bluuebunny/crossref_metadata_2025 huggingface dataset:
Explainable Boosting Machine approach identifies risk factors for acute renal failure
Authors: Körner Andreas , Sailer Benjamin , Sari-Yavuz Sibel , Haeberle Helene A. , Mirakaj Valbona , Bernard Alice , Rosenberger Peter , Koeppen Michael
Published: June 2024

Background

Risk stratification and outcome prediction are crucial for intensive care resource planning. In addressing the large data sets of intensive care unit (ICU) patients, we employed the Explainable Boosting Machine (EBM), a novel machine learning model, to identify determinants of acute kidney injury (AKI) in these patients. AKI significantly impacts outcomes in the critically ill.

Methods

An analysis of 3572 ICU patients was conducted. Variables such as average central venous pressure (CVP), mean arterial pressure (MAP), age, gender, and comorbidities were examined. This analysis combined traditional statistical methods with the EBM to gain a detailed understanding of AKI risk factors.

Results

Our analysis revealed chronic kidney disease, heart failure, arrhythmias, liver disease, and anemia as significant comorbidities influencing AKI risk, with liver disease and anemia being particularly impactful. Surgical factors were also key; lower GI surgery heightened AKI risk, while neurosurgery was associated with a reduced risk. EBM identified four crucial variables affecting AKI prediction: anemia, liver disease, and average CVP increased AKI risk, whereas neurosurgery decreased it. Age was a progressive risk factor, with risk escalating after the age of 50 years. Hemodynamic instability, marked by a MAP below 65 mmHg, was strongly linked to AKI, showcasing a threshold effect at 60 mmHg. Intriguingly, average CVP was a significant predictor, with a critical threshold at 10.7 mmHg.

Conclusion

Using an Explainable Boosting Machine enhance the precision in AKI risk factors in ICU patients, providing a more nuanced understanding of known AKI risks. This approach allows for refined predictive modeling of AKI, effectively overcoming the limitations of traditional statistical models.
Thyroid imaging reporting and data system with MRI morphological features for thyroid nodules: diagnostic performance and unnecessary biopsy rate
Authors: Zheng Tingting , Zhang Yuan , Wang Hao , Tang Lang , Xie Xiaoli , Fu Qingyin , Wu Pu-Yeh , Song Bin
Published: June 2024

Background

To assess MRI-based morphological features in improving the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) for categorizing thyroid nodules.

Methods

A retrospective analysis was performed on 728 thyroid nodules (453 benign and 275 malignant) that postoperative pathology confirmed. Univariate and multivariate logistic regression analyses were used to find independent predictors of MRI morphological features in benign and malignant thyroid nodules. The improved method involved increasing the ACR-TIRADS level by one when there are independent predictors of MRI-based morphological features, whether individually or in combination, and conversely decreasing it by one. The study compared the performance of conventional ACR-TIRADS and different improved versions.

Results

Among the various MRI morphological features analyzed, restricted diffusion and reversed halo sign were determined to be significant independent risk factors for malignant thyroid nodules (OR = 45.1, 95% CI = 23.2–87.5, P < 0.001; OR = 38.0, 95% CI = 20.4–70.7, P < 0.001) and were subsequently included in the final assessment of performance. The areas under the receiver operating characteristic curves (AUCs) for both the conventional and four improved ACR-TIRADSs were 0.887 (95% CI: 0.861–0.909), 0.945 (95% CI: 0.926–0.961), 0.947 (95% CI: 0.928–0.962), 0.945 (95% CI: 0.926–0.961) and 0.951 (95% CI: 0.932–0.965), respectively. The unnecessary biopsy rates for the conventional and four improved ACR-TIRADSs were 62.8%, 30.0%, 27.1%, 26.8% and 29.1%, respectively, while the malignant missed diagnosis rates were 1.1%, 2.8%, 3.7%, 5.4% and 1.2%.

Conclusions

MRI morphological features with ACR-TIRADS has improved diagnostic performance and reduce unnecessary biopsy rate while maintaining a low malignant missed diagnosis rate.
The association between dietary meal intake habits and coronary artery stenosis and cardio-metabolic risk factors
Authors: Taftian Marzieh , Sasanfar Bahareh , Sarebanhassanabadi Mohammadtaghi , Seyedhosseini Seyedmostafa , Khayyatzadeh Sayyed Saeid , Madadizadeh Farzan , Motallaei Maryam , Beigrezaei Sara , Golvardi-Yazdi Faezeh , Mirjalili Fatemeh , Salehi-Abargouei Amin
Published: June 2024

Background and objective

We are not aware of studies examining the association between dietary meal intake habits (DMIH) and severity of coronary artery stenosis (CAS). This study was conducted to investigate the relationship between DMIH and the severity of CAS as well as cardiometabolic risk factors in adults undergoing coronary angiography.

Methods

This cross-sectional study was done on 720 patients undergoing coronary angiography (aged 35–75 years) who were admitted to Afshar Hospital, a referral hospital for cardiovascular diseases in Yazd, Iran. Data on DMIH were gathered by interview. Blood samples were taken for biochemical analysis. Blood pressure, anthropometric indices, and body composition were also evaluated. The relationship between DMIH and the severity of CAS [examined by angiography based on Gensini Score (GS) and Syntax Score (SS)] and cardiometabolic risk factors were assessed using logistic regression and the analysis of covariance (ANCOVA), respectively, in crude and multivariable adjusted models.

Results

After adjustment for all possible confounding variables, the study revealed that people who ate 3 meals/day had a lower risk of severe CAS compared to people who ate 2 or fewer meals (OR = 0.48, 95% CI: 0.26, 0.88, P-trend = 0.02). There was an inverse association between the number of snacks /day and the severity of CAS (OR = 0.43, 95% CI: 0.22, 0.87, P-trend = 0.02). There was also an inverse relationship between breakfast frequency/week and the severity of CAS based on both GS and SS (P < 0.05). Breakfast consumption, meal frequency, lunch consumption, snack frequency, and more food consumption on holidays were also associated with different cardiometabolic markers and anthropometric measures (P < 0.05).

Conclusion

According to the results of the present study, meal frequency and breakfast consumption might be inversely associated with CAS and cardiometabolic risk factors.
Reproducibility and repeatability of quantitative T2 and T2* mapping of osteosarcomas in a mouse model
Authors: Roudi Raheleh , Pisani Laura J. , Pisani Fabrizio , Liang Tie , Daldrup-Link Heike E.
Published: June 2024

Background

New immunotherapies activate tumor-associated macrophages (TAMs) in the osteosarcoma microenvironment. Iron oxide nanoparticles (IONPs) are phagocytosed by TAMs and, therefore, enable TAM detection on T2*- and T2-weighted magnetic resonance images. We assessed the repeatability and reproducibility of T2*- and T2-mapping of osteosarcomas in a mouse model.

Methods

Fifteen BALB/c mice bearing-murine osteosarcomas underwent magnetic resonance imaging (MRI) on 3-T and 7-T scanners before and after intravenous IONP infusion, using T2*-weighted multi-gradient-echo, T2-weighted fast spin-echo, and T2-weighted multi-echo sequences. Each sequence was repeated twice. Tumor T2 and T2* relaxation times were measured twice by two independent investigators. Repeatability and reproducibility of measurements were assessed.

Results

We found excellent agreement between duplicate acquisitions for both T2* and T2 measurements at either magnetic field strength, by the same individual (repeatability), and between individuals (reproducibility). The repeatability concordance correlation coefficient (CCC) for T2* values were 0.99 (coefficients of variation (CoV) 4.43%) for reader 1 and 0.98 (CoV 5.82%) for reader 2. The reproducibility of T2* values between the two readers was 0.99 (CoV 3.32%) for the first acquisitions and 0.99 (CoV 6.30%) for the second acquisitions. Regarding T2 values, the repeatability of CCC was similar for both readers, 0.98 (CoV 3.64% for reader 1 and 4.45% for reader 2). The CCC of the reproducibility of T2 was 0.99 (CoV 3.1%) for the first acquisition and 0.98 (CoV 4.38%) for the second acquisition.

Conclusions

Our results demonstrated high repeatability and reproducibility of quantitative T2* and T2 mapping for monitoring the presence of TAMs in osteosarcomas.

Relevance statement

T2* and T2 measurements of osteosarcomas on IONP-enhanced MRI could allow identifying patients who may benefit from TAM-modulating immunotherapies and for monitoring treatment response. The technique described here could be also applied across a wide range of other solid tumors.

Key points

• Optimal integration of TAM-modulating immunotherapies with conventional chemotherapy remains poorly elucidated.

• We found high repeatability of T2* and T2 measurements of osteosarcomas in a mouse model, both with and without IONPs contrast, at 3-T and 7-T MRI field strengths.

• T2 and T2* mapping may be used to determine response to macrophage-modulating cancer immunotherapies.

Graphical Abstract
Unraveling Alzheimer’s: the promise of aducanumab, lecanemab, and donanemab
Authors: Ameen Taha Basit , Kashif Syeda Naveera , Abbas Syed Muhammad Iraj , Babar Kulsoom , Ali Syed Muhammad Sinaan , Raheem Abdul
Published: June 2024

Alzheimer’s disease (AD) is a neurodegenerative condition that causes cognitive decline, memory loss, and reduced personal autonomy. The pathology of AD involves the aggregation of abnormal brain proteins, specifically beta-amyloid plaques and tau tangles, disrupting neuronal communication and leading to the loss of brain cells. Aducanumab, a monoclonal antibody, demonstrates promise in clinical trials by selectively binding to aggregated amyloid-beta, leading to a notable decrease in plaque burden and potential cognitive benefits. However, regulatory approval for aducanumab remains controversial. Lecanemab and donanemab are recent additions to the AD’s treatment landscape, both targeting aggregated amyloid-beta. Lecanemab shares similarities with aducanumab in its mechanism of action, while donanemab employs a distinct approach by binding to a specific truncated form of amyloid-beta. Positive outcomes have been observed in early-stage clinical trials for both drugs, demonstrating a reduction in amyloid-beta plaques. While aducanumab’s approval offers hope for AD’s treatment, ongoing studies on lecanemab and donanemab are imperative for a comprehensive understanding of their potential in disease modification. Here, we show in this review the potential AD treatments, with a focus on their primary action targeting the reduction of amyloid-beta plaques ultimately giving a broader insight on the topic. The review emphasizes the necessity for long-term efficacy and safety data to assess the overall impact of these drugs on cognitive decline and functional outcomes for future researchers to endeavor. In conclusion, the development of amyloid-beta targeting monoclonal antibodies represents a significant stride in AD’s treatment, demanding further investigation to ascertain their true potential and role in the therapeutic arsenal for this challenging condition.
Charting the Course: Sequencing Immunotherapy for Multiple Myeloma
Authors: Mohan Meera , Van Oekelen Oliver , Akhtar Othman Salim , Cohen Adam , Parekh Samir
Published: June 2024

Multiple chimeric antigen receptor (CAR) T-cell and bispecific antibody (bsAb) therapies have been approved, demonstrating impressive clinical efficacy in relapsed/refractory multiple myeloma (MM). Currently, these treatment share overlapping approval indications in the relapsed/refractory space, highlighting the importance of optimal selection and sequencing to maximize clinical efficacy. For patients previously unexposed to T-cell–directed therapies, several factors should be weighed when both options are available. These factors include access and logistical challenges associated with CAR T-cell therapy, disease-specific factors such as tempo of disease relapse, in addition to patient-specific factors such as frailty, and distinct toxicity profiles across these agents. Sequential therapy, whether it involves CAR T-cell therapy followed by bsAb or vice versa, has demonstrated clinical efficacy. When sequencing these agents, it is crucial to consider various factors that contribute to treatment resistance with careful selection of treatments for subsequent therapy in order to achieve favorable long-term patient outcomes.
PD-L1, tumor mutational burden (TMB) and long-term survival in patients with non-small cell lung cancer (NSCLC) and brain metastases.
Authors: Adib Elio , Nassar Amin , Kwiatkowski David J. , Aizer Ayal
Published: June 2024

2034

Background: Brain metastases (BM) affect up to 50% of patients with NSCLC and are associated with poor prognosis in patients with non-targetable genomic alterations. Radiation forms the typical mainstay of intracranial management in such patients given the historically guarded intracranial efficacy of most systemic options. Immunotherapy-based approaches have shown promise but the extent that patients with BM may display extended survival with combination radiation- and immunotherapy-based approaches remains unclear. Methods: We identified 160 patients harboring non-squamous NSCLC with 486 newly-diagnosed BM between 2015-2023 managed with brain-directed radiation (either stereotactic-based, SRT or whole brain radiation therapy, WBRT) and immune checkpoint inhibition within 3 months of radiation at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (Boston, MA). PD-L1 tumor expression was categorized as <1%, 1-49%, 50-89%, and ≥90% based on immunohistochemistry. TMB was assessed via targeted next-generation sequencing. Cox-proportional hazards regression was used to assess all-cause mortality while Fine-Gray competing risks regression was used to assess other time-to-event based outcomes. Results: The median number of BM was 3 (IQR 1-7). Neurosurgical resection in advance of radiation was performed in 51/160 (32%) pts. SRT was used in 130/160 (81%) versus 30/160 (19%) patients treated with WBRT, respectively. Median follow-up time was 30.1 months (mo). Higher PD-L1 expression was associated with significantly longer overall survival (OS) with a median survival in patients with PD-L1<1%, 1-49%, 50-89% and ≥90% being 11.8, 14.4, 29.5 and 33.1 months, respectively (Table). Similarly, time to systemic death (TTSD) was longer in patients with higher PD-L1 expression, while time to neurologic death (TTND) was not different across categories. Higher TMB (≥10 vs. <10 mutations/megabase) was not associated with significantly longer OS, TTSD or TTND. Conclusions: Higher PD-L1 tumor expression was associated improved all-cause mortality, largely driven by reduction in systemic death. A significant percentage of patients with a very high PD-L1 displayed long-term survival, highlighting the potential importance of multimodality therapy in such patients, and demonstrating that clinicians should be cognizant of treatment-associated long-term toxicities in this population. [Table: see text]
Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort.
Authors: Strowd Roy E. , De La Fuente Macarena Ines , Bauer Todd Michael , Papadopoulos Kyriakos P. , Chen Ke , Perini Rodolfo F. , Liu Yanfang , McDermott David F.
Published: June 2024

2054

Background: Patients with progressive/recurrent glioblastoma (GBM) have very poor prognosis, and novel treatments are urgently needed. Hypoxia is a prominent feature of the tumor microenvironment in GBM and has been implicated as a potential mechanism of resistance to radiation therapy, which is a key part of standard-of-care treatment for GBM. HIF-2α has been suggested as a key therapeutic target because it plays a role in stabilizing the hypoxic environment in GBM tumors. Belzutifan, a first-in-class HIF-2α, has shown efficacy in advanced renal cell carcinoma and in von Hippel-Lindau disease–related renal cell carcinoma, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas. The phase 1 LITESPARK-001 trial (NCT02974738) was designed to evaluate belzutifan across solid tumors. Here, we report results from the GBM expansion cohort of LITESPARK-001. Methods: Patients enrolled in the GBM cohort had histologically confirmed, IDH wild type GBM that is first recurrent following radiation therapy and temozolomide according to the Response Assessment in Neuro-Oncology (RANO) criteria and had a measurable contrast-enhancing lesion by MRI imaging and a Karnofsky performance scale score ≥60%. Patients received belzutifan 120 mg by mouth twice daily. End points for this cohort included objective response rate (ORR), clinical benefit rate (CBR, CR + PR + SD of any duration), and progression-free survival (PFS) per RANO criteria by investigator assessment and safety. Results: Overall, 25 patients were enrolled in the GBM cohort. Median age was 63 years (range, 35-75), and most patients were male (n = 15; 60%). Median follow-up was of 1.9 months (range, 0.7-5.1). ORR was 0% (95% CI, 0.0-13.7) and CBR was 8% (95% CI, 1.0-26.0). Median PFS was 1.4 months (95% CI, 1.1-1.8). All patients (100%) experienced ≥1 adverse event and 15 (60%) experienced a grade 3-5 adverse event. The most common adverse events were anemia (n = 16 [64%]), fatigue (n = 13 [52%]), headache (n = 8 [32%]), muscular weakness (n = 8 [32%]). Two patients (8%) died from adverse events (both disease progression). No deaths were considered related to treatment. Conclusions: Antitumor activity was not observed with belzutifan for patients with GBM who received prior radiation therapy and temozolomide. The safety profile was similar to previous studies with belzutifan. Further efforts are warranted to identify therapies for patients with glioblastoma to improve outcomes. Clinical trial information: NCT02974738 .
Phase 1/2 study of the TGF-β-trap-enhanced oncolytic adenovirus, AdAPT-001, plus an immune checkpoint inhibitor for patients with immune refractory cancers.
Authors: Conley Anthony Paul , Ravi Vinod , Roland Christina Lynn , Reid Tony R. , Larson Chris , Caroen Scott , Williams Jeannie Ann , Oronsky Bryan , Stirn Meaghan , Abrouk Nacer , Burbano Erica , Kennedy Lucy Boyce
Published: June 2024

2506

Background: The benefit of immune checkpoint inhibition is limited to 20-40% of patients. Moreover, acquired resistance often arises. Also, certain tumor types like breast are more CI-refractory. Therefore, the focus is on new combination strategies to increase clinical benefit. This multicenter phase 2 trial evaluated AdAPT-001, an oncolytic adenovirus armed with a “TGF-β trap” that neutralizes the immunosuppressive cytokine, TGF-β, +/- a checkpoint inhibitor (CI) in resistant patients some of whom previously failed a CI. Methods: Eligible patients with refractory tumors, many of them sarcomas, received 1 or more intratumoral injections of AdAPT-001 at dose level 1 x 1012 viral particles every 2 weeks +/- a CI at Investigator discretion. The CI was administered every 2nd-3rd week. Adverse events were recorded and managed. The primary endpoints of this combination therapy were objective response rate (ORR) and progression free survival (PFS). Results: 36 patients (22 males and 14 females) enrolled with a median age of 60.8 years (range 23-86) from Feb 2023-Dec 2023. 24/36 enrolled patients received AdAPT-001 with a CI and 12 patients received AdAPT-001 single agent. The most common treatment related adverse events (TRAE) were transient flu-like symptoms (fever, chills, vomiting, fatigue) 10/36 (27.7%), and injection related events 10/36 (27.7%). Notably, only 1 patient, 1/24 (4.0%), developed an immune-related AE, hypophysitis. All other related AEs were Grade 1/2. 33/36 patients were evaluable for response analysis; monotherapy produced 2/9 (22.2%) favorable responses (complete response (CR): eccrine carcinoma; confirmed partial response (cPR): acral melanoma); and produced a 4/9 (44.4%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. The combination of AdAPT-001 plus a CI produced 7/24 (29.1%) favorable responses (1 clinical CR: angiosarcoma; 6 cPRs: 3 sarcoma, 1 triple negative breast cancer, 1 head and neck cancer, 1 squamous cell carcinoma; and a 15/24 (62.5%) clinical benefit rate defined as CR/PR/SD greater than 12 weeks. 21/33 failed a CI before enrollment (16/24 before AdAPT-001 + CI). The PFS was 3.5 months (95% CI: 1.8-NA months). Conclusions: Combination therapy of AdAPT-001 with a CI is well tolerated and demonstrates a high ORR including 1 patient with a CR per RECIST 1.1, 1 patient with a clinical CR and 6 PRs. In several cutaneous sarcomas treated with AdAPT-001 plus a CI, radiologic SD belied how much better they looked visually--not only smaller, but less irregular and more circumscribed. Clinical trial information: NCT04673942 . [Table: see text]
Phase 1 study of BA3071, an anti–CTLA-4 conditionally active biologic, in combination with nivolumab in advanced solid tumors.
Authors: Thomas Jacob Stephen , Selfridge Jennifer Eva , Albany Costantine , Taylor Matthew H. , Mehmi Inderjit , Kwatra Vineet , Hu-Lieskovan Siwen , de Souza Paul L. , Llorin-Sangalang Judith Dubal , Aysola Kartik , Hamid Omid
Published: June 2024

2602

Background: Immune checkpoint inhibition of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) in combination with programmed cell death protein 1 (PD-1) has demonstrated durable clinical benefit in patients with advanced solid tumors. However, dose density is limited due to toxicity. BA3071 is a conditionally active biologic (CAB) anti–CTLA-4 monoclonal antibody that blocks the interaction of CTLA-4 with its ligands CD80 and CD86 [1]. CABs are activated within the acidic tumor microenvironment. Conditional and reversible binding of BA3071 may reduce on- and off-tumor immune-related adverse events (AEs) and autoimmunity, avoid tissue-mediated drug deposition, and improve pharmacokinetics. We evaluated the safety and antitumor activity of BA3071 in patients with advanced solid tumors. Methods: Patients naïve to anti–CTLA-4 therapy with advanced solid tumors received escalating doses of single-agent BA3071 every 3 weeks (Q3W) at cycle 1, followed by combination BA3071 + nivolumab from cycle 2 onward. Treatment continued until disease progression or unacceptable toxicity. Response assessment was performed Q6W with RECIST v1.1. Results: Eighteen patients were treated with BA3071 (7–700 mg) and nivolumab (240 mg); 61% had received ≥3 lines of prior systemic therapy, and all patients had experienced failure of anti–PD-1 therapy. Four patients experienced grade 3 related treatment-emergent AEs (TEAEs; hypertension, increased lipase, atrial fibrillation, gastritis, and diabetic ketoacidosis); no grade 4 related TEAEs were observed. Two patients experienced grade 3 immune-related TEAEs (diarrhea [BA3071 350 mg] and diabetic ketoacidosis [BA3071 700 mg]). Among 16 efficacy-evaluable patients, 9 experienced stable disease, and 2 out of 5 patients receiving BA3071 in the 350-mg cohort achieved confirmed RECIST v1.1 responses (complete response in cervical carcinoma and partial response in gastroesophageal carcinoma). One patient with metastatic small cell lung cancer who received 7 mg BA3071 remained without progression for >1 year (69 weeks). Conclusions: Treatment with the novel, conditionally active anti–CTLA-4 agent BA3071, in combination with anti–PD-1 therapy (at doses higher than those currently approved for anti–CTLA-4/PD-1 therapy), yielded confirmed responses with a promising tolerability profile. Phase 1 dose escalation of BA3071 continues at 700 mg up to 1000 mg, and phase 2 monotherapy and combination therapy expansion cohorts are currently enrolling at a starting dose level of 350 mg. 1. Chang HW et al. Proc Natl Acad Sci USA.2021;118(9):e2020606118. Clinical trial information: NCT05180799 .
Tislelizumab first-line (1L) gastric/gastroesophageal junction cancer (G/GEJ) treatment efficacy on patient-reported outcome (PRO)-based symptom endpoints adjusting for informative missing data bias: Results from RATIONALE 305.
Authors: Serrano Daniel , Xu Hui , Sheng Tao , Li Liyun , Barnes Gisoo , Oh Do-Youn
Published: June 2024

2605

Background: PRO-based symptom endpoints are rarely associated with treatment efficacy in oncology trials. PRO analyses emphasize early treatment cycles to avoid bias arising from study dropout (SDO; eg, due to death or other intercurrent events). SDO is thought to induce data missing not at random (MNAR), thereby biasing estimates and inference. However, separation between arms on other efficacy endpoints (eg, overall survival [OS]) typically occurs at cycles subsequent to the analysis period cutoff for PRO-based endpoints. This research examined treatment efficacy in PRO-based symptom endpoints in treatment cycles occurring later than typically analyzed. To protect against MNAR bias associated with later cycles, joint models (JMs) were employed. Methods: RATIONALE 305 was a randomized, double-blind, placebo-controlled, phase 3 trial comparing efficacy and safety of tislelizumab + chemotherapy (tislelizumab) with placebo + chemotherapy (chemo) as 1L treatment for patients with locally advanced, unresectable, or metastatic G/GEJ adenocarcinoma. EORTC-STO22 symptom domain scores were analyzed. Change from baseline (CFBL) in each domain was analyzed for up to 21 cycles between baseline and Cycle 38 (cycle with no less than 10% of baseline surviving). Treatment efficacy for STO22 endpoints was analyzed using JMs. The JM linked a linear mixed model (LMM) for STO22-domain CFBL to a Cox proportional hazards model for OS, adjusting LMM estimates for the potential MNAR bias arising from OS-based SDO. The LMM and Cox model were adjusted for study randomization factors of region (East Asia vs Rest of World), PD-L1 status (positive vs. negative), and peritoneal metastases (present vs. absent). All analyses were conducted using JMBayes2 package in R version 4.3.2. Results: STO22 pain results are reported; all domains will be presented. For tislelizumab (n=465) vs. chemo (n=467), subjects remaining at Cycle 38 were 46 (10%) and 28 (6%), respectively. Tislelizumab was associated with a constant lower level of pain compared with chemo (-2.08; P=0.0109). Tislelizumab was associated with a 21% reduction in risk of death ( P=0.0269). Conclusions: In this analysis, compared with chemo, tislelizumab + chemo was associated with lower pain and longer survival. Joint models for PRO-based symptom endpoints may illuminate patient-centric therapeutic benefits. [Table: see text]
Efficacy and safety of FCN-159, a MEK1/2 inhibitor in pediatric participants with neurofibromatosis type 1: Results from a phase 2 trial.
Authors: Wang JinHu , Li Wenbin , Zeng Kang , Lin Xiaoxi , Li Yanling , Guan Zhonghai , Kang Zhuang , Li Changxing , Hu Xiaojie , Ma Yaohui , Wu Zhuli , Wang Xingli , Han Pu , Lin Hongmei , Zhong Wen
Published: June 2024

3096

Background: Neurofibromatosis type 1(NF1) is an autosomal dominant tumor predisposition syndrome characterized by NF1 gene variants, resulting in over-activation of the RAS pathway. Plexiform neurofibroma (PN) is benign tumors that arise from nerve tissue and are a hallmark feature of NF1. They typically grow along nerves and cause disfigurement, pain, and other complications depending on their location and size. FCN-159, a highly potent and selective inhibitor of MEK1/2 by targeting inhibition of the RAS pathway, holds promise as a therapeutic agent for treating NF1-related PN. Methods: A multi-center, open-label phase 1/2 clinical trial was conducted to assess the safety and efficacy in pediatric patients(pts) with NF1-related PN. Here, we reported the safety and efficacy outcomes observed during phase 2 in pediatric pts, who received FCN-159 at the 5 mg/m2 dose once daily on a continuous basis in a 28-day cycle. Preliminary findings from the phase 1/2 trial were previously disclosed at ASCO 2023. Results: As of November 24, 2023,46 pts enrolled. The median age is 8.0 years (range 2-17). The most frequent PN related complications were disfigurement (69.6%) and pain (63.0%). Median volume of target neurofibroma were 37.7 cm³ (range 2.2-1144.1). Efficacy outcomes are reported for 43 pts (modified intent-to-treat population). With the median follow-up of 15.1 months (range 14.1-16.4), the investigator and Blinded Independent Review Committee (BIRC) assessed ORR were 48.8% and 30.2%, respectively. The mDoR and median mPFS were not reached. Preliminary efficacy data are presented in the table. Among the 16 pediatric subjects with tumor pain at baseline (overall tumor pain NRS≥1) and at least one post-baseline assessment, pain scores decreased by at least 2 points in 81.3% (13/16) pts, and pain scores reduced to 0 points (indicating no pain sensation) in 81.3% (13/16) pts, signifying clinically meaningful improvement. 43 pts (93.5%) experienced TRAEs with grade ≥3 TRAEs occurred in 8 pts (17.4%), including dermatitis acneiform (4.3%), folliculitis (4.3%), pneumonia (2.2%), upper respiratory tract infection (2.2%), ejection fraction decreased (2.2%), and blood creatine phosphokinase increased (2.2%). 2 pts (4.3%) reported treatment-related serious adverse events (one case of dermatitis acneiform and pneumonia each). No TRAEs resulting in dose reduction, discontinuation or death. Conclusions: FCN-159 demonstrated good tolerability and exhibited notable anti-tumor activity in pediatric pts with NF1-related PN. Clinical trial information: NCT04954001 . [Table: see text]
Real-world first-line serplulimab-based immunochemotherapy for extensive-stage small cell lung cancer: The multicenter ASTRUM-005R study.
Authors: Wu Lin , Hu ChengPing , Su Wenzhong , Yu Yan , Hong Wei , Liu Zhigang , Su Haichuan , Liu Zhentian , Wang Caixia , Pu Qing , Guo Hui , Min Xuhong , Chen Yifei
Published: June 2024

e20106

Background: In the phase 3 ASTRUM-005 study (NCT04063163), serplulimab, an anti-PD-1 monoclonal antibody, combined with chemotherapy, demonstrated promising antitumor activity as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC). This led to its approval by the NMPA and designation as an orphan drug by the FDA. Here, we present a multicenter cohort study investigating the real-world efficacy and safety of first-line serplulimab-based immunochemotherapy for ES-SCLC in China. Methods: This cohort study enrolled adult patients with ES-SCLC at 12 sites in China from April 2022 to December 2023. These patients received at least two cycles of first-line serplulimab combined with an etoposide-platinum regimen and underwent at least one response assessment. The primary endpoint was real-world progression-free survival (rwPFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety profiles. Results: A total of 420 patients were enrolled and evaluated for both efficacy and safety. The participants had a median age of 63 years (range 30-84), with 361 (85.95%) being male and 310 (73.81%) having a history of smoking. Most patients (386, 91.91%) had an ECOG PS of 0 or 1. Comorbidities, excluding other primary tumors, were present in 40.95% (172 patients). Liver and brain metastases were observed in 32.14% (n = 135) and 21.67% (n = 91), respectively. The median number of immunochemotherapy cycles was 4 (range 2-6), with 45.24% (n = 190) receiving more than 4 cycles. The median rwPFS was 9.1 months (95% CI 8.2-9.7), with a 1-year rwPFS rate of 34.3%, surpassing the 1-year PFS rate of 28.2% reported for the Asian in the ASTRUM-005 study. The median rwPFS was 9.8 months (95% CI 9.1-12.8) in patients without liver metastasis, significantly longer than the 6.7 months (95% CI 6.1-8.7) in patients with liver metastasis ( P < 0.0001). Patients who received radiotherapy also had a significantly longer median rwPFS of 9.8 months (95% CI 8.6-15.1) compared to 8.7 months (95% CI 7.3-9.6) for patients who did not receive radiotherapy ( P = 0.022). Additionally, patients who received > 4 cycles of immunochemotherapy had a median rwPFS of 10.5 months (95% CI 9.3-13.3), which was significantly longer than the 6.6 months (95% CI 5.6-9.1) in patients who received ≤4 cycles ( P < 0.0001). The ORR was 69.71%, and OS was not yet mature. Safety analysis revealed grade ≥3 AEs occurring in 19.05% of the cases. Conclusions: This cohort study reports the real-world survival outcomes of first-line serplulimab-based immunochemotherapy and provides valuable insights in a clinical setting. The study complements the ASTRUM-005 study, offering further evidence in ES-SCLC.
Neuroendocrine features in small cell lung cancer (SCLC) and associations with platinum-sensitivity, metastatic tropism, and overall survival.
Authors: He Weston , Karkash Ahmad , Han Yan , Shi Justin Wang , Marin-Acevedo Julian A. A. , Tran Mya , Shields Misty Dawn
Published: June 2024

e20113

Background: SCLC heterogeneity can be classified into neuroendocrine (NE) subtypes (ASCL1, NeuroD1, POU2F3, YAP1) with plasticity along its NE spectrum. SCLC harbors conventional NE features on immunohistochemistry (IHC) utilized for diagnosis. In the era of chemoimmunotherapy, insight into the role of conventional SCLC NE IHC with proclivity for metastatic site tropism and therapeutic outcomes, including chemotherapy-free interval (CTFI) and overall survival (OS), has not been studied. Methods: We retrospectively reviewed patients with SCLC who received antineoplastic therapy within the Indiana University (IU) Health System Affiliates from January 2018 to January 2024. Data was stored in an institutional review board approved RedCap. Demographics, treatment, metastases, TTF-1 and NE IHC markers, CTFI, and OS were recorded. IHC expression of Chromogranin A, synaptophysin, and INSM-1 were utilized to classify tumors into NE-low (1-3 negative markers), NE-moderate ( < 3 positive markers), and NE-high (3 positive markers). ANOVA, Kruskal-Wallis, Chi-square, Fisher’s Exact, and log-rank tests were applied. Results: One-hundred and fifty-three patients diagnosed with SCLC were included. Forty-six patients with limited-stage (LS-SCLC, 30.1%) and 107 patients with extensive-stage (ES-SCLC, 69.9%) were identified. Classification by conventional NE IHC included NE-low (n = 41), NE-moderate (n = 18), and NE-high (n = 94), with enrichment for the NE-high category ( P = < 0.0001). No differences were observed in age, sex, smoking history, or stage across NE categories. TTF-1 positivity by IHC independently predicted NE-high ( P = 0.04). The presence of metastases did not significantly differ ( P = 0.93), but trends in enrichment of bone ( P = 0.16) and pancreatic ( P = 0.15) metastases were observed in NE-low. No difference in CTFI was identified between NE cohorts ( P = 0.28) . Median 1-year OS across the NE-low, -moderate, and -high categories was 57.2% (95% CI, 40.4-70.8%), 36.1% (13.7-59.4%), and 53.3% (42.2-63.1%), respectively (log-rank, P = 0.09). Conclusions: Conventional NE IHC fails to predict CTFI in the era of chemoimmunotherapy. SCLC significantly enriches for NE-high. TTF-1 can independently predict NE-high SCLC. Trends in metastatic tropism and shorter 1-year OS in NE-moderate SCLC were identified but limited by sample size. Enrollment expansion is ongoing. Exploration into NE subtypes and multi-omics is in process.
PD-(L)1 inhibitors plus anlotinib: A superior option for second-line treatment of extensive-stage small cell lung cancer.
Authors: Zhang Jian , Sun Yuping , Gao Qin ai
Published: June 2024

e20117

Background: To evaluate the efficacy of PD-(L)1 inhibitors plus anlotinib as the second-line therapy of extensive-stage small cell lung cancer (ES-SCLC) in the real-world. Methods: EL-SCLC (n = 389) patients who received second-line treatment at 3 cancer centers between January 2008 and January 2023 were retrospectively analyzed. All patients received PD-(L)1 inhibitors in combination with anlotinib and/or chemotherapy(I+A±C), or PD-(L)1 inhibitors in combination with chemotherapy(I+C), or chemotherapy alone (C) as the second-line therapy. The efficacy including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), as well as safety were compared among three groups. Results: The baseline clinical characteristics among 3 groups were largely balanced. Compared with I+C (ORR=17.6%, DCR=68.8%) and C (ORR=18.0%, DCR=53.9%), I+A±C treatment had significantly higher ORR (30.2%) and DCR (82.6%). In addition, treatment with I+A±C generated the longest mPFS (7.2 months) and mOS (33.5 months) compared to that with I+C (mPFS=4.6 months, mOS=19.0 months, both P < 0.001) or C (mPFS=3.4 months, P < 0.01; mOS=18.3 months, P=0.083). However, addition of chemotherapy upon I+A did’t impact PFS (7.2 vs. 7.1 months, P=0.431) and OS (NA vs. 33.5 months, P=0.598). Stratified analysis showed that patients with female gender and oligometastasis (≤ 3 metastasis sites) benefit more from I+A±C treatment compared to male patients and those with polymetastasis, respectively. In addition, the combination of anlotinib with PD-L1 inhibitors generated superior PFS compared to that with PD-1 inhibitors. In patients not receiving PD-(L)1 inhibitors in first-line therapy, I+A±C treatment showed better PFS. The incidence of ≥ grade 3 myelosuppression is much lower in I+A±C group than those in I+C and C groups (3.5% vs 11.2% vs 16.3%, P < 0.01). However, I+A±C treatment generated a higher prevalence of immune-related pneumonia (2.3% vs 0% vs 0%, P < 0.05) and hemoptysis (1.4% vs 0% vs 0.6%, P < 0.05) compared with I+C and C. Conclusions: PD-(L)1 inhibitors plus anlotinib and/or chemotherapy has promising efficacy and manageable toxicity as second-line therpay of ES-SCLC.
Therapeutic stratification for small cell lung cancer with multiplexed proteomic analysis.
Authors: Kim Tae Jung
Published: June 2024

e20130

Background: Even with standard platinum doublet therapy, most patients with small-cell lung cancer (SCLC) survive less than 1 year. For those with refractory or relapsed disease, second-line, single-agent chemotherapy is recommended. Pre-treated SCLC patients can opt for clinical trials of agents such as temozolomide, fluorouracil (5FU), and antibody-drug conjugates (ADC) targeting the proteins DLL3, CD56, or TROP2. Some of these therapies have produced responses in untreated SCLC. To assess the proportions of patients who would be likely to respond to these therapies, we profiled protein targets in clinical tumor biopsies of SCLC using quantitative mass spectrometry. Methods: Archived tumor samples from 99 SCLC patients were microdissected and solubilized for proteomic quantification of 58 therapeutically relevant biomarkers. In each sample, quantities of tumor protein were compared with pre-defined thresholds based on evidence from clinical studies or quantification limits of proteomic assays. Prevalence and protein expression levels in SCLC were compared with those of other cancer indications analyzed in the same clinical laboratory. Results: 15 of 83 (18%) SCLC tumors had low or absent MGMT protein expression ( < 200 attomoles per microgram [amol/ug]), indicating likely response to temozolomide. 14 of 88 (15%) overexpressed TYMP protein ( > 1335 amol/ug), suggesting a likely response to 5FU. Except for one patient, likely responder to temozolomide or 5FU were mutually exclusive. The prevalence of quantifiable levels of the ADC markers DLL3, TROP2, and CD56 were 43%, 49%, and 97%, respectively. The SCLC tumors expressed a wide range of DLL3 protein (range: 101 – 1201 amol/ug); median expression in SCLC was 2 times higher than in pediatric neurological cancers, while median expression of TROP2 was lower in SCLC than in other indications. CD56 protein levels in SCLC were similar to other indications, but with higher prevalence in SCLC. Conclusions: In patients with SCLC, clinical proteomics identified protein targets of multiple approved and investigational therapies. Multiplexed clinical proteomic testing revealed additional treatment options in SCLC patients, which may be useful in first-line or later-line settings.
Tislelizumab combined with nab-paclitaxel single-agent chemotherapy plus bevacizumab for patients with EGFR-TKIs-resistant advanced NSCLC with ECOG PS 0-2.
Authors: Xie Xiaohong , Zhou MaoLin , Yang YiLin , Lin Xinqing , Xie Zhanhong , Qin Yinyin , Zhang Jiexia , Liu Ming , Li Ru , Zhou ChengZhi
Published: June 2024

e20138

Background: Treatment options are limited for EGFR-TKIs-resistant advanced NSCLC. A retrospective study from our center showed that ICIs plus platinum-free, single-agent chemotherapy provided progression-free survival, overall response rate benefit, and a low rate of severe AEs in such pts. Meanwhile,there were many NSCLC patients after treatment failure with EGFR-TKIs who ECOG performance status was 2 ,they were excluded from existing prospective studies. This study was designed to further explore the efficacy and safety of Tis plus nab- paclitaxel and Beva foradvancedNSCLCpts with ECOG ps 0-2 failed to EGFR-TKIs. Methods: This is a single-arm, phase II study (NCT04310943). Pts with EGFR mutations who had failed to prior EGFR-TKIs accepted Tis (200mg, d1) ,nab-paclitaxel (100mg/m2, d1,8,15) and Beva (15mg/kg, d1) Q3W for up to 4 cycles, followed by Tis plus Beva (7.5mg/kg) maintenance therapy. Primary endpoints are 6m-PFS% and safety, secondary endpoints include ORR and 1-year OS rate. The planned sample size was 24 with unacceptable control of 25%, an expected value of 55%, a one-sided α of 0.05, and a power of 80%, Simon's two-stage design. Results: The median age was 57 (range: 30-70). Thirteen pts (54.2%) harbored EGFR exon 19del and 9 pts (37.5%) had exon 21 L858R at the initial diagnosis. There were 9 pts (37.5%) with ECOG ps 2 and18 pts (75%) with clinical stage IVB. Twelve pts (50%) had stable brain metastases. Fifteen pts (63.6%) progressed on both 1st/2nd and 3rd EGFR-TKIs. As of Dec30, 2023, The median follow-up time was 22.2 m (95%CI 0-51.1). Among the 21pts in the efficacy analysis set, the median PFS was 6.3 m(95%CI 5.5-7.1), the 6m-PFS % was 61.6%, the 6m-PFS% of pts with ECOG ps 2 was18.1%. The ORR was 61.9%, the median DOR was 4.4 m (95%CI 2.1-6.7), DCR was 100.0%. The median OS was 15.4 (95%CI 10.1-20.7) and 1y-OS% was 59.7%. The safety was manageable: the incidence of ≥grade 3 TRAE was 25%. Conclusions: Tislelizumab combined with nab-paclitaxel plus bevacizumab is effective with a manageable safety profile for EGFR-TKIs resistant NSCLC patients with ECOG ps 0-2. Clinical trial information: NCT04310943 . [Table: see text]
High LDL Particle and APOB Concentrations in Patients With Adrenal Cortical Adenomas
Authors: Sandooja Rashi , Saini Jasmine , Kittithaworn Annop , Gregg-Garcia Raul , Dogra Prerna , Atkinson Elizabeth , Yu Kai , Fell Vanessa , Simha Vinaya , Connelly Margery A , Dullaart Robin P F , Bancos Irina
Published: June 2024

Context

Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk.

Objective

This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS.

Methods

We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy.

Results

In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy.

Conclusion

Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk.
Rabson-Mendenhall Syndrome: Analysis of the Clinical Characteristics and Gene Mutations in 42 Patients
Authors: Gong Wenfeng , Chen Wenzhe , Dong Jianjun , Liao Lin
Published: June 2024

Aims

Rabson-Mendenhall syndrome (RMS) is a rare autosomal, recessive disorder characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. This study aims to analyze the clinical features and gene mutations in RMS, which have not been extensively studied.

Methods

PubMed, Embase, the China National Knowledge Infrastructure, and Wanfang were searched for “Rabson-Mendenhall syndrome” or “Black acanthosis hirsutism insulin resistance syndrome.”

Results

A total of 42 cases from 33 articles were included. The body mass index ranged from 18.50 to 20.00 kg/m2 with an average of 16.00 kg/m2. There were no overweight (25.00∼29.90 kg/m2) or obese (≥30.00 kg/m2) patients. Acanthosis was present in 29 cases (29/42, 69.05%); growth retardation in 25 cases (25/42, 59.52%); dental anomalies including absence of teeth, crowding, and malocclusion in 23 cases (23/42, 54.76%); and hirsutism in 17 cases (17/42, 40.48%). The average glycosylated hemoglobin was 9.35%, and the average fasting blood-glucose was 8.44 mmol/L; the mean fasting insulin was 349.96 μIU/mL, and the average fasting C-peptide was 6.00 ng/mL. Diabetes was reported in 25 cases (25/33, 75.76%) all of which were diagnosed before 23 years old. All 42 patients had recorded gene mutations, with 22 patients (22/42, 52.38%) having ≥ 2 mutations and 20 cases (20/42, 47.62%) having only 1 mutation. No statistical differences were found in clinical features and laboratory parameters between patients with different mutations.

Conclusion

The study indicates that RMS should be considered in young patients with hyperinsulinemia, hyperglycemia with low weight, acanthosis nigricans, growth retardation, dental anomalies, and hirsutism.
Noxious Nicotine
Authors: Røsstad Hilde Kristin
Published: June 2024

Many horticulturists in the 1950s used nicotine-based products both for personal consumption and for pesticidal application. Growers in postwar Norwegian horticulture were sometimes poisoned by nicotine sulfate, but many also smoked tobacco, and this was widely considered a way to ameliorate the negative effects. This might have made them ambivalent about the risks, even though they knew it could be hazardous in certain dosages. This article explores the ambiguity of the meaning of nicotine in Norwegian horticulture in the 1950s as well as how growers understood the risks tied to chemical components that potentially had other more mundane and culturally endorsed uses.