bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling symptom interplay: a network analysis of procrastination in gifted students
Authors: Bagheri Sajjad , Farahani Hojjatollah , Watson Peter , Bezdan Timea , Rezaiean Kosar
Published: June 2024

Background

This study explores the intricate web of symptoms experienced by academically gifted high school students, focusing on procrastination, rumination, perfectionism, and cognitive flexibility. The well-being of these gifted adolescents remains a pivotal concern, and understanding the dynamics of these symptoms is vital.

Methods

A diverse sample of 207 academically gifted high school students from Mashhad, Iran, participated in this study. Using convenience sampling, participants from grades 10, 11, and 12 were included, with detailed assessments conducted through questionnaires measuring the mentioned symptoms.

Results

Our network analysis uncovers compelling insights into the interplay of these symptoms: Procrastination, though moderately central, exerts significant influence within the network, underscoring its relevance. Cognitive flexibility, while centrally positioned, curiously exhibits a negative influence, potentially serving as a protective factor. Negative perfectionism emerges as the keystone symptom, with both high centrality and a positive influence. Rumination displays substantial centrality and a positive influence, indicating its role in symptom exacerbation. Positive perfectionism, moderately central, lacks direct influence on other symptoms.

Conclusion

This network analysis provides a nuanced understanding of the relationships among procrastination, rumination, perfectionism, and cognitive flexibility in academically gifted adolescents. Negative perfectionism and cognitive flexibility emerge as critical factors deserving attention in interventions aimed at enhancing the well-being of this unique group. Further research should explore causal relationships to refine targeted interventions.
Satellite orbit determination and time synchronization using GPS single-frequency observables in low and high solar activities
Authors: Tseng Tzu-Pang , Yeh Wen-Hao , Tsai Yung-Fu , Hsiao Tung-Yuan , Tsai Yi-Hsuan , Kuo Pei-Jung , Chen Kun-Lin , Hsiao Yu-Shen
Published: June 2024

We assess the orbit accuracy and time synchronization error using the L1 and C1 observables during the different solar activities. In general, GPS single-frequency (SF) observable can be used for commercial applications in satellite industry. The accuracy of satellite orbit determination using the SF observations is dominated by solar activities. The solar activities are indexed by the F10.7 value. The different solar activities lead to the ionosphere perturbation, triggering off the occurrence probability of ionospheric irregularities. The ionospheric irregularity affects the amplitude and phase of GPS signal. The affected amplitude and phase are indexed by the S4 value. We determine the GRACE satellite orbit using the SF GPS observations and compare the resulting orbit to that derived by dual-frequency observations for the effectiveness. The SF phase data are very sensitive to the variation in electron density and indirectly affects both the orbit accuracy and the time synchronization error. This is most likely caused by the phase ambiguity disturbed by the ionosphere. However, the C1 is relatively free from such a disturbance due to the strong signal-to-noise ratio (SNR) and the phase shift keying technique. The C1 performs the consistent solution over the low and high solar activities. However, this is not the case for the L1. The L1-derived orbit solution during the high solar activities is worse than that during the low solar activities. On the other hand, the time synchronization errors derived by the L1 and C1 are also different. The L1-derived time synchronization error has a relatively large perturbation as compared to the C1-derived one, which shows a consistent solution for a long-term period. This work suggests that the C1 observable is able to produce a consistent the orbit solution and time synchronization for the commercial applications of the satellite industry.

Graphical Abstract
Position dependence of recovery coefficients in 177Lu-SPECT/CT reconstructions – phantom simulations and measurements
Authors: Leube Julian , Claeys Wies , Gustafsson Johan , Salas-Ramirez Maikol , Lassmann Michael , Koole Michel , Tran-Gia Johannes
Published: June 2024

Background

Although the importance of quantitative SPECT has increased tremendously due to newly developed therapeutic radiopharmaceuticals, there are still no accreditation programs to harmonize SPECT imaging. Work is currently underway to develop an accreditation for quantitative 177Lu SPECT/CT. The aim of this study is to verify whether the positioning of the spheres within the phantom has an influence on the recovery and thus needs to be considered in SPECT harmonization. In addition, the effects of these recovery coefficients on a potential partial volume correction as well as absorbed-dose estimates are investigated.

Methods

Using a low-dose CT of a SPECT/CT acquisition, a computerized version of the NEMA body phantom was created using a semi-automatic threshold-based method. Based on the mass-density map, the detector orbit, and the sphere centers, realistic SPECT acquisitions of all possible 720 sphere configurations of both the PET and the SPECT versions of the NEMA Body Phantom were generated using Monte Carlo simulations. SPECT reconstructions with different numbers of updates were performed without (CASToR) and with resolution modeling (STIR). Recovery coefficients were calculated for all permutations, reconstruction methods, and phantoms, and their dependence on the sphere positioning was investigated. Finally, the simulation-based findings were validated using SPECT/CT acquisitions of six different sphere configurations.

Results

Our analysis shows that sphere positioning has a significant impact on the recovery for both of the reconstruction methods and the phantom type. Although resolution modeling resulted in significantly higher recovery, the relative variation in recovery within the 720 permutations was even larger. When examining the extreme values of the recovery, reconstructions without resolution modeling were influenced primarily by the sphere position, while with resolution modeling the volume of the two adjacent spheres had a larger influence. The SPECT measurements confirmed these observations, and the recovery curves showed good overall agreement with the simulated data.

Conclusion

Our study shows that sphere positioning has a significant impact on the recovery obtained in NEMA sphere phantom measurements and should therefore be considered in a future SPECT accreditation. Furthermore, the single-measurement method normally performed for PVC should be reconsidered to account for the position dependency.
Laparoscopic redo surgery for sigmoid volvulus following laparoscopic sigmoidectomy
Authors: Masui Hideyuki , Kawada Kenji , Inamoto Susumu , Wada Toshiaki , Sakai Yoshiharu , Obama Kazutaka
Published: June 2024

Background

Sigmoid volvulus (SV) is an acute abdominal condition characterized by torsion of the sigmoid colon around the mesentery, and often results in intestinal obstruction that may progress to bowel ischemia, necrosis, or perforation. Although SV commonly occurs due to predisposing factors like anatomic variations, age-related motility disorders, chronic constipation, and neurologic diseases, its incidence following sigmoid colon cancer surgery has rarely been reported. Herein, we report a rare case of recurrent SV following laparoscopic sigmoidectomy, which was successfully treated by laparoscopic redo surgery.

Case presentation

The patient was a 77-year-old man who had previously undergone laparoscopic sigmoidectomy for sigmoid colon cancer. Sixteen months postoperatively, he developed an incisional hernia at the umbilical site, which was treated with a laparoscopic repair using an intraperitoneal onlay mesh. After the hernia surgery, the patient had no anastomotic leakage or stenosis on regular follow-ups. However, 65 months after the first surgery, he presented with abdominal pain and distension. A computed tomography revealed that the remnant sigmoid colon was distended in a twisting manner around the anastomosis, leading to the diagnosis of SV. Although endoscopic de-torsion was successful, the SV recurred 2 months later, requiring elective laparoscopic redo surgery. The procedure involved resection of the sigmoid colon including the prior anastomosis with a left pararectal incision and DST re-anastomosis using a 25-mm circular stapler. The operation lasted 165 min with minimal bleeding and no complications. The postoperative course was uneventful. Pathological analysis confirmed fibrosis without malignancy. The patient remains well without recurrence of SV and anastomotic stenosis more than 5 years after surgery.

Conclusion

SV following sigmoid colon cancer surgery has rarely been reported. This case illustrates the potential need for prophylaxis against postoperative SV, especially in patients with long sigmoid colon undergoing laparoscopic surgery for colorectal cancer. Further, laparoscopic redo surgery following initial laparoscopic surgery for colorectal cancer can be performed with minimal invasiveness, especially if patient selection is properly managed.
Employability and career beliefs inventory: a brief version for unemployed persons
Authors: Silva Ana Daniela , Coscioni Vinicius , Barros Alexandra , do Céu Taveira Maria
Published: June 2024

Background

Considering that beliefs may be assessed and changed, inventories measuring employability and career beliefs may be of utmost importance for career interventions.

Objective

This study introduces the psychometric properties of a brief version of the Employability and Career Beliefs Inventory (ECBI) in a sample of unemployed persons.

Methods and results

Altogether, 2023 unemployed persons aged from 18 to 66 years old and living in Southern Portugal participated in an online survey. The ECBI’s original internal structure was tested and did not fit the data. Exploratory and confirmatory factor analyses were implemented, and a three-factor solution was retained. The three factors discriminate three types of beliefs named growth, pessimism, and flexibility. Measurement invariance models identified scalar equivalence across gender and educational degree, and metric invariance across age. All items fit the graded response model’s parameters. The growth and flexibility subscales were less effective in the assessment of low latent trait levels, whereas the opposite was observed with the pessimism subscale. Internal consistency is good yet discrimination between factors is questionable. Correlations to career decision-making self-efficacy evidence validity based on the relations to other constructs.

Conclusion

Despite the limitations, the brief version of the ECBI proposed in this study is ready for further use and development among unemployed persons.
Deep learning model for detection of hotspots using infrared thermographic images of electrical installations
Authors: Ukiwe Ezechukwu Kalu , Adeshina Steve A. , Jacob Tsado , Adetokun Bukola Babatunde
Published: June 2024

Hotspots in electrical power equipment or installations are a major issue whenever it occurs within the power system. Factors responsible for this phenomenon are many, sometimes inter-related and other times they are isolated. Electrical hotspots caused by poor connections are common. Deep learning models have become popular for diagnosing anomalies in physical and biological systems, by the instrumentality of feature extraction of images in convolutional neural networks. In this work, a VGG-16 deep neural network model is applied for identifying electrical hotspots by means of transfer learning. This model was achieved by first augmenting the acquired infrared thermographic images, using the pre-trained ImageNet weights of the VGG-16 algorithm with additional global average pooling in place of conventional fully connected layers and a softmax layer at the output. With the categorical cross-entropy loss function, the model was implemented using the Adam optimizer at learning rate of 0.0001 as well as some variants of the Adam optimization algorithm. On evaluation, with a test IRT image dataset, and a comparison with similar works, the research showed that a better accuracy of 99.98% in identification of electrical hotspots was achieved. The model shows good score in performance metrics like accuracy, precision, recall, and F1-score. The obtained results proved the potential of deep learning using computer vision parameters for infrared thermographic identification of electrical hotspots in power system installations. Also, there is need for careful selection of the IR sensor’s thermal range during image acquisition, and suitable choice of color palette would make for easy hotspot isolation, reduce the pixel to pixel temperature differential across any of the images, and easily highlight the critical region of interest with high pixel values. However, it makes edge detection difficult for human visual perception which computer vision-based deep learning model could overcome.
A phase II trial of alternating mXELOX/mXELIRI plus bevacizumab (BEV) as first-line treatment for metastatic colorectal cancer (mCRC).
Authors: Li Sheng , Zhu Liangjun , Li Xiaoyou , Huang Jiayuan , Xu Hanfeng
Published: June 2024

3574

Background: First-line fluoropyrimidine (FL), oxaliplatin (OX), irinotecan (IRI) plus BEV had better efficacy but worse safety vs FL, IRI plus BEV for mCRC. Preliminary data showed promising anti-tumor activity and acceptable toxicity of alternating FL plus OX and FL plus IRI. This study aimed to assess the alternating schedule of modified capecitabine (XEL), OX (i.e., mXELOX) plus BEV and modified XEL, IRI (i.e., mXELIRI) plus BEV for mCRC. Methods: This single-arm phase II trial was conducted in China. Patients aged 18–75 years, with histologically confirmed unresectable mCRC, ≥one measurable lesion via RECIST v1.1, ECOG PS of 0 to 2, and life expectancy of ≥3 months were eligible. Prior systemic therapies were not allowed except adjuvant chemotherapy. Induction treatment consisted of XEL 1000 mg/m2 bid D2–8 and D16–22, OX 85 mg/m2 D1, IRI 150 mg/m2 D15, and BEV 5 mg/kg D1 and 15 for 28-day cycles (up to six cycles). XEL 1000 mg/m2 bid D2–15 and BEV 7.5 mg/kg D1 for 21-day cycles were used as maintenance treatment. The primary endpoint was progression-free survival (PFS). Results: Between Apr 2020 and May 2023, 52 patients were included. As of Dec 30, 2023, median follow-up was 25.0 months. Mean age was 58.5±9.1 years old. 28 (54%) were male. 45 (87%) patients had either right-sided diseases, RAS or BRAF mutations. Median PFS was 11.0 months (95% CI 9.0–12.4). Subgroup analyses showed prior treatments, tumor locations and metastases, and BRAF mutations did not affect efficacy. RAS wild-type patients had longer PFS vs mutant patients (median 12.3 months vs 9.8 months; P=0.024). Objective response rate and disease control rate were 73% (59%–84%) and 94% (84%–99%), respectively. Overall survival (OS) reached 28.1 months (18.4–34.0). Efficacy data were detailed in the Table. Grade 3–4 treatment-related adverse events (TRAE) occurred in 17 (33%) of 52 patients. No treatment-related death was reported. The most common grade 3–4 TRAE were hypertension (13 [25%]), neutrophil count decreased (three [6%]), and hand-foot syndrome (two [4%]). Additionally, grade 3–4 TRAE of diarrhoea occurred in one [2%] patient and no grade 3–4 peripheral neuropathy was reported. Conclusions: Alternating mXELOX/mXELIRI plus BEV demonstrated promising anti-tumor activity against mCRC, with acceptable tolerability and no new safety signal. Further studies were warranted to confirm the efficacy of the regimen. Clinical trial information: NCT04324476 . [Table: see text]
Evaluating the potential of micronuclei DNA from erythrocytes for early detection or recurrence risk prediction of colorectal cancer.
Authors: Yao Xingyun , Sun Haobo , Jiao Yurong , Kong Xiangxing , Liu Chengcheng , Pan Jie , Zhu Fangchao , Meng Fei , Liang Honghao , Cao Yanfei , Li Jun , Ding Kefeng , Gao Xiaofei
Published: June 2024

3577

Background: Current development in stool- and cell-free DNA (cfDNA)-based technologies have demonstrated promising potentials in colorectal cancer (CRC) diagnosis. However, early detection of CRC and advanced adenoma (AA) remains challenging. Also, better predicting the recurrence risk following initial treatment serves as an important factor influencing survival of CRC patients. Micronuclei (MN) are extranuclear bodies containing chromatin segments resulting from errors in DNA repair. Elevated levels of MN+ erythrocytes have been studied in genotoxicity testing and cancer diagnosis. We have developed a method (WO2021/228246 A1) for purifying and sequencing micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. By comparing MN-DNA from healthy donors (HDs) and CRC patients, we identified significant changes in read densities at specific genomic locations in patients, which were termed as tumor-associated MN-DNA (taMN-DNA) signatures. Here, we explored the potential of MN-DNA for early detection or recurrence risk prediction of CRC patients. Methods: Peripheral blood (1-2ml) was obtained from a training cohort of 1165 individuals, a validation cohort of 290 individuals, and a test cohort of 363 individuals. MN-DNA was isolated and sequenced from erythrocytes. Predictive models were developed using distinctive taMN-DNA features identified by genome-wide analysis to differentiate between HD and AA or CRC. A clinical trial comparing MN-DNA with an approved multitarget stool DNA test (sDNA-FIT) was also conducted on 60 individuals (42 HDs, 6 AAs, and 12 CRCs). In addition, we conducted a retrospective study on CRC patients after postoperative treatment for evaluating the potential of MN-DNA in predicting CRC recurrence risk, with 28 non-recurrent after initial surgery and treatment and 6 relapsed patients enrolled. Results: The predictive CRC model built on taMN-DNA features achieved an AUC of 97.93%, with 88.61% sensitivity at 95.05% specificity, especially 89.58% sensitivity for early-stage (stage I-II) CRC in the test cohort. The detection of AA achieved an AUC of 93.01%, with 68.29% sensitivity at 92.48% specificity in the test cohort. Comparing MN-DNA to sDNA-FIT showed superior overall sensitivity (83.33% vs. 61.11%), AA sensitivity (83.33% vs. 16.66%), with comparable specificity (85.71% vs. 88.10%). Finally, 92.86% patients who had no recurrence were detected with negative prediction results, whereas 83.33% patients who had relapsed were detected positive prediction result. Conclusions: Our results demonstrate that MN-DNA within erythrocytes from 1-2ml peripheral blood enable accurate detection of AA and early-stage CRC as well as recurrence risk prediction. A larger clinical study (NCT05875584) is ongoing and will further validate the application of MN-DNA in CRC detection.
Sintilimab plus axitinib for advanced fumarate hydratase-deficient renal cell carcinoma: A multi-center, open-label, single-arm, phase II study (SAFH).
Authors: Zeng Hao , Zhang Xingming , Liang Jiayu , Zhao Junjie , Liu Haoyang , Zhang Yaowen , Chen Yuntian , Sun Guangxi , Sheng Xinan , Wang Yongquan , Liu Xiaodong , Huang Rui , Wei Qiang , Li Xiang , Liu Jiyan , Shen Pengfei , Shen Pengfei , Chen Ni , Yao Jin , Liu Zhenhua
Published: June 2024

4523

Background: Fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) is a rare and highly invasive subtype of renal cell carcinoma. Previous studies have shown that immune checkpoint inhibitor (ICI) plus tyrosine kinase inhibitor (TKI) can be considered for first-line systemic treatment of FH-dRCC. We aimed to provide high-quality prospective clinical trial evidence regarding the efficacy and safety of Sintilimab plus Axitinib in FH-dRCC. Methods: This study was an investigator-initiated, open-label, single-arm, multiple institutional, phase II trial in patients (pts) aged 18 years or older with treatment naive, advanced FH-dRCC. Patients received Sintilimab (intravenous injection, every 3 week) in combination with Axitinib (5mg, orally taken per day) as first-line treatment until disease progression or intolerant to treatment. The primary endpoint was objective response rate (ORR; RECIST v1.1) and progression-free survival (PFS). This study is registered with ClinicalTrials.gov, NCT04387500. Results: From June 2021 to August 2023, 52 patients were screened, and 41 patients were enrolled. The median follow up was 16.0 months. Thirty-eight patients were available for efficacy assessment. Confirmed complete response rate was 10.5% (4/38), ORR was 60.5% (23/38). Disease-controlled rate (DCR) was 86.8%. The median PFS was 19.83 months (95% CI: 7.68-31.99). All grade and ≥3 treatment-emergent adverse events occurred in 87.8% (36/41) and 22.0% (9/41), respectively. Details about FH mutation status were available in 40 patients, and different FH mutation patterns were found to be associated with different therapeutic efficacy. Conclusions: The combination of Sintilimab and Axitinib showed manageable safety profile and durable anti-tumor efficacy in FH-dRCC. Evaluating mutation status of FH gene could help to predict potential survival benefit from ICI plus TKI therapy. Clinical trial information: NCT04387500 .
CA-62: A new biomarker for the detection of early-stage renal cell carcinoma.
Authors: Tcherkassova Janneta , Tsurkan Sergei , Prostyakova Anna , Klinski Evgueni , Sekacheva Marina , Boroda Alexander , Moro Ricardo
Published: June 2024

4526

Background: The American Cancer Society classifies Renal Cell Carcinoma (RCC) to be among the ten most common cancers. However, in spite of this need, effective biomarkers for early-stage detection of RCC are not yet available. The purpose of this study was to assess the diagnostic characteristics of a carcinoma-specific transmembrane N-glycoprotein biomarker, CA-62, for the detection of early-stage kidney cancer. Blinded serum samples from 204 patients were included in the clinical study, of which 68 had TNM-classified stages IA, IB, IIA or IIB renal cell carcinomas, while 136 were drawn from healthy volunteers. Methods: Quantitative measurement of serum CA-62 levels was performed using a chemiluminescent immunoassay ("JVS Diagnostics" LLC). Statistical analysis (MedCalc; version 19.7.4, MedCalc Software Ltd, Belgium, EU) was used to assess the diagnostic characteristics of the CA-62 biomarker for detection of RCC, including sensitivity and specificity, and test accuracy. Results: Significantly higher median concentrations of CA-62 were found in sera of RCC patients compared to those found in healthy controls as follows; stage I A, B (8,935 U/mL), stage II A (6,291 U/mL), stage II B (8,808 U/mL), and healthy controls (2,815 U/mL). It was expected that serum CA-62 levels would be elevated at these early stages of RCC (Stages I-IIB), demonstrating significant overexpression of this epithelial carcinoma marker during the initial stages of cancerogenesis. The results of the study are presented in the table. Area under the ROC curve (AUC) for RCC patients vs. healthy controls was 0.98 with a 95% CI (0.950-0.994), z-statistics (67.3), and a significance of p<0.0001. Conclusions: CA-62 demonstrated a 94.3% sensitivity for RCC at 96% specificity during the early stages of kidney cancer. Given that CA-62 is not specific for kidney cancer, it is reasonable to suggest that use of a combination of CA-62 with some other biomarkers that may lack the sensitivity of CA-62 but are often elevated in renal cell carcinoma patients, such as tumor-infiltrating lymphocytes and/or possibly some inflammation biomarkers. In particular, the combination of transmembrane glycoproteins CA-62 and CD105, combined with biomarkers such as Endothelial Vascular Growth Factor (EVGF) and/or a growth factor derived from platelets (PDGF) could be successfully used for kidney cancer screening in order to achieve both high sensitivity and specificity for RCC detection.[Table: see text]
Changes in treatment (Rx) patterns and attrition rates in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Galarza Fortuna Gliceida , Jo Yeonjung , Hage Chehade Chadi , Narang Arshit , Gebrael Georges , Mathew Thomas Vinay , Chigarira Beverly , Anderson Ethan , Mazumder Archisman , Ozay Zeynep Irem , Agarwal Neeraj , Maughan Benjamin L. , Swami Umang
Published: June 2024

4527

Background: Rx landscape of mccRCC has evolved rapidly with the approval of antibodies directed against programmed cell death protein-1 (PD-1) in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or vascular endothelial growth factor receptor tyrosine kinase (TKI) inhibitors. However, real-world data on Rx trends and attrition before and after PD-1 inhibitor approval are lacking. Herein, we analyze them in a large real-world cohort in the United States. Methods: This IRB-approved retrospective study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Inclusion: Metastatic RCC with clear cell histology diagnosed between 1/1/2011 to 1/31/2022 receiving Rx with opportunity of at least 1 year follow up. Exclusion: Pts needing Rx for ≥2 malignancies. Based on the approval date of PD-1+CTLA4 of 4/16/18, pts were separated into 2 groups: b2018 (1L Rx before 4/16/2018) and a2018 (1L Rx after 4/16/18). Landmark analysis was performed at 1 year after Rx discontinuation to identify pts who died, were alive but did not need Rx, or starting next-line Rx. All analysis was done using R version 4.2.3. Results: Of 12707 pts, 7923 met the eligibility criteria (b2018: 4561 pts and a2018: 3362 pts). Rx trends are summarized in the table. 1L Rx for the majority of pts changed from TKI monotherapy (mono; 79%) b2018 to PD-1 combination therapies a2018 (58%). TKI mono remained the most common Rx in both groups after 1L (Table). In the b2018 cohort, 58% of patients received 2L Rx, and 32% received 3L. In the a2018 cohort, 42% and 16% received 2L and 3L, respectively. At 1-year landmark analysis after 1L discontinuation: in the b2018 group, 58% pts received next Rx, 30% died without further Rx, and 12% were alive without Rx while in the a2018 group, 42% pts received next Rx, 26% died without further Rx and 32% were alive without Rx. Conclusions: Despite the increase in the utilization of PD-1+CTLA-4 and PD-1+TKI regimens since 2018, a significant number of patients still did not receive novel combination regimens in the 1L mccRCC setting in this real-world population in the United States. Furthermore, with the uptake of PD-1 based combinations in 1L, a higher proportion of pts experience treatment free interval or were alive without further therapy at 1 year landmark analysis after 1L Rx discontinuation. These findings need validation in other datasets and can help patient counseling in clinics.[Table: see text]
Applying genomic analysis to refine unclassified renal cell carcinoma.
Authors: Yekeduz Emre , Braun David A. , El Hajj Chehade Razane , Eid Marc , Labaki Chris , Machaalani Marc , Nassar Amin , Nawfal Rashad , Saad Eddy , Saliby Renee Maria , Semaan Karl , Sun Maxine , Hirsch Michelle S. , Ürün Yüksel , El Zarif Talal , CHOUEIRI Toni K.
Published: June 2024

4551

Background: Despite the improvements in genomic and pathological techniques to identify renal cell carcinoma (RCC), 2-6% of all patients with RCC cannot be classified into a particular subgroup, thus called “unclassified” RCC (uRCC). Ascertaining the genomic profile of those patients may help select proper treatment and find novel targets. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database v15.0 was used to select patients with RCC by using the OncoTree codes. All included patients were divided into four groups based on the most frequent subtypes of RCC: clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chRCC), and uRCC. The Cancer Genome Atlas (TCGA) was additionally used to assess corresponding oncogenic signaling pathways. We employed the chi-squared test to compare categorical variables and applied the Benjamini-Hochberg correction to calculate Q-values, thereby controlling the false discovery rate. Results: Overall, 1,990 tumor samples from 1,888 patients were evaluated. uRCC was observed in 184 patients (9.7%), whereas most had ccRCC (n=1339, 70.9%), followed by pRCC (n=224, 11.9%) and chRCC (n=141, 7.5%). Age distribution at sample sequencing was comparable between uRCC and other RCC subtypes (P>0.05). The proportion of female patients with uRCC was higher at 38.4%, compared to 26.5% in ccRCC (Q=0.002) and 16.3% in pRCC (Q<0.001), yet was comparable to chRCC at 48.6% (Q=0.210). The prevalence of uRCC was also greater among black patients, accounting for 8.6% vs. 2.1% in ccRCC (Q=0.001). Among patients with uRCC (n=224), the most common genomic alterations (GAs) were detected in NF2 (15.8%), SETD2(15.8%), TP53 (13.9%), TERT(13.4%), and VHL(11.8%). NF2 alterations were also more prevalent in patients with uRCC than in patients with ccRCC (1.8%, Q<0.001), chRCC (0.7%, Q<0.001), and pRCC (5.8%, Q=0.058). Notably, median overall survival (OS) was poorer in uRCC patients with altered NF2(n=29) than in those with unaltered NF2(n=155, 30.7 vs. 87.1 months, p=0.058). Of patients with uRCC, 135 (72.5%) samples were from primary tumors and 39 (20.9%) from metastatic sites, with no difference in GA frequencies between the two. CDKN2A and CDKN2B were the most frequent co-mutated genes in uRCC (Q<0.001), followed by VHL and BAP1 (Q<0.001), and SETD2 and PBRM1 (Q=0.023). GAs in uRCC were primarily observed in pathways related to TP53 (42.8%), cell cycle (33.3%), PI3K (23.5%), and HIPPO (7.7%). Conclusions: uRCC exhibited a unique genomic profile distinct from other common RCC subtypes. Notably, NF2alterations were frequent and correlated with a poorer prognosis. [Table: see text]
Response and outcomes with immune checkpoint inhibitor (ICI) in patients (pts) with urothelial carcinoma (UC) and subtype histology (SH).
Authors: Bakaloudi Dimitra Rafailia , Makrakis Dimitrios , Talukder Rafee , Diamantopoulos Leonidas Nikolaos , Jindal Tanya , Nguyen Charles B , Hobeika Charbel , Mathew Thomas Vinay , Johnson Jeffrey , Marmolejo Castañeda David Humberto , Korolewicz James , Zakopoulou Roubini , Hui Gavin , Barata Pedro C. , Alonso Buznego Lucia Andrea , Brown Jason R , Stewart Tyler F. , Epstein Ilana B. , Khaki Ali Raza , Grivas Petros
Published: June 2024

4580

Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1st line [1L] upfront, maintenance avelumab [mAV], ≥2nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]
Tumor fraction and copy number burden from urinary cell-free tumor DNA (utDNA) to predict minimal residual disease prior to repeat-transurethral resection in high-risk non-muscle invasive bladder cancer (HR-NMIBC).
Authors: Linscott Joshua , Miyagi Hiroko , Gould Billie , Murthy Prithvi , Rose Kyle M , Camperlengo Lucia P , Bonora Giancarlo , Zemp Logan , Gilbert Scott Michael , Spiess Philippe E. , Sexton Wade J. , Meeks Joshua J , Du Pan , Jia Shidong , Li Roger
Published: June 2024

4600

Background: Genomic alterations detected in urinary cell-free tumor DNA (utDNA) are concordant with those from tissue samples in patients with urothelial carcinoma. In this prospective study, we demonstrate that utDNA alterations and copy number variation can be used to detect minimal residual disease (MRD) prior to standard-of-care repeat transurethral resection of bladder tumors (rTURBT) in patients with high risk non-muscle invasive bladder cancer (HR-NMIBC). Methods: A total of 53 patients with high-risk NMIBC were enrolled prior to rTURBT. PredicineWES+ whole exome sequencing with boosted 600+ oncogene coverage was performed on the index TURBT (iTURBT) tissue. Urine samples were collected immediately prior to rTURBT (preUR). Low Pass Whole Genome Sequencing (LP-WGS) was used to detect utDNA and estimate copy number burden (CNB). Tumor fraction (tf) detected in utDNA was measured using PredicineBEACON personalized ultra-deep sequencing MRD probes designed from somatic variants detected in iTURBT tissue. MRD probes leverage up to 60 patient-specific alterations and a fixed 500 gene hotspot panel. Analysis included receiver operator curves (ROC) to establish CNB and tf efficacy in detecting residual cancer, based on the pathological findings from rTURBT. Specific thresholds for test positivity were set from ROC analysis and used to evaluate performance characteristics of CNB and tf separately and then in step-wise model. Results: In this HR-NMIBC cohort, residual disease was detected in 36/53 pts (68%) on pathologic evaluation. Using the CNB score from preUR samples, residual disease was detected with an overall AUC of 0.86. Setting the CNB threshold >6.1 yielded a positive likelihood ratio of 11.7 and negative likelihood ratio of 0.37 for detecting MRD. For patients with personalized urinary tf (n=34), a receiver operator curve demonstrated an area under the curve (AUC) of 0.89. Median urinary tf was 3.5% for patients with MRD vs. <0.05% (undetectable) for disease-free patients (p<0.001). Best thresholds for MRD detection per Youden’s index were tf >=6.8% and CNB >6.1. When combined into a step-wise model, the two assays together led to improved performance with 85.7% sensitivity, 100.0% specificity and an overall accuracy of 91.4%. Conclusions: Minimal residual disease can be detected using utDNA prior to rTURBT with high accuracy, making this a promising urinary biomarker. If validated, the combined approach using CNB and tf from utDNA for the detection of MRD can be used to predict patients in need of maximal resection prior to starting intravesical therapy.
Long-term survival adjusted for treatment crossover in patients (pts) with myelofibrosis (MF) treated with momelotinib (MMB) vs danazol (DAN) in the MOMENTUM trial.
Authors: Gupta Vikas , Gerds Aaron Thomas , Vannucchi Alessandro , Kiladjian Jean-Jacques , Harrison Claire , Urbano Alisa , Huang Jireh , Ellis Catherine Elizabeth , Mesa Ruben A.
Published: June 2024

6571

Background: Anemia and transfusion dependence affect nearly all pts with MF and are associated with poor prognosis.The phase 3 MOMENTUM trial (NCT04173494) evaluatedMMB—a JAK1, JAK2, and ACVR1 inhibitor—vs DAN (2:1 randomization) in JAK inhibitor (JAKi)–experienced pts with MF and anemia who had symptoms and splenomegaly. While MMB showed spleen, symptom, and anemia benefits vs DAN at wk 24, comparative estimates of long-term overall and leukemia-free survival (OS and LFS) are confounded and may underestimate the MMB effect, as all pts in the DAN arm who entered the open-label phase of the trial crossed over to receive MMB at wk 24. We used a rank-preserving structural failure time (RPSFT) model to estimate the OS and LFS that might have been observed without crossover. Methods: This exploratory analysis evaluated survival over the entire MOMENTUM trial period; most pts entered an extended access study (NCT03441113) after wk 48. The RPSFT model assumes that treatment slows the speed of disease progression and death proportionally regardless of time of crossover. Analyses were conducted with and without recensoring, and CIs were constructed to appropriately account for additional model fitting uncertainty. Results: As of December 29, 2022, 38 (29%) and 20 (31%) deaths had occurred in the MMB and DAN arms, respectively. Risk of death was reduced with MMB vs DAN by 11% (HR, 0.89) with no crossover adjustment, and by 22% (HR, 0.78) and 13% (HR, 0.87) using the RPSFT model with and without recensoring, respectively. Similarly, 40 (31%) and 22 (34%) LFS events had occurred at data cutoff in the MMB and DAN arms, respectively. Risk of an LFS event was reduced with MMB vs DAN by 20% (HR, 0.80) with no crossover adjustment, and by 36% (HR, 0.64) and 23% (HR, 0.77) using the RPSFT model with and without recensoring, respectively (Table). Conclusions: Consistent with the original unadjusted survival analysis, RPSFT models adjusting for the effects of treatment crossover showed prolonged OS and LFS in pts initially randomized to MMB vs those initially randomized to DAN; HRs in favor of MMB were lower after crossover adjustment. While these RPSFT analyses maintain the significance level of the original unadjusted analysis ( P>.05), these results support the trend of long-term survival benefits with MMB vs DAN in JAKi–experienced pts with MF and anemia. Clinical trial information: NCT04173494 . Clinical trial information: NCT03441113 .[Table: see text]
Efficacy and safety of ibrutinib plus venetoclax in patients with mantle cell lymphoma (MCL) and TP53 mutations in the SYMPATICO study.
Authors: Wang Michael , Jurczak Wojciech , Trneny Marek , Belada David , Wrobel Tomasz , Ghosh Nilanjan , Keating Mary-Margaret , van Meerten Tom , Fernández-Álvarez Rubén , von Keudell Gottfried , Thieblemont Catherine , Peyrade Frederic , Andre Marc , Hoffmann Marc , Naganuma Maoko , Szafer-Glusman Edith , Lin Jennifer , Dean James P. , Neuenburg Jutta Katrin , Tam Constantine S.
Published: June 2024

7007

Background: TP53 mutations confer high risk of early progressive disease (PD) and poor outcomes with standard chemoimmunotherapy in patients (pts) with MCL. To date, data on novel treatment options for these pts are limited to small single-arm analyses. The phase 3 SYMPATICO study is evaluating ibrutinib (Ibr) + venetoclax (Ven) in 3 cohorts of pts with MCL. Primary analysis of the randomized phase showed superior PFS with Ibr+Ven vs Ibr+placebo (Pbo) in pts with relapsed/refractory (R/R) MCL (Wang M et al, ASH 2023) with similar hazard ratios for pts with and without TP53mutations (0.57 [95% CI, 0.33–0.97] and 0.52 [95% CI, 0.32–0.82], respectively). Here, we report efficacy and safety of Ibr+Ven in pts with TP53 mutations across cohorts. Methods: The SYMPATICO cohorts are: open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in R/R MCL (n=21); randomized phase to evaluate Ibr+Ven (n=134) vs Ibr+Pbo (n=133) in R/R MCL; and open-label cohort to evaluate first-line (1L) Ibr+Ven (n=78). Data were pooled across cohorts for pts with TP53mutations treated with oral Ibr 560 mg once daily and Ven (5-wk ramp-up to 400 mg once daily) for 2 y, then single-agent Ibr 560 mg until PD or unacceptable toxicity. Response was assessed by investigators per Lugano criteria. Results: In total, 74 pts with TP53 mutations received Ibr+Ven in the safety run-in phase (n=5), the randomized phase (n=40), and the 1L cohort (n=29). At baseline, median age was 67 y, 96% of pts had ECOG PS of 0–1, 43% had high-risk simplified MIPI score, 36% had bulky disease ≥5 cm, 64% had bone marrow involvement, and 39% had splenomegaly. With a median time on study of 40.1 mo (range, 0.6+ to 60.7), median PFS was 20.9 mo vs not reached (NR) in pts without TP53 mutations. ORR was 84%, and the CR rate was 57%. Median OS was 47.1 mo. Outcomes were generally comparable in 1L and R/R MCL (Table). Median duration of treatment was 15.9 mo (range, 0.3–58.9); at data cutoff, treatment was ongoing with Ibr in 24% of pts and with Ven in 4%. The most frequent grade ≥3 AEs (in ≥10% of pts) were neutropenia (32%), anemia (15%), and thrombocytopenia (15%). Conclusions: Ibr+Ven demonstrated promising efficacy with high CR rates and durable remissions in high-risk pts with MCL and TP53mutations in SYMPATICO (n=74; 29 1L and 45 R/R), the largest single-study cohort of such pts reported to date. Clinical trial information: NCT03112174 . [Table: see text]
Efficacy and safety of immunotherapy plus chemotherapy for lung cancer neoadjuvant treatment: A network meta-analysis based on randomized controlled trials.
Authors: Li Shen , Yang Jiaqing , Xu Chenhao , Ma Xuelei
Published: June 2024

8026

Background: With immunotherapy's swift progress in lung cancer treatment, combining immunotherapy with chemotherapy (CT) for neoadjuvant use has attracted significant interest, though direct comparisons of its efficacy and safety are still scarce. This study aims to comprehensively evaluate the efficacy and safety of immunotherapy combined with chemotherapy versus chemotherapy alone in the neoadjuvant treatment of lung cancer. Methods: We searched databases, including PubMed and EMBASE, for phase II and III randomized global trials that assessed neoadjuvant lung cancer treatment with immunotherapy combined with chemotherapy. We performed a Bayesian random-effects network meta-analysis to evaluate efficacy, presenting Hazard Ratios (HRs) and 95% Confidence Intervals (95%CI). Bias risk was determined using the Cochrane risk of bias tool, and evidence quality was appraised via the CINeMA framework. Results: Our analysis included eight randomized controlled trials, comprising a total of 3,316 patients. The results indicated that, compared to neoadjuvant chemotherapy alone, the Event-Free Survival (EFS) was highest for the durvalumab+CT group, ranking first with an HR of 2 (95% CI: 1.0 to 3.7). The pembrolizumab+CT group ranked second with an HR of 1.8 (95% CI: 0.76 to 4.2), followed by the nivolumab+CT group in third place with an HR of 1.7 (95% CI: 0.95 to 3.1). Both the nivolumab and ipilimumab+CT and toripalimab+CT groups tied for fourth place with HRs of 1.4 (95% CI: 0.58 to 3.5) and 1.5 (95% CI: 0.70 to 3.2), respectively. The camrelizumab+CT group had the lowest EFS ranking, with an HR of 1.7 (95% CI: 0.74 to 3.8). The combination of nivolumab+ipilimumab+CT showed the most favorable outcomes in terms of Pathologic Complete Response (PCR) and R0 resection rates among the six treatments, with lnOR values of 3.17 and 1.48, respectively. This combination also had the lowest occurrence of treatment-related adverse events greater than grade 3, with an lnOR value of -1.38. Conclusions: This network meta-analysis indicates that durvalumab, when combined with chemotherapy, offers the best EFS among the immunotherapy options evaluated, demonstrating good safety and efficacy. Concurrent use of nivolumab and ipilimumab resulted in the highest pCR and R0 resection rates. Moreover, for patients with lung cancer, the preliminary evidence supports the value of combining immunotherapy with chemotherapy as a neoadjuvant treatment strategy over chemotherapy alone. [Table: see text]
Investigation of the role of personalized molecular residual disease in the assessment of high-risk non-small cell lung cancer (NSCLC) post-operation.
Authors: Zhou Yu-Heng , Lin Yaobin , Rao Bing-Yu , Feng Shoucheng , Teng Jiaman , Cheng Shaochen , Zhong Jiasheng , Long Hao
Published: June 2024

8027

Background: Radical surgical resection is preferred treatment for early-stage Non-Small Cell Lung Cancer (NSCLC) patients. Despite this, recurrence and metastasis significantly impact patient survival. High-risk factors like Tumor Thrombus (TT) and Spread Through Air Spaces (STAS) are known to exacerbnate the recurrence and metastasis rates, yet there is lacking research exploring the association between these riskes and treatment outcomes. The study aims to evaluate the utility of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) in assessing and monitoring high-risk NSCLC post-operatively. Methods: NSCLC patients underwent curative surgery (R0) were recruited in this study and their tissue samples were collected after surgical resection. Whole exome sequencing (WES) was performed to identify somatic mutation information across individual, from which bespke molecular residual disease (MRD) detection panel was designed and used in later detection. Plasma samples were collected 3-4 weeks post-surgery and analyzed for MRD status through using next-generation sequencing (NGS) at 100,000x sequencing depths. Results: The study enrolled 124 NSCLC patients with a median age of 60 years (ranged 29-86)., The cohort comprised 63 male (77.3%) and 61 females (22.7%). Pathologically, 92 patients were classified in stage I, 5 as stage II, 17 as stage III, and 10 as stage IV. A total of 10,260 somatic mutationwere identified across 6,315 genes, including 639 insertions/deletions (InDels), 9613 single nucleotide variants (SNVs), and 8 gene fusions. The most prevalent mutations were EGFR (58.87%), followed by TTN (45.97%), TP53 (40.32%), CEP192 (20.97%), XIRP2 (19.35%), ZFHX4 (19.35%), and TOPAZ1 (16.94%). The MRD positivity was observed in 29.0% (36/124) of patients, with a higher incidence in males (34.9%, 22/63) than females (22.9%, 14/61). By stage, MRD positivity was 16.3% (16/92) in stage I, 40.0% (2/5) in stage II, 47.0% (8/17) in stage III, and 100% (10/10) in stage IV patients. Among patients with risk factors, 31.6% (12/38) with STAS, , 60.0% (6/10) with TT, and 53.8% (7/13) with pleural invasion were MRD positive, which indicating a higher postoperative MRD positivity in high-risk groups. Conclusions: NSCLC patients with high-risk factors, such as STAS and TT, , exhibit a high rate postoperative MRD positivity, even after R0 resection. Current research reports indicate that the MRD post-operation is an indicator of recurrence, metastasis, and poor prognosis. The findings imply that NSCLC patients harboring these high-risk factors are more susceptible to recurrence and metastasis, possibly necessitating postoperative adjuvant therapy for effective management.