , Rha Sun Young , Waddell Tom , Sabbatini Roberto , Barthelemy Philippe , Burgents Joseph E. , Ren Min , Brown Ian , CHOUEIRI Toni K.
Published: June 2024

4524

Background: In the primary analysis of the CLEAR trial of patients (pts) with aRCC, L+P significantly improved efficacy vs S (Motzer NEJM 2021). Results were further confirmed at the final prespecified OS analysis (Motzer JCO 2024). Here, we discuss patterns of progression and subsequent therapy in CLEAR. Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomly assigned (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were region and MSKCC prognostic risk group. To explore progression pattern within individual organs, time to progression was defined for each organ independently using lesions within each specific organ only, based on Independent Image Review per RECIST v1.1. Medians and quartiles were estimated with Kaplan-Meier (KM) method; 95% CIs were estimated with a generalized Brookmeyer and Crowley method. Hazard ratio (HR) reported is for L+P vs S based on Cox regression model with treatment as factor; HR was stratified by region and MSKCC prognostic groups. The Efron method was used for correction for ties. Results: The HRs (95% CI) of time to progression for L+P vs S across tumors in different organs were: bone, 0.40 (0.25-0.63); CNS, 0.47 (0.19-1.19); kidney, 0.65 (0.37-1.14); liver, 0.52 (0.32-0.84); lung, 0.48 (0.36-0.62); and lymph nodes, 0.63 (0.46-0.85). At overall disease progression, the median sums of diameters of target lesions were lower with L+P vs S (29.8mm vs 42.8mm; Table). In the L+P arm, 181 pts received subsequent anticancer regimens during survival follow-up (43 received axitinib and 101 received cabozantinib). In the S arm, 246 pts received subsequent anticancer regimens (47 received axitinib and 107 received cabozantinib). The median duration of axitinib as the first anticancer regimen (95% CI) after L+P was 23.7 months (5.3-not estimable [NE]), and after S was 12.6 months (6.8-NE). The median duration of cabozantinib as the first anticancer regimen (95% CI) after L+P was 13.2 months (8.2-NE), and after S was 7.1 months (4.1-20.0). Conclusions: Pts in the L+P arm trended to show later progression across tumors in different organs. At overall disease progression, the tumor burden of target lesions was lower with L+P vs S; and pts in the L+P arm stayed on 2L axitinib or cabozantinib longer than pts in the S arm. Together, these results continue to support L+P as a standard-of-care 1L therapy in pts with aRCC. Clinical trial information: NCT02811861 . [Table: see text]
Effect of antibiotic, proton pump inhibitor, H2 blocker, metformin and statin use on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Hobeika Charbel , Dawsey Scott , Patgunarajah Ubenthira , Lynn David , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Paul G. Jr.  , Diaz-Montero C. Marcela , Gupta Shilpa
Published: June 2024

4589

Background: Some reports suggest that concomitant medications like metformin (M) and statins (S) may enhance efficacy of ICIs in various solid tumors via immune remodeling. Meanwhile other drugs like antibiotics (Abx), proton-pump inhibitors (PPI), H2 blockers (H2b)—may negatively impact outcomes with ICI by affecting the gut microbiome. We report the effect (Abx), (PPI), (H2b), (M)and (S) in our larger cohort of mUC pts treated with ICI; atezolizumab (A), pembrolizumab (P), and maintenance Avelumab (Av). Methods: In our cohort of 474 pts with mUC treated with >/=2 cycles of ICI with A, P or Av between 2015 and 2023, we retrospectively reviewed the use of (Abx), (PPI), (H2b), (M) and (S) and their timing in relation to ICI start (within 60 or 30 days (d) prior to and after ICI start). Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression analysis. Results: Of 474 pts, 18.99% received A, 56.75% received P and 24.26% received Av. Median follow-up was 15.6 months. Survival data was available for 455 pts. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with significantly worse OS while Abx use within 60 (d) post ICI start was associated with significantly worse PFS. PPI use was associated with significantly worse OS and PFS when used 60 (d) prior to ICI use. Metformin was associated with significantly worse PFS when used 60 days prior to ICI start and H2b and Sta did not have any effect on survival outcomes in our cohort. (Table) Conclusions: In our large cohort of pts with mUC treated with either A, P or Av, (Abx), (PPI) and (M) use 60 (d) prior to ICI start were associated with worse OS and PFS. These findings have the potential to influence clinical practice, considering a higher threshold for prescribing antibiotics or PPIs in mUC pts planned to start ICI. These findings warrant further validation in prospective trials. [Table: see text]
Association between hemoglobin (Hb) improvement and patient-reported outcomes (PROs) in patients (pts) with myelofibrosis (MF) and anemia: Post hoc pooled analysis of momelotinib (MMB) phase 3 trials.
Authors: Palmer Jeanne M. , Mazerolle Flora , Liu Tom , M'Hari Manal , Regnault Antoine , Zhang Shiyuan , Cardellino Anna , Wang Zhaohui , Strouse Bryan , Sahni Jasmine , LeBlanc Thomas William
Published: June 2024

6574

Background: Pts with MF experience debilitating symptoms that negatively impact health-related quality of life (HRQOL), a burden compounded in those with anemia. Prior analysis of the phase 3 SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) trials found that achieving transfusion independence at wk 24 was associated with improved PROs, but the association of anemia severity by Hb level with PROs was inconclusive (Mesa, ASCO 2023, Poster 7066). This new post hoc analysis explored the impact of Hb improvement on PROs in pts with MF and anemia. Methods: The pooled treatment-agnostic analysis set included pts with anemia (baseline [BL] Hb <10 g/dL) from 3 phase 3 trials: S1 (JAK inhibitor [JAKi] naive; MMB vs ruxolitinib), S2 (JAKi experienced; MMB vs best available therapy), and MOMENTUM (JAKi experienced; MMB vs danazol). The EQ-5D-5L was administered, and health state index (UK value set) and visual analog scale (VAS) scores derived, in all 3 trials. Patient Global Impression of Change (PGIC) was administered in S1/S2. Hb improvement was defined as an increase of ≥1, ≥1.5, or ≥2 g/dL from BL at wk 24. Multivariate (MV) analyses included change in EQ-5D-5L scores from BL as the dependent variable, with wk 24 Hb improvement and key BL characteristics as independent variables. Results: Mean age of the anemic subpopulation (N=480) was 68.8 y; 62% were male, 81% were White, and 64% had primary MF.436 pts were evaluable for Hb improvement at wk 24; 298 and 297 were evaluable for EQ-5D-5L index and VAS scores, respectively. Mean improvements from BL in index and VAS scores were greater in pts who achieved Hb improvement at any threshold than in those who did not (Table). 241 pts were evaluable for Hb improvement at wk 24 in S1/S2; 215 were evaluable for PGIC. Hb improvement was associated with a higher percentage of pts with any symptom improvement and lower percentage with symptom worsening based on PGIC (Table). In MV analyses, Hb improvement at any threshold was significantly associated with positive change in EQ-5D-5L VAS scores at wk 24 (mean change estimates of 5.5 to 7.3); similar trends were observed in MV analyses for EQ-5D-5L index scores. Conclusions: In these trial populations, Hb improvement at wk 24 was associated with improved HRQOL and symptoms in pts with MF and anemia. These results highlight the value of treatments with anemia-related benefits in improving the pt experience in MF. Clinical trial information: NCT04173494 ; NCT02101268 ; NCT01969838 . [Table: see text]
Analysis of outcomes in resected early-stage non-small cell lung cancer (NSCLC) with rare targetable driver mutations.
Authors: Ghazali Nadia , Feng Jamie , Hueniken Katrina , Waddell Thomas K. , Yasufuku Kazuhiro , Pierre Andrew , Donahoe Laura , Wakeam Elliot , Cypel Marcelo , Yeung Jonathan , Keshavjee Shaf , De Perrot Marc , Leighl Natasha B. , Liu Geoffrey , Bradbury Penelope Ann , Sacher Adrian G. , Eng Lawson , Stockley Tracy , Tsao Ming Sound , Shepherd Frances A.
Published: June 2024

8052

Background: As postoperative adjuvant NSCLC treatment has evolved with EGFR and ALK targeted therapies, consideration may be given to treating other NSCLC with targetable mutations. Thus, having baseline outcomes for early-stage NSCLC with these targetable mutations is crucial, given their rarity. This study reports on recurrence-free survival (RFS) and overall survival (OS) in patients with resected NSCLC with treatable rare driver mutations. Methods: A retrospective single centre study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue based next-generation sequencing identified mutations in KRAS G12C, EGFR Exon20, ERBB2, ALK, ROS1, BRAFV600E, MET exon14 skipping, RET. Baseline characteristics, adjuvant chemotherapy, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRAS G12C cohort was used as the reference for survival comparisons. Results: Among 201 patients (mean age: 66.4, 63% female) 61% had stage I, 19% stage II, 20% stage III. Predominant histology was adenocarcinoma (95%) and lobectomy (77%) was the most common surgery. Adjuvant chemotherapy was given to 37% (median 4 cycles). Mutations identified included: KRAS G12C (87, 43%), EGFR Exon 20 (27, 13%), ERBB2 (23, 11%), MET (20, 10%), ALK (14, 7%), ROS1 (13, 6%), BRAF (10, 5%) and RET (5, 2%). For all patients, 5-year survival probabilities were 75% stage I, 56% stage II (Hazard ratio [HR]: 2.17, p=0.038), 55% for stage III (HR: 2.38, p=0.015). Stage was also a significant predictor of RFS: stage II (HR: 1.90, p=0.04), stage III (HR: 2.26, p=0.006) vs stage I. TP53 co-mutation was associated with poorer OS (stage-adjusted HR (aHR): 2.50, p=0.004) and RFS (aHR: 1.70, p=0.037). All patients with rare mutations had shorter RFS compared to those with KRAS G12C mutation (Table). The difference for ERBB2 was significant (aHR 2.26, p=0.014), with only 37% of patients relapse free at 5 years. In contrast, except for ERBB2, other mutations were associated with better OS, with fusion mutations having the greatest difference (aHR 0.24, p=0.021). ERBB2 mutation had the highest cumulative incidence of brain metastasis, 29% at 5 years. Conclusions: Despite consistently poorer RFS, our study shows that, with the exception of ERBB2, OS of all other rare mutations was superior to KRAS G12C mutated NSCLC. TP53 co-mutation was demonstrated to be prognostic of poorer outcome. These dichotomous results may be explained by the use of targeted treatments at relapse, and suggest a potential role of targeted agents in the adjuvant setting. [Table: see text]
Prediction of recurrence in stage I EGFR mutation-positive NSCLC: Combination of CT appearance and selected co-occurring gene alterations by machine learning.
Authors: Tateishi Akiko , Horinouchi Hidehito , Takasawa Ken , Kouno Nobuji , Mizuno Takaaki , Okubo Yu , Yoshida Yukihiro , Watanabe Shun-ichi , Miyake Mototaka , Kusumoto Masahiko , Inaba Koji , Igaki Hiroshi , Yatabe Yasushi , Mukai Masami , Tanaka Katsuya , Mihara Naoki , Shiraishi Kouya , Kohno Takashi , Ohe Yuichiro , Hamamoto Ryuji
Published: June 2024

8053

Background: Predicting the risk of postoperative recurrence is becoming increasingly important in patients (pts) with resectable EGFR mutation positive ( EGFRm) non-small cell lung cancer (NSCLC) after the ADAURA trial. The presence of non-solid ground-grass opacity (GGO) component on computed tomography (CT) images is known to affect the prognosis of stage I lung cancer. Only a few reports investigating the relationship between gene alterations and CT images in stage I EGFRm NSCLC. Methods: We have developed a machine learning-based model to predict recurrence within five years in TNM stage I (UICC 8th) EGFRm NSCLC pts who underwent surgery between 1985 and 2019 using whole exome sequencing in the PRISM project. We evaluated the pts’ characteristics, recurrence-free survival (RFS), the CT appearance (pure GGO and part solid [GGO]), without GGO [pure solid]), and consolidation tumor ratio (CTraio). Then, we analyzed the correlation between the image findings and gene alterations predicting a high risk of recurrence. Results: Among 1351 pts, stage I, EGFRm were 308 (22.8%). The median RFS for stage I EGFR-m pts was 123.2 months (m). In the prediction model, TP53 and RBM10 genes were among the gene alterations that had a high impact on the high-risk recurrence within five years. Among the 302 stage I, EGFRm pts for whom CT images were available, 166 (55.6%) pts had GGO, and 137 (45.4%) pts had pure solid appearance. The median CTratio was 0.87. The median RFS was not reached (NR) for GGO, 86.5m for pure solid (hazard ratio [HR] 2.42 [1.58-3.73], p<0.0001). There was a negative correlation indicating that the larger the CTratio, the shorter the RFS (p<0.0047). The proportion of TP53 mutation (TP53m) was lower in GGO and higher in pure solid (p<0.0001, Table). The median RFS was NR for GGO plus TP53m-negative pts, was 119.7m for GGO plus TP53m-positive pts, 84.8m for pure solid plus TP53m-negative pts, and 98.8m for pure solid plus TP53m-positive pts, respectively. Among pts with 0≦CTratio<0.5 46 (15.2%), with 0.5≦CTratio<1 119 (39.4%), and with CTratio=1 137 (45.4%), the proportion of TP53m increased as the CTratio increased. Conclusions: We found a linear relationship between CTratio and proportion of co-occurring TP53m with EGFRm. Combination of CT appearance (GGO or pure solid) and co-occurring TP53m can predict recurrence in stage I, EGFRm NSCLC. [Table: see text]
A phase II, open-label, combination therapy of durvalumab and ceralasertib in relapsed and refractory small cell lung cancer (SUKSES-N4).
Authors: Lee Se-Hoon , Kim Jiyeon , Park Sehhoon , Mortimer Peter G. , Kim Heejung (Rosa) , Smith Simon , Dean Emma , Kim Yu Jung , Jung Hyun Ae , Sun Jong-Mu , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil
Published: June 2024

8104

Background: In extensive stage small-cell lung cancer (SCLC), the standard first-line treatment is an immune checkpoint inhibitor (ICI) combined with chemotherapy. However, in the relapsed or refractory setting, the benefits of ICI-based combinations are modest, regardless of prior ICI exposure. Ceralasertib, a selective ATR inhibitor, not only enhances DNA damage, inducing apoptosis, but also affects immune and inflammatory pathways. This study assesses the safety and efficacy of combining durvalumab with ceralasertib in SCLC patients. Methods: This open-label, phase II, multi-cohort umbrella trial recruited relapsed and refractory SCLC patients independent of biomarker status. Initially, patients received 1500mg of durvalumab on day 1, followed by 240mg of ceralasertib twice daily from day 15 to 28 of a 28-day cycle (Dose A). An amendment aligned the dosing regimen to other studies to 240mg of ceralasertib twice daily from day 1 to 7, with 1500mg of durvalumab administered on day 8 (Dose B). The primary endpoint was the objective response rate (ORR), with a target enrollment of 40 evaluable patients. Results: Between June 2022 and May 2023, forty-two patients were recruited (Dose A: 27; Dose B: 15). The median age was 67 (range: 43-83), with a predominance of males (n = 36) and smokers (n = 40). ECOG PS scores were 0 (n = 1) or 1 (n = 41), and nearly half (n = 20, 47.6%) had prior ICI exposure. The ORR per RECIST was 9.5%, with a disease control rate of 26.2%, including 4 partial responses (PR) and 7 cases of stable disease (SD). Median progression-free survival (PFS) was 1.64 months (95% CI: 1.61-1.97), and overall survival was 7.16 months (95% CI: 6.07-13.9). The duration of responses was notable, showing PFS of 4.8, 17.0, and 18.3 months in ICI-naïve PR patients and 14.1 months in ICI-exposed patient currently still ongoing on treatment. A sustained clinical benefit of up to 10.7 months was observed in an ICI-naïve patient with SD. Hematologic adverse events (AEs) included thrombocytopenia as grade 4 (n = 9) and grade 3 (n = 3), anemia as grade 3 (n = 3), and neutropenia as grade 4 (n = 3) and grade 3 (n = 1). Other AEs were mostly grades 1 or 2 and manageable. Exploratory biomarker analysis is in progress and will be presented. Conclusions: Ceralasertib and durvalumab combination therapy have demonstrated durable responses in select patients with manageable hematologic toxicity. Biomarker research is ongoing to identify patients most likely to benefit from this treatment strategy. Clinical trial information: NCT04361825 .
Comprehensive molecular characterization of thymic epithelial tumors.
Authors: Kim Chul , Adeyelu Tolulope Tosin , Maniar Rohan , Farrell Alex Patrick , Zaemes Jacob Peter , Solzak Jeffrey Peter , Hancock Bradley Allen , Elliott Andrew , Micaily Ida , Nagasaka Misako , Nieva Jorge J. , Borghaei Hossein , Halmos Balazs , Ma Patrick C. , Radovich Milan , Badve Sunil S , Loehrer Patrick J.
Published: June 2024

8113

Background: Thymic epithelial tumors (TETs), which include thymomas (T) and thymic carcinomas (TC), are rare, yet they are the most common neoplasms in the anterior mediastinum. TETs can lead to significant morbidity and mortality. To develop more effective therapeutics for TETs, it is necessary to better understand their molecular underpinnings. Herein, we present the findings from an in-depth molecular characterization of TETs. Methods: TETs samples (n = 138; 55 from thymus and 78 from metastatic sites) were profiled using next generation sequencing (NGS) of DNA (592-genes/WES) and RNA (WTS) at Caris Life Sciences (Phoenix, AZ). Prevalence was calculated for pathogenic SNVs/Indels, deficient mismatch repair/microsatellite instability (dMMR/MSI) status assessed by IHC and NGS, PD-L1 expression measured by IHC (SP142; positive: ≥ 2+, ≥ 5%), and high tumor mutational burden (TMB-High) defined as ≥ 10 mut/Mb. The relative expression (transcript per million -TPM) of surface antigens (surfaceome) were evaluated. Pathway enrichment was determined by Gene Set Enrichment Analysis (GSEA). Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate. Results: Central pathology review showed that the 138 TET samples were comprised of 34.8% (n = 48) thymic carcinomas (TC) and 65.2% (n = 90) thymomas (T). Thymomas were further stratified into the WHO classification subtypes (n = 10 A, 13 AB, 6 B1, 15 B2, and 46 B3). Median patient age was 60.5 years (range: 17-88). TP53 was the most frequently mutated gene in TETs. GTF2I mutations were found in 8 cases exclusively in thymomas. KIT mutations were identified in B3 and TC. KRAS, HRAS, and PIK3CA mutations were present in < 3% of all TETs patients. Genomic alterations in cell cycle-related genes (n = 19, 13.8%), the DNA repair pathway (n = 11, 8.0%), and chromatin remodeling (n = 27, 19.6%) were also observed in TETs, with these alterations more prevalent in TC compared to T. dMMR/MSI-H was detected in a subset of TETs, specifically B3 thymoma (n = 1) and TC (n = 4), showing a correlation with TMB-H in 80% of these cases. GSEA revealed that the MYC, angiogenesis, and mTORC1 pathways are more enriched in TC than in T. Surfaceome genes ( ERBB2: fold change (FC) = 1.51, ERBB3: FC = 1.45, TROP2: FC = 1.45, NECTIN-4: FC = 1.77 and MESOTHELIN: FC = 5.25) were significantly highly expressed in TC compared to T. Conclusions: Our findings offer insights into the molecular characteristics of TETs and reveal potential therapeutic targets. The relatively high prevalence of dMMR/MSI-H status in TC underscores the potential utility of assessing dMMR/MSI-H in patients with TC. [Table: see text]
Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): Final analysis results of DESTINY-Lung02.
Authors: Janne Pasi A. , Goto Yasushi , Kubo Toshio , Ninomiya Kiichiro , Kim Sang-We , Planchard David , Ahn Myung-Ju , Smit Egbert F. , De Langen Adrianus Johannes , Perol Maurice , Pons-Tostivint Elvire , Novello Silvia , Hayashi Hidetoshi , Shimizu Junichi , Kim Dong-Wan , Pereira Kaline , Cheng Fu-Chih , Taguchi Ayumi , Cheng Yingkai , Goto Koichi
Published: June 2024

8543

Background: In the DESTINY-Lung02 primary analysis (data cutoff, Dec 23, 2022), T-DXd 5.4 mg/kg and 6.4 mg/kg demonstrated strong and durable responses and an acceptable and generally manageable safety profile in patients with previously treated HER2 ( ERBB2)-mutant ( HER2m) mNSCLC (Goto et al. 2023). We report updated efficacy and safety results from the final analysis of DESTINY-Lung02. Additional analyses, including data on clinically relevant subgroups and patient-reported outcomes, are planned for presentation. Methods: In this randomized, blinded, multicenter, phase 2 trial, patients with previously treated HER2m mNSCLC were randomly assigned 2:1 to receive T-DXd 5.4 mg/kg or 6.4 mg/kg once every 3 weeks. The primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR), and key secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The study was not powered to statistically compare the 2 doses. Results: Patients were randomly assigned to T-DXd 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50). At the final analysis data cutoff (Aug 25, 2023), the median duration of follow-up (range) was 15.8 months (mo) (1.1-28.6) and 16.5 mo (0.6-28.7) with T-DXd 5.4 and 6.4 mg/kg, respectively (additional 8 mo follow-up since last DCO). Updated efficacy results are presented in the table. After a median treatment duration (range) of 7.7 mo (0.7-27.6) and 8.3 mo (0.7-24.0) with T-DXd 5.4 and 6.4 mg/kg, respectively, drug-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 39.6% (40/101) and 60.0% (30/50) of patients in each arm. Lower rates of drug-related TEAEs associated with drug discontinuation (14.9% [15/101]), dose reduction (16.8% [17/101]), and drug interruption (30.7% [31/101]) were observed with T-DXd 5.4 mg/kg than 6.4 mg/kg (26.0% [13/50], 34.0% [17/50], and 54.0% [27/50], respectively). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis was reported in 14.9% (15/101) and 32.0% (16/50) of patients in the T-DXd 5.4 and 6.4 mg/kg arms, respectively; most events were grade 1 or 2 (1 grade 5 event in each arm). Conclusions: In this final analysis, T-DXd 5.4 and 6.4 mg/kg continued to show strong and durable responses, which was consistent with the primary analysis, and no significant changes in toxicity were observed with longer follow-up. The approved T-DXd 5.4 mg/kg dose was associated with a more favorable benefit-risk profile and a reduced incidence of adjudicated drug-related ILD/pneumonitis. Clinical trial information: NCT04644237 . [Table: see text]
Revisiting Timing and Decision Modeling for Allogeneic Hematopoietic Stem-Cell Transplantation in Myelodysplastic Syndromes
Authors: Cutler Corey
Published: June 2024

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology , to patients seen in their own clinical practice.
BF170 hydrochloride enhances the emergence of hematopoietic stem and progenitor cells
Authors: Liu WenYe , Ding YuYan , Shen Zheng , Xu Cong , Yi William , Wang Ding , Zhou Yi , Zon Leonard I. , Liu Jing-Xia
Published: June 2024

Generation of hematopoietic stem and progenitor cells (HSPCs) ex vivo and in vivo, especially the generation of safe therapeutic HSPCs, still remains inefficient. In this study, we have identified compound BF170 hydrochloride as a previously unreported pro-hematopoiesis molecule, using the differentiation assays of primary zebrafish blastomere cell culture and mouse embryoid bodies (EBs), and we demonstrate that BF170 hydrochloride promoted definitive hematopoiesis in vivo. During zebrafish definitive hematopoiesis, BF170 hydrochloride increases blood flow, expands hemogenic endothelium (HE) cells and promotes HSPC emergence. Mechanistically, the primary cilia-Ca2+-Notch/NO signaling pathway, which is downstream of the blood flow, mediated the effects of BF170 hydrochloride on HSPC induction in vivo. Our findings, for the first time, reveal that BF170 hydrochloride is a compound that enhances HSPC induction and may be applied to the ex vivo expansion of HSPCs.
High-throughput assays to assess variant effects on disease
Authors: Ma Kaiyue , Gauthier Logan O. , Cheung Frances , Huang Shushu , Lek Monkol
Published: June 2024

Interpreting the wealth of rare genetic variants discovered in population-scale sequencing efforts and deciphering their associations with human health and disease present a critical challenge due to the lack of sufficient clinical case reports. One promising avenue to overcome this problem is deep mutational scanning (DMS), a method of introducing and evaluating large-scale genetic variants in model cell lines. DMS allows unbiased investigation of variants, including those that are not found in clinical reports, thus improving rare disease diagnostics. Currently, the main obstacle limiting the full potential of DMS is the availability of functional assays that are specific to disease mechanisms. Thus, we explore high-throughput functional methodologies suitable to examine broad disease mechanisms. We specifically focus on methods that do not require robotics or automation but instead use well-designed molecular tools to transform biological mechanisms into easily detectable signals, such as cell survival rate, fluorescence or drug resistance. Here, we aim to bridge the gap between disease-relevant assays and their integration into the DMS framework.
TMEM16F scramblase regulates angiogenesis via endothelial intracellular signaling
Authors: Shan Ke Zoe , Le Trieu , Liang Pengfei , Dong Ping , Lowry Augustus J. , Kremmyda Polina , Claesson-Welsh Lena , Yang Huanghe
Published: June 2024

TMEM16F (also known as ANO6), a Ca2+-activated lipid scramblase (CaPLSase) that dynamically disrupts lipid asymmetry, plays a crucial role in various physiological and pathological processes, such as blood coagulation, neurodegeneration, cell–cell fusion and viral infection. However, the mechanisms through which it regulates these processes remain largely elusive. Using endothelial cell-mediated angiogenesis as a model, here we report a previously unknown intracellular signaling function of TMEM16F. We demonstrate that TMEM16F deficiency impairs developmental retinal angiogenesis in mice and disrupts angiogenic processes in vitro. Biochemical analyses indicate that the absence of TMEM16F enhances the plasma membrane association of activated Src kinase. This in turn increases VE-cadherin phosphorylation and downregulation, accompanied by suppressed angiogenesis. Our findings not only highlight the role of intracellular signaling by TMEM16F in endothelial cells but also open new avenues for exploring the regulatory mechanisms for membrane lipid asymmetry and their implications in disease pathogenesis.
Desmosomes at a glance
Authors: Perl Abbey L. , Pokorny Jenny L. , Green Kathleen J.
Published: June 2024

Desmosomes are relatives of ancient cadherin-based junctions, which emerged late in evolution to ensure the structural integrity of vertebrate tissues by coupling the intermediate filament cytoskeleton to cell–cell junctions. Their ability to dynamically counter the contractile forces generated by actin-associated adherens junctions is particularly important in tissues under high mechanical stress, such as the skin and heart. Much more than the simple cellular ‘spot welds’ depicted in textbooks, desmosomes are in fact dynamic structures that can sense and respond to changes in their mechanical environment and external stressors like ultraviolet light and pathogens. These environmental signals are transmitted intracellularly via desmosome-dependent mechanochemical pathways that drive the physiological processes of morphogenesis and differentiation. This Cell Science at a Glance article and the accompanying poster review desmosome structure and assembly, highlight recent insights into how desmosomes integrate chemical and mechanical signaling in the epidermis, and discuss desmosomes as targets in human disease.
PTEN and the PTEN-like phosphatase CnrN have both distinct and overlapping roles in a Dictyostelium chemorepulsion pathway
Authors: Consalvo Kristen M. , Rijal Ramesh , Beruvides Steven L. , Mitchell Ryan , Beauchemin Karissa , Collins Danni , Scoggin Jack , Scott Jerome , Gomer Richard H.
Published: June 2024

Little is known about eukaryotic chemorepulsion. The enzymes phosphatase and tensin homolog (PTEN) and CnrN dephosphorylate phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] to phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Dictyostelium discoideum cells require both PTEN and CnrN to induce chemorepulsion of cells away from the secreted chemorepellent protein AprA. How D. discoideum cells utilize two proteins with redundant phosphatase activities in response to AprA is unclear. Here, we show that D. discoideum cells require both PTEN and CnrN to locally inhibit Ras activation, decrease basal levels of PI(3,4,5)P3 and increase basal numbers of macropinosomes, and AprA prevents this increase. AprA requires both PTEN and CnrN to increase PI(4,5)P2 levels, decrease PI(3,4,5)P3 levels, inhibit proliferation, decrease myosin II phosphorylation and increase filopod sizes. PTEN, but not CnrN, decreases basal levels of PI(4,5)P2, and AprA requires PTEN, but not CnrN, to induce cell roundness. Together, our results suggest that CnrN and PTEN play unique roles in AprA-induced chemorepulsion.
Persistent Pain After Breast Cancer Treatment, an Underreported Burden for Breast Cancer Survivors
Authors: Strijbos Bo T. M. , Janssen Loes , Voogd Adri C. , Zwaans Willem A. R. , Roumen Rudi M. H. , Maaskant-Braat Adriana J. G.
Published: June 2024

Background

Many patients who have undergone surgery experience persistent pain after breast cancer treatment (PPBCT). These symptoms often remain unnoticed by treating physician(s), and the pathophysiology of PPBCT remains poorly understood. The purpose of this study was to determine prevalence of PPBCT and examine the association between PPBCT and various patient, tumor, and treatment characteristics.

Patients and Methods

We conducted a questionnaire-based cross-sectional study enrolling patients with breast cancer treated at Máxima Medical Center between 2005 and 2016. PPBCT was defined as pain in the breast, anterior thorax, axilla, and/or medial upper arm that persists for at least 3 months after surgery. Tumor and treatment characteristics were derived from the Dutch Cancer Registry and electronic patient files.

Results

Between February and March 2019, a questionnaire was sent to 2022 women, of whom 56.5% responded. Prevalence of PPBCT among the responders was 37.9%, with 50.8% reporting moderate to severe pain. Multivariable analyses showed that women with signs of anxiety, depression or a history of smoking had a higher risk of experiencing PPBCT. Women aged 70 years or older at diagnosis were significantly less likely to report PPBCT compared with younger women. No significant association was found between PPBCT and treatment characteristics, including type of axillary surgery and radiotherapy.

Conclusions

A considerable percentage of patients with breast cancer experience PPBCT. Women with signs of anxiety or depression and women with a history of smoking are more likely to report PPBCT. Further research is required to understand the underlying etiology and to improve prevention and treatment strategies for PPBCT.
Why Didn’t the College Premium Rise Everywhere? Employment Protection and On-the-Job Investment in Skills
Authors: Doepke Matthias , Gaetani Ruben
Published: June 2024

Why has the college wage premium risen rapidly in the United States since the 1980s but not in European economies such as Germany? We argue that differences in employment protection can account for much of the gap. We develop a model in which firms and workers make relationship-specific investments in skill accumulation. The incentive to invest is stronger when employment protection creates an expectation of long-lasting matches. We argue that changes in the economic environment have reduced relationship-specific investment for less educated workers in the United States, but not for better-protected workers in Germany. (JEL I23, I26, J24, J31, J41, J63)
Silicone-induced granuloma, hypercalcemia and chronic kidney disease in a transgender patient
Authors: Cardoso Barros Tattieri Alenninne , Narciso Júnior José , Cunha Lima Alcântara Aline , Da Silva Junior Geraldo Bezerra , Lima Rafael Siqueira Athayde
Published: June 2024

Background: hypercalcemia mediated by a silicone-induced granulomatous reaction is a condition that, despite being rare, must be remembered since there is an increasing demand for aesthetic procedures among the general population. It is necessary to rule out other causes of hypercalcemia, such as hyperparathyroidism, hypercalcemia of malignancy, infectious and non-infectious granulomatous diseases, as well as the use of drugs. Case presentation: We present a patient with a history of large amounts of silicone implants who was admitted to a hospital presenting hypercalcemia and chronic kidney disease. A skin biopsy revealed a granulomatous foreign body reaction associated with exogenous siliconomatous material. Treatment with corticosteroids was initiated, with partial renal function improvement, with no renal replacement therapy needed. Conclusion: Patients with silicone implants should be carefully monitored for renal function and may be informed to avoid nephrotoxic agents as there is sufficient evidence that this type of aesthetic procedure can trigger hypercalcemia and CKD.
Examining The Impact of Customer Satisfaction and Brand Image toward Consumer Loyalty on Bank Syariah Indonesia
Authors:   Program Studi Manajemen, Universitas Muhammadiyah Riau, Riau, Nofirda Fitri Ayu , Susanto Perengki ,   Fakultas Ekonomi dan Bisnis, Universitas Negeri Padang, Padang
Published: June 2024

Abstract. Bank Syariah Indonesia is a financial institution whose principal business is to provide credit and services in payment and money circulation that operates in accordance with sharia principles. This research is intended to see the role of customer satisfaction and brand image mediating customer engagement on Bank Syariah Indonesia customer loyalty. Through the purposive sampling method, the number of samples is determined to be at least 120 respondents. Data collection using questionnaire dissemination. Structural Equation Modeling (SEM- AMOS) analysis technique version 26 was used in this study. These results show that Customer Satisfaction has a significant effect on Customer Loyalty, Brand Image has a significant effect on Customer Loyalty, Customer Engagement has a significant effect on Customer Loyalty. Customer Satisfaction has a significant effect on Customer Loyalty through Customer Engagement, and Brand Image has a significant effect on Customer Loyalty through Customer Engagement. Keywords: Customer satisfaction, brand image, customer engagement, customer loyalty