bluuebunny/crossref_metadata_2025 huggingface dataset:
A genetically engineered epothilone analog as a novel oral microtubule inhibitor: A clinical study of utidelone capsule for advanced breast cancer.
Authors: Zhang Pin , Wang Wenna , Chen Xi , Tang Li , Qiu Rongguo , Gong Zheng , Xu Binghe
Published: July 2024

e13115

Background: Utidelone, a genetically engineered epothilone analog, is a potential best-in-class novel microtubule stabilizing agent. Utidelone injection was approved for advanced breast cancer in China in 2021. Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral formulation-Utidelone Capsule (UTD2). As of now, there has been no oral microtubule stabilizing agent approved in China and the United States. UTD2 may benefit patients in various aspects including effectiveness, safety, better compliance, reduced medical cost, and facilitation of combination therapy, especially with other oral anti-cancer drugs. This is the first clinical study in China to investigate the efficacy and safety of UTD2 monotherapy for treatment of advanced breast cancer. Methods: This is an ongoing open-label, multi-center study (NCT05700084) consisting of three parts: dose escalation, bioavailability and food effect, and in combination with capecitabine for treatment of metastatic breast cancer. Here we report the preliminary results from single center for part I with determination of DLT and MTD as the primary objective, and efficacy, PK profile and safety in patients with pretreated metastatic breast cancer as the secondary objectives. Eligible patients are aged 18-70 years with confirmed advanced breast cancer refractory to prior standard therapies, and have an ECOG PS of 0-1, life expectancy ≥12weeks. Patients are treated with UTD2 monotherapy, at starting dose of 50 mg/m2/d-5day for two patients, with planned escalation (3+3) to 75 mg/m2/d-5day and 75 mg/m2/d-7day, then to 85 mg/m2/d-7day or down to 70 mg/m2/d-7day in a 21-day cycle. Results: As of 25th January 2024, 5 advanced breast cancer patients were enrolled, who had received prior treatment in advanced settings. Dose escalation is ongoing, and 75mg/m2/d-7day cohort is under evaluation. Four patients were evaluated for efficacy with an outcome of 2 PR (each for 50 and 75mg/m2/d-5day dose) and 2 SD (75mg/m2/d-5day dose) with treatment durations of 2 to 8 cycles. Most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included peripheral sensory neuropathy (PN), dizziness and loss of appetite. There were two patients encountered Grade 3 TEAEs including one with PN and one with diarrhea/insomnia, that recovered through dose reduction or supportive treatment. No grade 4/5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: These preliminary results suggested promising efficacy with a manageable safety profile of UTD2 in pretreated metastatic breast cancer patients. This study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT05700084 .
Treatment (Tx) patterns, efficacy and safety of eribulin for advanced and heavily pretreated breast cancer (ABC): Updated results from a single-center, real-world study.
Authors: Yang Jiao , Ma Xinyue , Zhao Shidi , Zhao Xiaoai , Wang Le , Dong Danfeng , Yang Jin
Published: July 2024

e13118

Background: We evaluated the Tx patterns, efficacy and safety of eribulin for heavily pretreated ABC in real-world practice. Previous results were reported at the 2023 ASCO (e13118), updated results for longer follow-up and additional enrollment are presented here. Methods: Patients (pts) with ABC who had progression on anthracycline taxane Tx and received eribulin (1.4 mg/m2 IV on Days 1 and 8 of a 21-day cycle) between April 2020 and October 2023 were enrolled. Response was evaluated using RECIST v1.1. Pts were considered as taxanes sensitive if taxanes treatment duration of last line use exceeds 6 months, otherwise were considered as taxanes resistant. Results: 89 pts were enrolled. Median (range) age was 54 (30–79) years; 80.9% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, and 40.4% pts had a median of 3 prior lines of chemotherapy. 67.4% of pts had Ki67 >30% and 46.0% had HR+/HER2− disease. 88.7% of pts had visceral metastasis. Eribulin was monotherapy in 30.3% of pts, and combined with bevacizumab, capecitabine, bevacizumab + capecitabine, and anti-HER2 agents in 28.1%, 9.0%, 3.4%, and 25.8%, respectively. The objective response rate was 22.5%; disease control rate was 84.3%. Median progression-free survival (PFS) overall was 6.0 (95% CI, [3.5–8.5]) months (mo). Univariate analysis indicated pts with HER2+ disease had longer PFS than pts with HR+/HER2− or triple-negative BC (median, 13.5, 4.5, and 3.7 mo, respectively; P = 0.011; Table). Pts with Ki67 expression ≤30% had longer PFS than pts with Ki67 >30% (median, 8.0 vs. 4.0 mo; P = 0.02). Pts with grade I-II had longer PFS than pts with grade III (median, 10.5 vs. 4.0 mo; P = 0.003). Pts sensitive to Taxane had longer PFS than pts resistant to Taxane (median, 8.0 vs. 4.0 mo; P = 0.007). Among the 18 pts with a partial response, median PFS was 11.4 mo. The most common adverse events were leukopenia (44.9%), neutropenia (37.1%) and anemia (36.0%). Neurotoxicity was rare (6.7%). Conclusions: In this single-center study of pts with heavily pre-treated ABC in China, eribulin Tx resulted in favorable PFS irrespective of molecular subtype, with a manageable safety profile. In pts with a large tumor burden and a good PS, eribulin-based combinations may further improve outcomes. [Table: see text]
DNA methylation-based biological age and time to relapse in triple negative breast cancer.
Authors: Nannini Drew Robert , Nandu Nitish , Hildebrandt Gerhard , Cortese Rene
Published: July 2024

e13126

Background: Triple negative breast cancer (TNBC) represents 15% of all breast cancer cases and is one of the most aggressive forms of breast cancer with a poorer prognosis. Due to the lack of receptors, TNBC is not amendable to hormonal or anti-HER2 therapies and current gene expression arrays have limited clinical utility in TNBC. The identification of biomarkers associated with TNBC may aid in elucidating the underlying biological mechanisms of this disease and may also have implications for risk stratification, diagnosis, and prognosis of TNBC. The purpose of this study was to investigate the association between markers of biological aging and time to relapse in TNBC. Methods: DNA methylation and clinical data from a publicly available dataset (GSE141441) were used in this analysis. Breast tissue specimens in female TNBC patients who received (n=56) and who did not receive (n=110) chemotherapy underwent DNA methylation profiling using the Illumina Infinium HumanMethylation450K BeadChip. Five DNA methylation-based biological age metrics were calculated: intrinsic epigenetic age acceleration (IEAA), extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), GrimAge acceleration (GrimAA), and DunedinPACE (Pace of Aging Calculated from the Epigenome). Multiple linear and quantile regression analyses were performed to examine the association between the aging metrics and time to TNBC relapse. Interaction and stratified analyses by Ki-67 was additionally performed. Results: After adjusting for chronological age, GrimAA ( P=0.024) and DunedinPACE ( P=0.019) were negatively associated with time to relapse among patients who did not receive chemotherapy. Specifically, a 1-year increase in GrimAA and 1 unit increase in the pace of aging were associated with a 1.77-month and a 53.62-month shorter relapse of TNBC, respectively. Additionally, Ki-67 significantly modified the association between IEAA ( P=0.023) and DunedinPACE ( P=0.035) among patients who received chemotherapy with a 2.75- and a 42.17-month shorter relapse of TNBC among those with a Ki-67 index greater than 50% per unit increase in IEAA and DunedinPACE, respectively. Conclusions: We observed DNA methylation markers of biological age were associated with time to relapse in TNBC patients and these associations were modified by Ki-67. These biomarkers may have prognostic utility in TNBC relapse and potentially, may aid in oncological precision medicine efforts for personalized treatment regimens and surveillance. [Table: see text]
Effect of PLCE1-driven aerobic glycolysis through ENO1 modulation on immune evasion in esophageal squamous cell carcinoma (ESCC).
Authors: Cui Xiaobin , Yang Ju , Sun Mengfei , He Shangfeng , Zhou Ziru , Chen Yunzhao
Published: July 2024

e16016

Background: Our prior investigations have demonstrated that PLCE1 actively promotes tumorigenesis, angiogenesis, and cell cycle progression in ESCC. However, the precise role of PLCE1 in glycolysis and its influence on the tumor immune microenvironment (TIME) remain elusive. Methods: To elucidate potential pathways regulated by PLCE1, we applied Affymetrix GeneChip, Affymetrix ClariomD Array, and IP-MS techniques to identify molecules interacting with PLCE1. Subsequently, we validated the involement of PLCE1 in glycolysis through assessments of glycolytic product production in both in vivo and in vitro assays. The underlying mechanisms by which PLCE1 influences glycolysis were further probed through a combination of IP assays, tumor growth experiments, and ubiquitination assays. Next, we conducted multi-color immunofluorescence staining to examine the infiltration of immune cells in human ESCC tissues. We utilized a transgenic PLCE1-/- C57BL/6 mice model to investigate the immune cell distribution in TIME. Results: PLCE1 emerges as a pivotal regulator in glycolytic processes within ESCC cell lines. Knockdown of PLCE1 instigates a notable attenuation of glycolysis, achieved through the modulation of ENO1 expression, a key enzyme in glycolysis. This effect was also observed in vivo. We have elucidated a novel pathway in which PLCE1 orchestrates a reduction in the expression of FBXW7, an E3 ubiquitin ligase, thereby attenuating FBXW7-mediated ubiquitination of ENO1 and fostering ENO1 stability. Based on mutations identified through sequencing of ESCC tissue and drawing from previous studies, we have pinpointed the specific interacting sites between FBXW7 and ENO1. Substrate phosphorylation is necessary for the recognition of FBXW7. We unveil a mechanism wherein PLCE1 interacts with CDK2 to augment ENO1 phosphorylation, potentiating FBXW7 recognition. Nonetheless, CDK2-mediated ENO1 phosphorylation fails to elicit FBXW7-mediated ubiquitination due to limited FBXW7 expression in ESCC. Elevated tumor glycolysis induced by PLCE1 via ENO1 engenders heightened lactate production, thereby dampening cytokine production and CD8+ T cell activation. In human ESCC tissues, a diminished CD8+ T cell population is observed proximal to PLCE1+ENO1+ tumor cells, concomitant with an augmented accumulation of exhausted CD8+ PD1+ T cells in their vicinity. In an ESCC murine model, a more robust infiltration and cytokine production, coupled with diminished PD-1 expression on both CD4+ and CD8+ T cells, is noted in the PLCE1-/- genotype. This effect was particularly prominent upon ENO1 inhibitor administration. Conclusions: Our investigation elucidates that PLCE1 orchestrates the glycolytic pathway in ESCC by upregulating the expression of ENO1, consequently hindering the infiltration and activation of CD8+ T cells, thus fostering an immunosuppressive TIME.
Survival outcomes in patients with stage IV gastric cancer with Krukenberg tumors: A systematic review and meta-analysis.
Authors: Anwar Junaid , Abdelhakeem Ahmed , Khan Muhammad Shariq , Arslan Hafiz Muhammad , Sarfraz Zouina , Saeed Anwaar
Published: July 2024

e16020

Background: Stage IV gastric cancer patients with Krukenberg tumors tend to have poor survival outcomes, usually less than 2 years. The management of such tumor groups remains unstandardized, and whether oophorectomy improves survival is unknown. In this study, we systematically analyze the survival outcomes in gastric cancer patients with ovarian metastases who received either standard chemotherapy, surgical resection of ovarian metastases, or combined chemotherapy and surgery. Methods: We synthesized randomized controlled trials and observational studies, which were retrieved by systematically searching MEDLINE (PubMed), Embase, and the Cochrane Library through January 25, 2024, using the Boolean logic. Participants included individuals with pathologically and radiologically confirmed ovarian metastasis or clinically symptomatic cases with imaging evidence. Statistical analyses were conducted using R (v.4.3.2., Vienna) (PROSPERO ID-CRD42023488373). Results: A total of 1502 patients from 17 retrospective studies were pooled for differential overall survival (OS) outcomes ( Table). The OS in the standard chemotherapy cohort using the random effects model was 6.708 months (95% CI: 3.867 to 9.548). Heterogeneity was non-significant (P = 0.3854) with I2 of 5.5%. In the surgical resection cohort, OS was 12.786 months (95% CI: 6.9 to 18.671). I2 was 0%, and heterogeneity was low (P = 0.6013). In the combined chemotherapy and surgical resection cohort, OS was 16.228 months (95% CI: 12.254 to 20.202). I2 was 0%, and heterogeneity was insignificant (P = 0.9632). Conclusions: This meta-analysis provides novel insights into survival outcomes associated with distinct therapeutic modalities in gastric cancer with krukenberg metastases, contributing valuable evidence for clinical decision-making and future research directions. While the combined approach of chemotherapy and surgery demonstrates the highest effect size for OS, judicious consideration of patient-centric approaches is imperative in the oncological care landscape. [Table: see text]
Retrospective study of continued immunotherapy in patients with advanced esophageal squamous cell carcinoma after progression on first-line immunotherapy combination chemotherapy.
Authors: Yu Weiyong , Wan Li
Published: July 2024

e16025

Background: Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced esophageal squamous cell carcinoma. However, the disease progression pattern after first-line immunotherapy resistance and the second-line treatment options are not fully understood. This retrospective study was designed to explore the efficacy of continued immunotherapy in advanced esophageal squamous cell carcinoma patients after progression on first-line immunotherapy combination chemotherapy. Methods: We retrospectively analyzed the efficacy of second-line continued immunotherapy in patients with stage IV esophageal squamous cell carcinoma who experienced disease progression after first-line immunotherapy at Huai 'an First People's Hospital from July 2020 to December 2023. The main outcome were progression-free survival (PFS), 3-and 6-month PFS rates, objective response rate (ORR), disease control rate(DCR)and overall survival (OS). Results: A total of 30 eligible patients were included. Median age was 67 years, 20 (66.7%) patients were male. 14 patients achieved partial response (PR), 8 stable disease (SD), illustrating an ORR of 46.7% and a DCR of 73.3%. Median PFS was 3.85 months. In the second-line treatment regimen, 21 (70%) were immunotherapy combined chemotherapy, and the others were immunomonotherapy or combined anti-angiogenic drugs. Conclusions: The current retrospective data shows that a considerable number of patients still could benefit from second-line immunotherapy after the progress of first-line immunotherapy in patients with advanced ESCC. This result brings new hope for the increasingly large population of immune resistance esophageal cancer patients. [Table: see text]
Association of a clinical model based on skeletal muscle radiation attenuation with efficacy for patients with gastric cancer treated with chemotherapy plus PD-1 antibodies: A single-center retrospective study.
Authors: Zhou Chenfei , Sun Yan , van Dijk David P.J. , Xi Wenqi , Jiang Jinling , Guo Liting , Wu Junwei , Qi Feng , Zhang Xuekun , Ji Jun , Cai Qu , Zhu Zhenggang , Rensen Sander S.M. , Olde Damink Steven W.M. , Zhang Jun
Published: July 2024

e16029

Background: Biomarkers to select gastric cancer (GC) patients who can benefit from PD-1 antibody-based treatment are under investigation. We aimed to assess the association between body composition parameters and efficacy of chemotherapy plus PD-1 antibodies in GC patients. Methods: Clinical information of GC patients receiving perioperative chemotherapy with or without PD-1 antibodies was reviewed. Tumor regression grade (TRG) of gastric cancer was recorded after resection. Radiation attenuation and index of skeletal muscle, visceral adipose tissue and subcutaneous adipose tissue were calculated based on computed tomography (CT) images at the third lumbar (L3) level using SliceOmatic software. Associations between clinical parameters and patients’ outcomes including TRG, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: A total of 120 patients treated with chemotherapy plus PD-1 antibodies (IO cohort) and 82 patients treated with chemotherapy alone (CTx cohort) were enrolled. TRG0/1 rates in the IO cohort and CTx cohort were 45.8% and 32.9%. High skeletal muscle radiation attenuation (SMRA), neutrophil to lymphocyte ratio (NLR) < 2.65, and weight loss < 5% were associated with TRG0/1 in the IO cohort but not in the CTx cohort. High SMRA was an independent prognostic factor of PFS in the IO cohort (HR = 0.333, 95%CI 0.115-0.970, P= 0.044). A clinical model based on SMRA, NLR and weight loss was established to stratify patients into 3 groups, including group 1: High SMRA with NLR < 2.65 and weight loss < 5%, group 2: High SMRA with NLR≥2.65 and/or weight loss≥5%, and group 3: Low SMRA. In the IO cohort, patients in group 1 showed higher TRG0/1 rate (n = 27/40, 67.5%, P< 0.001) than group 2 (n = 26/63, 41.3%) and group 3 (n = 2/17, 11.8%). The clinical model was also associated with patients’ survival. Conclusions: A clinical model combining baseline SMRA, NLR and weight loss could identify well-responding GC patients treated with chemotherapy plus PD-1 antibodies.
Efficacy and safety of surufatinib, toripalimab, nab-paclitaxel in combination with radiotherapy or surgery in the first-line treatment of esophageal squamous cell cancer: A single-centered prospective clinical trial.
Authors: Huang Xiang , Chen Jing , Wang Hongchi , Cong Yang , Li Ye , Liu Fang
Published: July 2024

e16047

Background: Chemotherapy(CT) plus immune checkpoint inhibitors (ICIs) has become the current standard of care in the first-line treatment of metastatic esophageal squamous cell cancer(ESCC). In locally advanced setting, radiochemotherapy with or without resection remains the standard of care. Surufatinib, a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R, in combination with PD-1 inhibitors have demonstrated synergistic anti-tumor activities in previous studies. This single-centered prospective clinical trial aims to evaluate the efficacy and safety of surufatinib(SUR), toripalimab(TOR), nab-paclitaxel(NAB) in combination with radiotherapy or surgery in the first-line treatment of locally advanced(LA) or metastatic(R/M) ESCC. Methods: Eligible patients(pts) with confirmed LA or R/M, ECOG PS 0-2 and no prior systematic treatment were enrolled in the trial. Pts would receive 260mg/m2 NAB and TOR 240mg on day 1 and SUR 250mg once daily in each 21-day cycle as induction therapy for two cycles, followed by surgery or another two cycles of concurrent chemoradiotherapy(CCRT) with NAB, SUR and radiotherapy, in which involved-field irradiation were conducted at the dose of 50-63 Gy/25-30F, 1.8-2 Gy per fraction, 5 fractions per week. As maintenance therapy, daily SUR and TOR every three week were administered until disease progression or unacceptable toxicities. Progression-free survival (PFS) was the primary endpoint. Results: As of Jan 7, 2024, 16 pts were enrolled, of whom 15 were evaluable. 14(87.5%) pts were male. The median age was 69.5 (range: 45-79). Tumor located in upper(18.8%), middle(25%) and lower(56.2%) thoracic. 1(6.2%) is Stage II disease, 12(75%) Stage III and 3(18.8%) Stage IV. 8 (50%) pts were with PD-L1 CPS greater than 1, 5 (31.25%) pts greater than 5, and 3 (18.75%) pts greater than 10. PD-L1 CPS of 6(37.50%) pts was unknown. With a median follow-up time of 5 (range: 1-12) months, despite the immatureness of PFS, the 12-month PFS rate was 77.14% (95% CI: 48.89%-100%). The objective response rate was 93.3% (14/15), and disease control rate was 100% (15/15). Five of the included pts met the resection criteria during treatment and underwent subsequent R0 resection. The most common adverse events (≥20%) of all grades were hypoesthesia (62.5%), nausea and vomiting (50%), and white blood cell decrease (43.75%). Conclusions: The combination ofsurufatinib, toripalimab, nab-paclitaxel with radiotherapy or surgery has demonstrated promising efficacy and a well-tolerated safety profile as a potential first-line treatment for LA or R/M ESCC. This ongoing trial merits further investigation and holds significant implications for clinical practice.
Gastric juice piR-015551: A promising prognostic biomarker for gastric cancer.
Authors: Ji Xuezhong , Liu Weitai , Wu Xinhua , Feng Jifeng , He Xia , Zhou Guoren , Peng Wei
Published: July 2024

e16074

Background: Emerging reports demonstrated that PIWI-interacting RNAs (piRNAs) played an indispensable role in tumorigenesis. However, it still remains elusive whether piR-015551 in gastric juice specific in stomach could be employed as a biomarker for gastric cancer (GC). The present work is aiming at exploring the possibility of piR-015551 in gastric juice as a potential marker to judge for diagnosis and prognosis of gastric cancer. Methods: Gastric juice was collected from 66 GC patients and 66 healthy individuals. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) was employed to measure the levels of piR-015551 expression. Then, the pattern of piR-015551 expression in gastric juice was determined between GC patients and healthy individuals. A receiver operating characteristic (ROC) curve was constructed for distinguishing GC from healthy individuals. Results: Gastric juice piR-015551 levels in GC were higher than those of controls (P < 0.0001). The value of area under ROC (AUC) was 0.885 (sensitivity, 90.9%; specificity, 74.2%; 95% confidence interval, 0.8286 to 0.9414). High gastric juice piR-015551 expression was signally correlated with tumor size (P = 0.013) and TNM stage (P = 0.001). GC patients with high piR-015551 expression in gastric juice exerted a poorer overall survival (OS) (P = 0.0152) and progression-free survival (PFS) (P = 0.013). COX regression analysis verified that gastric juice piR-015551 expression was an independent prognostic risk variable for OS (P < 0.05). Conclusions: The current study suggested that piR-015551 in gastric juice had the potential to be a useful biomarker for GC detection and prognosis prediction.
Multidisciplinary care for patients with gastroesophageal cancers (GEC): A quality improvement initiative in community cancer clinics.
Authors: Dooyema Samuel , Broderick Stephen , Storey Janet , Dewald Ilona , Carter Jeffrey D. , Heggen Cherilyn , McKinnon Kelly E. , Ajani Jaffer A.
Published: July 2024

e16096

Background: Evidence-based guidelines for GEC management recommend multimodal care, which involves close coordination between medical, surgical, and radiation oncologists, together with specialists to manage symptoms and treatment-related adverse events (AEs). Optimizing the high level of multidisciplinary care required for effective GEC management poses substantial challenges for community oncology care teams. Methods: In August-October 2023, 57 healthcare providers (HCPs) from 4 US community oncology clinics completed surveys on challenges, barriers, and improvements needed in the multimodal care of patients with GEC. Based on findings from the baseline data, 70 HCPs participated in audit/feedback (AF) sessions to review site-specific gaps and challenges and develop action plans to address identified gaps. Follow-up surveys will evaluate the impact of changes in practice following action plan implementation. Results: Providers identified their 3 top challenges to providing care for patients with GEC: interdisciplinary care coordination, providing patient-centered supportive care, and managing AEs. They reported that care coordination was hampered by low frequency and poor-quality communication between medical oncology and surgical teams, by misalignment on methods of communication, and by a lack of relationship between the specialties. About one-third of HCPs reported recognizing and managing AEs as the most challenging aspect of caring for patients with GEC, including AEs that were immune-related (26%), dermatologic (19%), gastrointestinal (19%), neurologic (14%), immunosuppression-related (10%), and respiratory (5%). After the AF sessions, HCPs reported improving communication and coordination among care team members as an important means of improving and individualizing patient care plans and integrating new therapies into clinical workflows. Action plans included streamlining communication with surgical teams, increased use of patient navigation, and ensuring that every patient is reviewed through the multidisciplinary tumor board. With regard to AE management, action plans included improving patient education on AE identification, and better communication within the team on nutritional support. HCPs who participated showed improved confidence, knowledge, and competence in appropriately sequencing systemic therapy and surgical interventions. Conclusions: GEC care teams from community cancer clinics reported dissatisfaction with multidisciplinary care coordination, including poor communication between specialists involved in multimodal care of patients with GEC. Integration of sustainable changes in clinical workflows driven by this initiative improved oversight of multimodal care, improved workflows, and improved AE management.
Long term results of a new treatment strategy for follicular low grade lymphoma (FLGL).
Authors: Cabanillas Fernando , Gutierrez Sierra Thyra , Torres Adelba , Abreu-Albelo Jose , Hagemeister Fredrick B.
Published: July 2024

e19035

Background: FLGL usually presents with widespread but asymptomatic lymphadenopathy, low SUVs on PET and normal LDH. It's considered incurable and standard of care has been 'watch and wait' (W&W) followed later by treatment if necessary. We have described a subset of patients that we termed clinically discordant indolent histology (“CDIH”) whose behavior is more aggressive. CDIH is defined as presence of any of these: B symptoms, high LDH, SUV >14 on PET, Ki-67 index >30% or involvement of areas such as lung, pleura, soft-tissue, CNS and bones. Our study aims to assess real-world long-term outcome of managing FLGL with and without CDIH. Methods: We analyzed 186 previously untreated FLGL cases treated at our center from June 2002-July 2023, without opting for W&W. CDIH cases typically received R-CHOP x6, then 4 FND. Non-CDIH mainly received FND-R. All received 2 years maintenance rituximab. Main objective was to assess 10-year PFS and OS of stage IV cases, comparing it in a real-world setting against our previously published MD Anderson (MDACC) data. Secondary objectives were to compare our 10-year PFS and OS in stage IV cases against historical controls based on the FLIPI-2 score. We also sought to determine prognostic value of CDIH as compared to FLIPI-2, evaluate early relapse rate (2 yrs), and assess rate of transformation to aggressive lymphoma. Results: Median age: 58 (26-93). Median follow up: 96 mos (6-261). Stage III-IV: 76%. CDIH was present in 56%. Our PFS 10 yrs for non-CDIH=96% vs CDIH=77% (p=0.002). For stage IV, PFS 10 yrs = 82% vs MDACC's 50% using FND-R. OS 10-yr= 90% vs MDACC's 85%. 67 pts were followed >10 years; a relapse occurred in only 5 (7%). Our PFS 10 yr for favorable FLIPI-2 (score 0)= 97%, for intermediate (1-2) =88%, unfavorable (3-5)= 72% (p=.15). Our PFS results were consistently superior to literature data across all FLIPI-2 scores. Transformation to DLBCL= 6/186 (3%) compared to 20-30% historical controls; 5 of 6 transformations were in cases with CDIH and 4 occurred within 3 yrs. Early (<2 yr) relapse rate= 2% in contrast with 20% literature data; all 4 early relapses were CDIH. Conclusions: Our findings emphasize several advantages of initiating treatment early and basing it on presence or absence of CDIH. Our data highlight the need to 1- identify CDIH for potential use of doxorubicin treatment. 2- CDIH as prognostic factor seems more effective than FLIPI-2. 3- PFS 10 yr results are remarkably superior to both literature controls and to our previous experience at MDACC with FND-R. 4- Only 7% relapses beyond 10 yrs suggest potential for cure, according to our results and those from MDACC. [Table: see text]
A phase 1, open-label, dose escalation study on the safety and tolerability of ANK-101 in advanced solid tumors.
Authors: Park Jong Chul , Butler Marcus O. , Curti Brendan D. , Emens Leisha A. , Pastor Danielle M. , Elassal Joseph , Kaufman Howard L. , Kirkwood John M.
Published: July 2024

TPS2689

Background: IL-12 is a cytokine that can stimulate both innate and adaptive tumor immunity. Clinical trials of intravenous IL-12 demonstrated anti-tumor activity limited by significant systemic toxicity, including patient deaths. ANK-101 is an anchored immunotherapy that links IL-12 to aluminum hydroxide through an alum-binding protein (ABP). The ANK-101 complex anchors IL-12 in the tumor microenvironment (TME), resulting in prolonged local retention and low levels of systemic absorption. Preclinical studies in murine tumor models showed that ANK-101 is retained at the injection site for up to 28 days, recruits and activates T and NK cells, promotes M1 myeloid cell differentiation, induces regression of both injected and un-injected tumors, and induces immunologic memory. Methods: This is a first-in-human, open-label dose escalation study of ANK-101 in advanced solid tumors with a planned sample size of 12-36 participants. The first three dose escalation cohorts include a single participant, and then study enrollment follows a standard 3+3 dose escalation design. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥1/3 or ≥2/6 patients experience a DLT. An additional ten patients will be enrolled at the recommended dose for expansion (RDE). Participants will be treated with intratumoral ANK-101 every 3 weeks for 4 cycles. Imaging or clinical assessments will be performed at week 12. If there is no significant clinical deterioration or unacceptable toxicity at this visit, participants may receive four more cycles. Eligible patients must have an advanced solid malignancy refractory to standard treatment and be accessible for injection and biopsy, measurable disease by RECIST v1.1, and ECOG PS of 0-1. Key exclusion criteria include tumors close to vital structures, uncontrolled bleeding disorders, and active autoimmune disease. Primary objectives of the study are to determine the safety and tolerability of ANK-101 and identify the RDE. Secondary objectives include pharmacokinetics (PK) and immunogenicity (ADA) of ANK-101 and clinical activity as measured by ORR, DCR, DOR and PFS by RECIST v1.1. Exploratory objectives include assessment of QOL using FACT-G and profiling immune-based pharmacodynamic (PD) changes. PD assessments will include serum cytokines and circulating immune cells, and local levels of PD-L1, CD8+ T cells, and CD68+ macrophages, and changes in gene expression within the TME. This clinical trial is in progress. Clinical trial information: NCT06171750 .
Association of Physical Activity Patterns With Nocturnal Hypoglycemia Events in Youth With Type 1 Diabetes
Authors: Hormazábal-Aguayo Ignacio , Huerta-Uribe Nidia , Muñoz-Pardeza Jacinto , Ezzatvar Yasmin , Izquierdo Mikel , García-Hermoso Antonio
Published: July 2024

Aims

This study sought to elucidate the interactions among physical activity (PA) patterns, mean glucose concentrations, and the incidence of nocturnal hypoglycemia events in children and adolescents with type 1 diabetes, examining the moderating influence of daily dosage on these associations.

Methods

Eighty-two participants aged 6 to 18 years (43.9% girls) from the Diactive-1 Cohort Study, diagnosed with type 1 diabetes, were included. Data collection involved continuous glucose monitoring, accelerometry to assess real-world PA, as well as documentation of daily insulin doses and carbohydrate counting over the same 7 days.

Results

A total of 19 participants experienced at least 1 nocturnal hypoglycemia event over a span of 574 measurement days (106 days with and 451 days without nocturnal hypoglycemia). Higher levels of vigorous PA (VPA) were associated with lower same-day mean glucose levels (P = .014). Additionally, higher levels of moderate PA (P = .023), VPA (P = .011), and moderate-to-vigorous PA (P = .010) were associated with a greater number of nocturnal hypoglycemia events. Specifically, a significant association was identified between VPA and nocturnal hypoglycemia events when the daily insulin dose was at or above 1.04 units per kilogram of body weight per day (P = .016).

Conclusion

Daily VPA is associated with glucose reductions, potentially leading to more hypoglycemic episodes, particularly when there is an excess of daily insulin. This highlights the need for careful insulin management in children and adolescents with type 1 diabetes engaging in VPA.
Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice
Authors: Esser Nathalie , Mongovin Stephen M , Barrow Breanne M , Zraika Sakeneh
Published: July 2024

Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut−/−) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut−/− mice, and was similar in plasma, pancreas, and kidney in NEPGut−/− vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut−/− displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.
Use of Patient-Specific Interbody Cages Through a Minimally Invasive Lateral Approach for Unstable Lumbar Spondylodiskitis
Authors: Yen Chun-Po , Ben-Israel David , Desai Bhargav , Vollmer Dennis , Shaffrey Mark E. , Smith Justin S.
Published: July 2024

BACKGROUND AND OBJECTIVES:

Patients with diskitis/osteomyelitis who do not respond to medical treatment or develop spinal instability/deformity may warrant surgical intervention. Irregular bony destruction due to the infection can pose a challenge for spinal reconstruction. The authors report a lateral approach using patient-specific interbody cages combined with posterior or lateral instrumentation to achieve spinal reconstruction for spinal instability/deformity from spondylodiskitis.

METHODS:

This is a retrospective review of 4 cases undergoing debridement, lateral lumbar interbody fusion using patient-specific interbody cages, and supplemental lateral or posterior instrumentation for spinal instability/deformity after spondylodiskitis. The surgical technique is reported, as are the clinical and imaging outcomes.

RESULTS:

Four male patients with a mean age of 69 years comprised this study. One had lateral lumbar interbody fusion at L2/3 and 3 at L4/5. The mean hospital stay was 5.8 days. The mean follow-up was 8.5 months (range 6-12 months). There were no approach-related neurological injuries or complications. The mean visual analog scale back pain scores improved from 9.5 to 1.5, and the mean Oswestry disability index improved from 68.5 to 23 at the end of the follow-up. The mean lumbar lordosis increased from 18° to 51°. The segmental angle increased from 6.5° to 18°. The coronal shift was 2.8 cm preoperatively and 0.9 cm postoperatively. The coronal Cobb angle reduced from 8.8° preoperatively to 2.8° postoperatively. On postoperative computed tomography, all patients had interval development of bridging bone across the surgical level through or around the cage. None of them developed cage migration or subsidence.

CONCLUSION:

Patients with irregular bony destruction due to diskitis/osteomyelitis may benefit from patient-specific cages for spinal reconstruction to address spinal instability and deformity.
Use of acoustic signals in Cape fur seal mother–pup reunions: individual signature, signal propagation and pup home range
Authors: Martin Mathilde , Gridley Tess , Immerz Antonia , Elwen Simon H. , Charrier Isabelle
Published: July 2024

The Cape fur seal (Arctocephalus pusillus pusillus) is one of the most colonial mammals, with colonies of up to hundreds of thousands of individuals during the breeding season. During the lactation period, mothers and pups are regularly separated as females undertake multi-day foraging trips at sea. Mothers and pups use a mutual vocal recognition system to reunite after separation. Such communication is highly constrained by both high background noise and risk of individual confusion owing to the density of seals. This study aimed to experimentally assess the acoustic features relevant for mother–pup vocal identification and the propagation properties of their calls. Playback experiments revealed that mother and pup individual vocal signatures rely on both temporal and frequency parameters: amplitude and frequency modulations, timbre and fundamental frequency (f0). This is more parameters than in any colonial species studied so far. The combinational use of acoustic features reinforces the concept that both environmental and social constraints may have acted as selective pressures on the individual vocal recognition systems. Theoretical propagation distances of mother and pup vocalisations were estimated to be below the range of distances at which mother–pup reunions can occur. This suggests that Cape fur seals may have strong abilities to extract vocal signals from the background noise, as previously demonstrated in the highly colonial king penguin. Investigating the transmission of information throughout the propagation of the signal as well as the ability of the receiving individual to decipher vocal signatures is crucial to understanding vocal recognition systems in the wild.
Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols
Authors: Eren Ozgur Can , Bagci Pelin , Balci Serdar , Ohike Nobuyuki , Saka Burcu , Sokmensuer Cenk , Leblebici Can Berk , Xue Yue , Reid Michelle D. , Krasinskas Alyssa M. , Kooby David , Maithel Shishir K. , Sarmiento Juan , Cheng Jeanette D. , Taskin Orhun Cig , Kapran Yersu , Tarcan Zeynep Cagla , Luchini Claudio , Scarpa Aldo , Basturk Olca , Adsay N. Volkan
Published: July 2024

Background

Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach.

Methods

Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed.

Results

In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001).

Conclusions

G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.
Intraparotid Sentinel Lymph Node Dissection for Melanoma: A Systematic Review and Meta-Analysis
Authors: Kfir Uriel , Ronen Ohad
Published: July 2024

Background

Surgical management of head and neck cutaneous melanoma (HNCM) has evolved tremendously since sentinel lymph node biopsy (SLNB) has become the prominent tool of prognosis and staging. This meta-analysis aimed to evaluate the safety and efficiency of intraparotid SLNB compared with a more extensive surgery of superficial parotidectomy (SP).

Methods

The electronic database of PubMed and Scopus were searched for publications until 10 March 2022. In addition, the study included data of patients from our institution who underwent cherry-picking procedures. Pooled estimates were calculated using the random-effects model. Heterogeneity was calculated using the I2 test.

Results

The pooled result regarding the rate of SLNB excision success was 97 % (95 % confidence interval [CI], 0.95–0.99; p < 0.0001), and the pooled probability of a positive SLNB result was 16 % (95 % CI 0.12–0.20; p < 0.0001). Failure of SLNB had pooled results of 4 % (95 % CI 0.02–0.06; p < 0.0009). For SP, no study examining N0 HNCM patients has met the authors’ inclusion criteria. Cherry-picking SLNB had temporary and permanent facial nerve paralysis relative risks (RRs) of 0.12 (95 % CI 0.06–0.27; p < 0.0001) and 0.46 (95 % CI 0.17–1.22; p < 0.0001), respectively, compared with historical data from four weighted meta-analyses of SP.

Conclusions

The data from this study suggest that intraparotid SLNB performed for N0 HNCM patients is a safe and reliable procedure, with very low complication rates. Failure of the procedure did not exceed 4 %. Therefore, intraparotid SLNB may be superior to an extensive surgery such as SP and should be examined in future prospective trials.
Synthesis of Au and Ag catalysts with controlled sizes of metal particles
Authors: Κυριακίδου Ελένη
Published: July 2024

Η απόδοση των υποστηριζόμενων μεταλλικών καταλυτών εξαρτάται σε μεγάλο βαθμό από τη δομή και τη σύνθεση των μεταλλικών σωματιδίων και τη φύση του υποστρώματος. Προκειμένου να επιτευχθεί καλύτερος έλεγχος αυτών των παραμέτρων, έχει προταθεί συνθετική οδός που βασίζεται στη χρήση παραγόντων μορφοποίησης. Μεταξύ των διαφορετικών παραγόντων μορφοποίησης, τα δενδριμερή πολυ(αμιδοαμίνης) (PAMAM) έχουν προσελκύσει πολύ πρόσφατα την προσοχή ως σταθεροποιητές νανοσωματιδίων. Σε αυτή τη διατριβή, τα νανοσύνθετα Au/G4OH συντέθηκαν σε υδατικά διαλύματα και χρησιμοποιήθηκαν ως πρόδρομοι για την παρασκευή νανοσωματιδίων Au που υποστηρίζονται από SiO2. Στοιχειακή ανάλυση, μετρήσεις UV-Vis και STEM χρησιμοποιήθηκαν για την εκτίμηση της έκτασης των αλληλεπιδράσεων Au-δενδριμερούς και για να αποδειχθεί πώς το pH του διαλύματος επηρεάζει τον αριθμό των ατόμων Au που συμπλέκονται με κάθε μόριο δενδριμερούς, καθώς και το τελικό μέγεθος των υποστηριζόμενων σε SiO2 νανοσωματιδίων χρυσού. Σε pH=7, μπορούν να σχηματιστούν νανοσύνθετα Au5/G4OH με μεγέθη νανοσωματιδίων Au κάτω των 2 nm και να χρησιμοποιηθούν ως πρόδρομοι για την παρασκευή στερεών καταλυτών. Δείχνουμε ότι τέτοια νανοσύνθετα μπορούν να εναποτεθούν άθικτα στην επιφάνεια του SiO2 και να δώσουν πολύ διασκορπισμένα και σχεδόν ομοιόμορφα νανοσωματίδια Au με διαστάσεις της τάξης των 1,6 nm.Μία από τις απλούστερες, λιγότερο δαπανηρές μεθόδους παρασκευής καταλυτών είναι ο υγρός εμποτισμός, όπου ένα υπόστρωμα οξειδίου έρχεται σε επαφή για ορισμένο χρόνο με ένα υγρό διάλυμα που περιέχει τον πρόδρομο μετάλλου. Σε ορισμένες περιπτώσεις, όταν ελέγχονται οι συνθήκες εμποτισμού, είναι δυνατό να καταλήξουμε με ομοιόμορφα και πολύ διασκορπισμένα μεταλλικά σωματίδια. Ένα από αυτά τα παραδείγματα είναι η «Ισχυρή Ηλεκτροστατική Προσρόφηση» (SEA). Σε αυτή τη διπλωματική, η επέκταση της SEA γίνεται σε ένα σημαντικό ευγενές μέταλλο, το ασήμι. Πραγματοποιήθηκε αξιολόγηση της προσρόφησης διαμίνης Ag (Ag(NH3)2+) σε υποστρώματα με χαμηλό και μεσαίο σημείο μηδενικού φορτίου (PZC) (Nb2O5, SiO2, Al2O3 και ZrO2) και αυτή η γνώση χρησιμοποιήθηκε για την παρασκευή μονομεταλλικών υψηλής διασποράς νανοσωματιδίων Ag. TPR χρησιμοποιήθηκε για τον προσδιορισμό της θερμοκρασίας αναγωγής των τελικών καταλυτικών υλικών Ag/SiO2 (χαμηλό-PZC) και Ag/Al2O3 (μεσαία PZC). Τέλος, χρησιμοποιήθηκαν επίσης μετρήσεις STEM και XRD για την απεικόνιση και τον προσδιορισμό του μεγέθους των υποστηριζόμενων μεταλλικών νανοσωματιδίων, αντίστοιχα.
Understanding the Dynamic and Episodic Nature of Technostressors and Their Effects on Cyberdeviance: A Daily Field Investigation
Authors: Chen Yang , Benitez Jose , Cheung Christy M. K.
Published: July 2024

From a management perspective, our results first reveal the detrimental impacts of daily technostressors on the functioning of an organization and its employees. Managers should be cognizant of these consequences and create a relaxing work environment or design tools to reduce technostressors. Managers can institute more daily breaks and ensure that employees have autonomy over when to take breaks and what they do during their break time. We also encourage executives to avoid using information and communication technologies to technologically invade the lives and personal time of employees in the evening after work. Second, to reduce the incidence of daily cyberdeviance, managers should offer assistance programs to their employees to teach them how to control or manage their emotional and cognitive resources and to better cope with techno-overload and techno-invasion. Third, the moderating effect of technology self-efficacy suggests that there are added benefits to selecting and training employees with high technology self-efficacy, as doing so not only helps employees to cope with techno-overload but also enables them to regulate their immediate emotions rather than engage in daily cyberdeviance at work.